BARCELONA – The current routine use of intravenous fentanyl in the cardiac catheterization lab for patient comfort during coronary angiography has been called into question by the results of a double-blind randomized trial presented at the annual congress of the European Society of Cardiology.

The trial, known as PACIFY, showed that IV fentanyl delayed absorption of the oral P2Y12 inhibitor ticagrelor (Brilinta) by up to 4 hours. That’s a disturbing finding that could account for the relatively high risk of stent thrombosis in the first hours after percutaneous coronary intervention, according to lead investigator John W. McEvoy, MD, a cardiologist at Johns Hopkins University in Baltimore.

“These data challenge the routine and nonselective use of fentanyl for cardiac catheterization and PCI, particularly when rapid platelet inhibition is desirable,” he said, adding, “This would represent a significant change in U.S. cath lab practice.”

PACIFY (Platelet Aggregation After Ticagrelor Inhibition and Fentanyl) was a single-center trial in which 212 patients undergoing PCI were randomized in double-blind fashion to fentanyl or no fentanyl on top of a local anesthetic and IV midazolam (Versed). In addition, the 70 subjects undergoing PCI with stent placement received a 180-mg loading dose of ticagrelor intraprocedurally.

The primary endpoint was ticagrelor plasma concentration during the first 24 hours after the drug’s administration. Secondary endpoints were patients’ self-reported maximum pain during the procedure and platelet inhibition at 2 hours.

The plasma concentration time area under the curve over the course of 24 hours was superior in the no-fentanyl group by a margin of 3,441 ng/mL–1 per hour to 2,016 ng/mL–1 per hour. Moreover, 37% of fentanyl recipients displayed high platelet reactivity at 2 hours as measured by light transmission platelet aggregometry, compared with none of the no-fentanyl controls.

Pain was similarly well controlled in both treatment arms, casting doubt on the widespread belief among U.S. interventionalists that routine administration of fentanyl in the cath lab is necessary for patient comfort. Patients in the control arm could receive bailout fentanyl upon request; only two did so.

Dr. McEvoy reported having no financial conflicts regarding this study, which was conducted free of commercial support.
 

[email protected]

BARCELONA – The current routine use of intravenous fentanyl in the cardiac catheterization lab for patient comfort during coronary angiography has been called into question by the results of a double-blind randomized trial presented at the annual congress of the European Society of Cardiology.

The trial, known as PACIFY, showed that IV fentanyl delayed absorption of the oral P2Y12 inhibitor ticagrelor (Brilinta) by up to 4 hours. That’s a disturbing finding that could account for the relatively high risk of stent thrombosis in the first hours after percutaneous coronary intervention, according to lead investigator John W. McEvoy, MD, a cardiologist at Johns Hopkins University in Baltimore.

“These data challenge the routine and nonselective use of fentanyl for cardiac catheterization and PCI, particularly when rapid platelet inhibition is desirable,” he said, adding, “This would represent a significant change in U.S. cath lab practice.”

PACIFY (Platelet Aggregation After Ticagrelor Inhibition and Fentanyl) was a single-center trial in which 212 patients undergoing PCI were randomized in double-blind fashion to fentanyl or no fentanyl on top of a local anesthetic and IV midazolam (Versed). In addition, the 70 subjects undergoing PCI with stent placement received a 180-mg loading dose of ticagrelor intraprocedurally.

The primary endpoint was ticagrelor plasma concentration during the first 24 hours after the drug’s administration. Secondary endpoints were patients’ self-reported maximum pain during the procedure and platelet inhibition at 2 hours.

The plasma concentration time area under the curve over the course of 24 hours was superior in the no-fentanyl group by a margin of 3,441 ng/mL–1 per hour to 2,016 ng/mL–1 per hour. Moreover, 37% of fentanyl recipients displayed high platelet reactivity at 2 hours as measured by light transmission platelet aggregometry, compared with none of the no-fentanyl controls.

Pain was similarly well controlled in both treatment arms, casting doubt on the widespread belief among U.S. interventionalists that routine administration of fentanyl in the cath lab is necessary for patient comfort. Patients in the control arm could receive bailout fentanyl upon request; only two did so.

Dr. McEvoy reported having no financial conflicts regarding this study, which was conducted free of commercial support.
 

[email protected]

BARCELONA – The current routine use of intravenous fentanyl in the cardiac catheterization lab for patient comfort during coronary angiography has been called into question by the results of a double-blind randomized trial presented at the annual congress of the European Society of Cardiology.

The trial, known as PACIFY, showed that IV fentanyl delayed absorption of the oral P2Y12 inhibitor ticagrelor (Brilinta) by up to 4 hours. That’s a disturbing finding that could account for the relatively high risk of stent thrombosis in the first hours after percutaneous coronary intervention, according to lead investigator John W. McEvoy, MD, a cardiologist at Johns Hopkins University in Baltimore.

“These data challenge the routine and nonselective use of fentanyl for cardiac catheterization and PCI, particularly when rapid platelet inhibition is desirable,” he said, adding, “This would represent a significant change in U.S. cath lab practice.”

PACIFY (Platelet Aggregation After Ticagrelor Inhibition and Fentanyl) was a single-center trial in which 212 patients undergoing PCI were randomized in double-blind fashion to fentanyl or no fentanyl on top of a local anesthetic and IV midazolam (Versed). In addition, the 70 subjects undergoing PCI with stent placement received a 180-mg loading dose of ticagrelor intraprocedurally.

The primary endpoint was ticagrelor plasma concentration during the first 24 hours after the drug’s administration. Secondary endpoints were patients’ self-reported maximum pain during the procedure and platelet inhibition at 2 hours.

The plasma concentration time area under the curve over the course of 24 hours was superior in the no-fentanyl group by a margin of 3,441 ng/mL–1 per hour to 2,016 ng/mL–1 per hour. Moreover, 37% of fentanyl recipients displayed high platelet reactivity at 2 hours as measured by light transmission platelet aggregometry, compared with none of the no-fentanyl controls.

Pain was similarly well controlled in both treatment arms, casting doubt on the widespread belief among U.S. interventionalists that routine administration of fentanyl in the cath lab is necessary for patient comfort. Patients in the control arm could receive bailout fentanyl upon request; only two did so.

Dr. McEvoy reported having no financial conflicts regarding this study, which was conducted free of commercial support.
 

[email protected]

Trivalent and quadrivalent inactivated influenza vaccine (IIV) and quadrivalent live attenuated influenza vaccine (LAIV) all gave statistically significant protection against any flu in U.S. children aged 2-17 years in 2015-2016, Katherine A. Poehling, MD, of Wake Forest University, Winston-Salem, N.C., and her associates reported in a study of more than 1,000 children.

“This study also adds to the clinical evidence suggesting that effectiveness of LAIV against influenza A(H1N1)pdm09 strains has been lower than observed with IIV since the 2009 influenza A(H1N1) pandemic,” the researchers concluded.

Cynthia Goldsmith/CDC photo #10073

[email protected]

Trivalent and quadrivalent inactivated influenza vaccine (IIV) and quadrivalent live attenuated influenza vaccine (LAIV) all gave statistically significant protection against any flu in U.S. children aged 2-17 years in 2015-2016, Katherine A. Poehling, MD, of Wake Forest University, Winston-Salem, N.C., and her associates reported in a study of more than 1,000 children.

“This study also adds to the clinical evidence suggesting that effectiveness of LAIV against influenza A(H1N1)pdm09 strains has been lower than observed with IIV since the 2009 influenza A(H1N1) pandemic,” the researchers concluded.

Cynthia Goldsmith/CDC photo #10073

[email protected]

Trivalent and quadrivalent inactivated influenza vaccine (IIV) and quadrivalent live attenuated influenza vaccine (LAIV) all gave statistically significant protection against any flu in U.S. children aged 2-17 years in 2015-2016, Katherine A. Poehling, MD, of Wake Forest University, Winston-Salem, N.C., and her associates reported in a study of more than 1,000 children.

“This study also adds to the clinical evidence suggesting that effectiveness of LAIV against influenza A(H1N1)pdm09 strains has been lower than observed with IIV since the 2009 influenza A(H1N1) pandemic,” the researchers concluded.

Cynthia Goldsmith/CDC photo #10073

[email protected]

ORLANDO – TC-325 (Hemospray), a proprietary mineral powder blend developed for endoscopic hemostasis, promoted immediate hemostasis and prevented rebleeding in patients with malignant gastrointestinal bleeding in a randomized pilot trial.

Nine of 10 patients randomized to receive treatment with TC-325 experienced immediate hemostasis, compared with 4 of 10 patients randomized to receive standard of care (usually argon plasma coagulation, sometimes with radiation therapy), Alan Barkun, MD, of McGill University, Montreal reported at the World Congress of Gastroenterology at ACG 2017.

Five of six patients in the standard of care group who did not achieve immediate hemostasis crossed over to TC-325. Hemostasis was then achieved at index endoscopy in 80% of these crossovers, said Dr. Barkun, whose work received the 2017 GI Bleeding Category Award at the congress.

“So a total of 15 patients were treated with Hemospray among both groups, and 100% of them achieved immediate hemostasis,” he said. “We also assessed feasibility of recruitment and randomization, and it was indeed demonstrated in the context of this feasibility trial.”

Secondary measures, including the use of additional hemostatic approaches, blood transfusions, length of stay, and mortality, among others, did not differ between the two groups.

“This pilot trial is the first to assess TC-325 in patients with malignant bleeding, allowing us to plan for adequate powering and demonstrating feasibility for a larger multicenter, randomized, controlled trial,” he said. “Although this trial was not powered to seek statistically significant differences, the observed results suggest that TC-325 may indeed be a promising hemostatic modality in managing patients with malignant bleeding in achieving both immediate hemostasis and in our minds, surprisingly, perhaps delayed rebleeding.”

Hemospray, which is approved in Canada for upper/lower gastrointestinal bleeding of any etiology, as well as in Mexico and in some countries in Europe, Asia, and South America, works by forming a mechanical barrier over the bleeding site. The powder absorbs water, then acts both cohesively and adhesively to form that barrier, according to information from Cook Medical, which developed the product. It is not currently approved for this indication in the United States.

“An adequately powered randomized, controlled trial is now needed to better determine any beneficial downstream effect on subsequent rebleeding and health care resource use when compared to existing standard of care,” he concluded.

Dr. Barkun is an advisory committee/board member and consultant for Cook Medical and has received grant/research support from the company.

[email protected]

ORLANDO – TC-325 (Hemospray), a proprietary mineral powder blend developed for endoscopic hemostasis, promoted immediate hemostasis and prevented rebleeding in patients with malignant gastrointestinal bleeding in a randomized pilot trial.

Nine of 10 patients randomized to receive treatment with TC-325 experienced immediate hemostasis, compared with 4 of 10 patients randomized to receive standard of care (usually argon plasma coagulation, sometimes with radiation therapy), Alan Barkun, MD, of McGill University, Montreal reported at the World Congress of Gastroenterology at ACG 2017.

Five of six patients in the standard of care group who did not achieve immediate hemostasis crossed over to TC-325. Hemostasis was then achieved at index endoscopy in 80% of these crossovers, said Dr. Barkun, whose work received the 2017 GI Bleeding Category Award at the congress.

“So a total of 15 patients were treated with Hemospray among both groups, and 100% of them achieved immediate hemostasis,” he said. “We also assessed feasibility of recruitment and randomization, and it was indeed demonstrated in the context of this feasibility trial.”

Secondary measures, including the use of additional hemostatic approaches, blood transfusions, length of stay, and mortality, among others, did not differ between the two groups.

“This pilot trial is the first to assess TC-325 in patients with malignant bleeding, allowing us to plan for adequate powering and demonstrating feasibility for a larger multicenter, randomized, controlled trial,” he said. “Although this trial was not powered to seek statistically significant differences, the observed results suggest that TC-325 may indeed be a promising hemostatic modality in managing patients with malignant bleeding in achieving both immediate hemostasis and in our minds, surprisingly, perhaps delayed rebleeding.”

Hemospray, which is approved in Canada for upper/lower gastrointestinal bleeding of any etiology, as well as in Mexico and in some countries in Europe, Asia, and South America, works by forming a mechanical barrier over the bleeding site. The powder absorbs water, then acts both cohesively and adhesively to form that barrier, according to information from Cook Medical, which developed the product. It is not currently approved for this indication in the United States.

“An adequately powered randomized, controlled trial is now needed to better determine any beneficial downstream effect on subsequent rebleeding and health care resource use when compared to existing standard of care,” he concluded.

Dr. Barkun is an advisory committee/board member and consultant for Cook Medical and has received grant/research support from the company.

[email protected]

ORLANDO – TC-325 (Hemospray), a proprietary mineral powder blend developed for endoscopic hemostasis, promoted immediate hemostasis and prevented rebleeding in patients with malignant gastrointestinal bleeding in a randomized pilot trial.

Nine of 10 patients randomized to receive treatment with TC-325 experienced immediate hemostasis, compared with 4 of 10 patients randomized to receive standard of care (usually argon plasma coagulation, sometimes with radiation therapy), Alan Barkun, MD, of McGill University, Montreal reported at the World Congress of Gastroenterology at ACG 2017.

Five of six patients in the standard of care group who did not achieve immediate hemostasis crossed over to TC-325. Hemostasis was then achieved at index endoscopy in 80% of these crossovers, said Dr. Barkun, whose work received the 2017 GI Bleeding Category Award at the congress.

“So a total of 15 patients were treated with Hemospray among both groups, and 100% of them achieved immediate hemostasis,” he said. “We also assessed feasibility of recruitment and randomization, and it was indeed demonstrated in the context of this feasibility trial.”

Secondary measures, including the use of additional hemostatic approaches, blood transfusions, length of stay, and mortality, among others, did not differ between the two groups.

“This pilot trial is the first to assess TC-325 in patients with malignant bleeding, allowing us to plan for adequate powering and demonstrating feasibility for a larger multicenter, randomized, controlled trial,” he said. “Although this trial was not powered to seek statistically significant differences, the observed results suggest that TC-325 may indeed be a promising hemostatic modality in managing patients with malignant bleeding in achieving both immediate hemostasis and in our minds, surprisingly, perhaps delayed rebleeding.”

Hemospray, which is approved in Canada for upper/lower gastrointestinal bleeding of any etiology, as well as in Mexico and in some countries in Europe, Asia, and South America, works by forming a mechanical barrier over the bleeding site. The powder absorbs water, then acts both cohesively and adhesively to form that barrier, according to information from Cook Medical, which developed the product. It is not currently approved for this indication in the United States.

“An adequately powered randomized, controlled trial is now needed to better determine any beneficial downstream effect on subsequent rebleeding and health care resource use when compared to existing standard of care,” he concluded.

Dr. Barkun is an advisory committee/board member and consultant for Cook Medical and has received grant/research support from the company.

[email protected]

Angiosarcoma is also known as malignant hemangioendothelioma, hemangiosarcoma, and lymphangiosarcoma. It is an uncommon, high-grade malignant vascular neoplasm of the inner lining of blood vessels. Unlike most sarcomas, it occurs more superficially, most often on the head and neck (particularly on the scalp). This neoplasm occurs twice as often in males as it does in females. Angiosarcomas can occur in the breast after radiation therapy, as well as in the liver and spleen, but 60% are cutaneous.
 

Courtesy Parteek Singla, MD, and Susannah McClain, MD

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to [email protected].

Angiosarcoma is also known as malignant hemangioendothelioma, hemangiosarcoma, and lymphangiosarcoma. It is an uncommon, high-grade malignant vascular neoplasm of the inner lining of blood vessels. Unlike most sarcomas, it occurs more superficially, most often on the head and neck (particularly on the scalp). This neoplasm occurs twice as often in males as it does in females. Angiosarcomas can occur in the breast after radiation therapy, as well as in the liver and spleen, but 60% are cutaneous.
 

Courtesy Parteek Singla, MD, and Susannah McClain, MD

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to [email protected].

Angiosarcoma is also known as malignant hemangioendothelioma, hemangiosarcoma, and lymphangiosarcoma. It is an uncommon, high-grade malignant vascular neoplasm of the inner lining of blood vessels. Unlike most sarcomas, it occurs more superficially, most often on the head and neck (particularly on the scalp). This neoplasm occurs twice as often in males as it does in females. Angiosarcomas can occur in the breast after radiation therapy, as well as in the liver and spleen, but 60% are cutaneous.
 

Courtesy Parteek Singla, MD, and Susannah McClain, MD

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to [email protected].

To the Editor:

Purpura annularis telangiectodes of Majocchi (PATM) is a type of pigmented purpuric dermatosis (PPD). Patients present with nonblanchable, annular, symmetric, purpuric, and telangiectatic patches, often on the legs, with histology revealing a perivascular lymphocytic infiltrate and extravasated erythrocytes.^1,2 A variety of medications have been linked to the development of PPD. We describe a case of levofloxacin-induced PATM.

RELATED ARTICLE: Granulomatous Changes Associated With Pigmented Purpuric Dermatosis

A 42-year-old man presented with a rash on the arms, trunk, abdomen, and legs of 1 month’s duration. He reported no associated itching, bleeding, or pain, and no history of a similar rash. He had a history of hypothyroidism and had been taking levothyroxine for years. He had no known allergies and no history of childhood eczema, asthma, or allergic rhinitis. Notably, the rash started shortly after the patient finished a 2-week course of levofloxacin, an antibiotic he had not taken in the past. The patient resided with his wife, 3 children, and a pet dog, and no family members had the rash. Prior to presentation, the patient had tried econazole cream and then triamcinolone acetonide cream 0.5% without any clinical improvement.

A complete review of systems was unremarkable. Physical examination revealed scattered, reddish brown, annular, nonscaly patches on the back, abdomen (Figure 1), arms, and legs with nonblanching petechiae within the patches.

A punch biopsy of the left inner thigh demonstrated patchy interface dermatitis, superficial perivascular inflammation, and numerous extravasated red blood cells in the papillary dermis (Figure 2). The histologic features were compatible with the clinical impression of PATM. The patient presented for a follow-up visit 2 weeks later with no new lesions and the old lesions were rapidly fading (Figure 3).

Pigmented purpuric dermatoses are a group of conditions that have different clinical morphologies but similar histopathologic examinations.² All PPDs are characterized by nonblanching, nonpalpable, purpuric lesions that often are bilaterally symmetrical and present on the legs.^2,3 Although the precise etiology of these conditions is not known, most cases include a perivascular lymphocytic infiltrate along with the presence of extravasated erythrocytes and hemosiderin deposition in the dermis.² Of note, PATM often is idiopathic and patients usually present with no associated comorbidities.³ The currently established PPDs include progressive pigmentary dermatosis (Schamberg disease), PATM, pigmented purpuric lichenoid dermatosis of Gougerot and Blum, lichen aureus, and eczematidlike purpura of Doucas and Kapetanakis.^2,4

RELATED ARTICLE: Granulomatous Pigmented Purpuric Dermatosis

The lesions of PATM are symmetrically distributed on the bilateral legs and may be symptomatic in most cases, with severe pruritus being reported in several drug-induced PATM cases.^3,5 Although the exact etiology of PPDs currently is unknown, some contributing factors that are thought to play a role include exercise, venous stasis, gravitational dependence, capillary fragility, hypertension, drugs, chemical exposure or ingestions, and contact allergy to dyes.³ Some of the drugs known to cause drug-induced PPDs fall into the class of sedatives, stimulants, antibiotics, cardiovascular drugs, vitamins, and nutritional supplements.^3,6 Some medications that have been reported to cause PPDs include acetaminophen, aspirin, carbamazepine, diltiazem, furosemide, glipizide, hydralazine, infliximab, isotretinoin, lorazepam, minocycline, nitroglycerine, and sildenafil.^3,7-15

Although the mechanism of drug-induced PPD is not completely understood, it is thought that the ingested substance leads to an immunologic response in the capillary endothelium, which results in a cell-mediated immune response causing vascular damage.³ The ingested substance may act as a hapten, stimulating antibody formation and immune-mediated injury, leading to the clinical presentation of nonblanching, symmetric, purpuric, telangiectatic, and atrophic patches at the site of injury.^1,3

Levofloxacin is a broad-spectrum antibiotic that has activity against both gram-positive and gram-negative bacteria. It inhibits the enzymes DNA gyrase and topoisomerase IV, preventing bacteria from undergoing proper DNA synthesis.¹⁶ Our patient’s rash began shortly after a 2-week course of levofloxacin and faded within a few weeks of discontinuing the drug; the clinical presentation, time course, and histologic appearance of the lesions were consistent with the diagnosis of drug-induced PPD. Of note, solar capillaritis has been reported following a phototoxic reaction induced by levofloxacin.¹⁷ Our case differs in that our patient had annular lesions on both photoprotected and photoexposed skin.

The first-line interventions for the treatment of PPDs are nonpharmacologic, such as discontinuation of an offending drug or allergen or wearing supportive stockings if there are signs of venous stasis. Other interventions include the use of a medium- or high-potency topical corticosteroid once to twice daily to affected areas for 4 to 6 weeks.¹⁸ Some case series also have shown improvement with narrowband UVB treatment after 24 to 28 treatment sessions or with psoralen plus UVA phototherapy within 7 to 20 treatments.^19,20 If the above measures are unsuccessful in resolving symptoms, other treatment alternatives may include pentoxifylline, griseofulvin, colchicine, cyclosporine, and methotrexate. The potential benefit of treatment must be weighed against the side-effect profile of these medications.^2,21-24 Of note, oral rutoside (50 mg twice daily) and ascorbic acid (500 mg twice daily) were administered to 3 patients with chronic progressive pigmented purpura. At the end of the 4-week treatment period, complete clearance of skin lesions was seen in all patients with no adverse reactions noted.²⁵

Despite these treatment options, PATM does not necessitate treatment given its benign course and often self-resolving nature.²⁶ In cases of drug-induced PPD such as in our patient, discontinuation of the offending drug often may lead to resolution.

In summary, PATM is a PPD that has been associated with different etiologic factors. If PATM is suspected to be caused by a drug, discontinuation of the offending agent usually results in resolution of symptoms, as it did in our case with fading of lesions within a few weeks after the patient was no longer taking levofloxacin.

To the Editor:

Purpura annularis telangiectodes of Majocchi (PATM) is a type of pigmented purpuric dermatosis (PPD). Patients present with nonblanchable, annular, symmetric, purpuric, and telangiectatic patches, often on the legs, with histology revealing a perivascular lymphocytic infiltrate and extravasated erythrocytes.^1,2 A variety of medications have been linked to the development of PPD. We describe a case of levofloxacin-induced PATM.

RELATED ARTICLE: Granulomatous Changes Associated With Pigmented Purpuric Dermatosis

A 42-year-old man presented with a rash on the arms, trunk, abdomen, and legs of 1 month’s duration. He reported no associated itching, bleeding, or pain, and no history of a similar rash. He had a history of hypothyroidism and had been taking levothyroxine for years. He had no known allergies and no history of childhood eczema, asthma, or allergic rhinitis. Notably, the rash started shortly after the patient finished a 2-week course of levofloxacin, an antibiotic he had not taken in the past. The patient resided with his wife, 3 children, and a pet dog, and no family members had the rash. Prior to presentation, the patient had tried econazole cream and then triamcinolone acetonide cream 0.5% without any clinical improvement.

A complete review of systems was unremarkable. Physical examination revealed scattered, reddish brown, annular, nonscaly patches on the back, abdomen (Figure 1), arms, and legs with nonblanching petechiae within the patches.

A punch biopsy of the left inner thigh demonstrated patchy interface dermatitis, superficial perivascular inflammation, and numerous extravasated red blood cells in the papillary dermis (Figure 2). The histologic features were compatible with the clinical impression of PATM. The patient presented for a follow-up visit 2 weeks later with no new lesions and the old lesions were rapidly fading (Figure 3).

Pigmented purpuric dermatoses are a group of conditions that have different clinical morphologies but similar histopathologic examinations.² All PPDs are characterized by nonblanching, nonpalpable, purpuric lesions that often are bilaterally symmetrical and present on the legs.^2,3 Although the precise etiology of these conditions is not known, most cases include a perivascular lymphocytic infiltrate along with the presence of extravasated erythrocytes and hemosiderin deposition in the dermis.² Of note, PATM often is idiopathic and patients usually present with no associated comorbidities.³ The currently established PPDs include progressive pigmentary dermatosis (Schamberg disease), PATM, pigmented purpuric lichenoid dermatosis of Gougerot and Blum, lichen aureus, and eczematidlike purpura of Doucas and Kapetanakis.^2,4

RELATED ARTICLE: Granulomatous Pigmented Purpuric Dermatosis

The lesions of PATM are symmetrically distributed on the bilateral legs and may be symptomatic in most cases, with severe pruritus being reported in several drug-induced PATM cases.^3,5 Although the exact etiology of PPDs currently is unknown, some contributing factors that are thought to play a role include exercise, venous stasis, gravitational dependence, capillary fragility, hypertension, drugs, chemical exposure or ingestions, and contact allergy to dyes.³ Some of the drugs known to cause drug-induced PPDs fall into the class of sedatives, stimulants, antibiotics, cardiovascular drugs, vitamins, and nutritional supplements.^3,6 Some medications that have been reported to cause PPDs include acetaminophen, aspirin, carbamazepine, diltiazem, furosemide, glipizide, hydralazine, infliximab, isotretinoin, lorazepam, minocycline, nitroglycerine, and sildenafil.^3,7-15

Although the mechanism of drug-induced PPD is not completely understood, it is thought that the ingested substance leads to an immunologic response in the capillary endothelium, which results in a cell-mediated immune response causing vascular damage.³ The ingested substance may act as a hapten, stimulating antibody formation and immune-mediated injury, leading to the clinical presentation of nonblanching, symmetric, purpuric, telangiectatic, and atrophic patches at the site of injury.^1,3

Levofloxacin is a broad-spectrum antibiotic that has activity against both gram-positive and gram-negative bacteria. It inhibits the enzymes DNA gyrase and topoisomerase IV, preventing bacteria from undergoing proper DNA synthesis.¹⁶ Our patient’s rash began shortly after a 2-week course of levofloxacin and faded within a few weeks of discontinuing the drug; the clinical presentation, time course, and histologic appearance of the lesions were consistent with the diagnosis of drug-induced PPD. Of note, solar capillaritis has been reported following a phototoxic reaction induced by levofloxacin.¹⁷ Our case differs in that our patient had annular lesions on both photoprotected and photoexposed skin.

The first-line interventions for the treatment of PPDs are nonpharmacologic, such as discontinuation of an offending drug or allergen or wearing supportive stockings if there are signs of venous stasis. Other interventions include the use of a medium- or high-potency topical corticosteroid once to twice daily to affected areas for 4 to 6 weeks.¹⁸ Some case series also have shown improvement with narrowband UVB treatment after 24 to 28 treatment sessions or with psoralen plus UVA phototherapy within 7 to 20 treatments.^19,20 If the above measures are unsuccessful in resolving symptoms, other treatment alternatives may include pentoxifylline, griseofulvin, colchicine, cyclosporine, and methotrexate. The potential benefit of treatment must be weighed against the side-effect profile of these medications.^2,21-24 Of note, oral rutoside (50 mg twice daily) and ascorbic acid (500 mg twice daily) were administered to 3 patients with chronic progressive pigmented purpura. At the end of the 4-week treatment period, complete clearance of skin lesions was seen in all patients with no adverse reactions noted.²⁵

Despite these treatment options, PATM does not necessitate treatment given its benign course and often self-resolving nature.²⁶ In cases of drug-induced PPD such as in our patient, discontinuation of the offending drug often may lead to resolution.

In summary, PATM is a PPD that has been associated with different etiologic factors. If PATM is suspected to be caused by a drug, discontinuation of the offending agent usually results in resolution of symptoms, as it did in our case with fading of lesions within a few weeks after the patient was no longer taking levofloxacin.

To the Editor:

Purpura annularis telangiectodes of Majocchi (PATM) is a type of pigmented purpuric dermatosis (PPD). Patients present with nonblanchable, annular, symmetric, purpuric, and telangiectatic patches, often on the legs, with histology revealing a perivascular lymphocytic infiltrate and extravasated erythrocytes.^1,2 A variety of medications have been linked to the development of PPD. We describe a case of levofloxacin-induced PATM.

RELATED ARTICLE: Granulomatous Changes Associated With Pigmented Purpuric Dermatosis

A 42-year-old man presented with a rash on the arms, trunk, abdomen, and legs of 1 month’s duration. He reported no associated itching, bleeding, or pain, and no history of a similar rash. He had a history of hypothyroidism and had been taking levothyroxine for years. He had no known allergies and no history of childhood eczema, asthma, or allergic rhinitis. Notably, the rash started shortly after the patient finished a 2-week course of levofloxacin, an antibiotic he had not taken in the past. The patient resided with his wife, 3 children, and a pet dog, and no family members had the rash. Prior to presentation, the patient had tried econazole cream and then triamcinolone acetonide cream 0.5% without any clinical improvement.

A complete review of systems was unremarkable. Physical examination revealed scattered, reddish brown, annular, nonscaly patches on the back, abdomen (Figure 1), arms, and legs with nonblanching petechiae within the patches.

A punch biopsy of the left inner thigh demonstrated patchy interface dermatitis, superficial perivascular inflammation, and numerous extravasated red blood cells in the papillary dermis (Figure 2). The histologic features were compatible with the clinical impression of PATM. The patient presented for a follow-up visit 2 weeks later with no new lesions and the old lesions were rapidly fading (Figure 3).

Pigmented purpuric dermatoses are a group of conditions that have different clinical morphologies but similar histopathologic examinations.² All PPDs are characterized by nonblanching, nonpalpable, purpuric lesions that often are bilaterally symmetrical and present on the legs.^2,3 Although the precise etiology of these conditions is not known, most cases include a perivascular lymphocytic infiltrate along with the presence of extravasated erythrocytes and hemosiderin deposition in the dermis.² Of note, PATM often is idiopathic and patients usually present with no associated comorbidities.³ The currently established PPDs include progressive pigmentary dermatosis (Schamberg disease), PATM, pigmented purpuric lichenoid dermatosis of Gougerot and Blum, lichen aureus, and eczematidlike purpura of Doucas and Kapetanakis.^2,4

RELATED ARTICLE: Granulomatous Pigmented Purpuric Dermatosis

The lesions of PATM are symmetrically distributed on the bilateral legs and may be symptomatic in most cases, with severe pruritus being reported in several drug-induced PATM cases.^3,5 Although the exact etiology of PPDs currently is unknown, some contributing factors that are thought to play a role include exercise, venous stasis, gravitational dependence, capillary fragility, hypertension, drugs, chemical exposure or ingestions, and contact allergy to dyes.³ Some of the drugs known to cause drug-induced PPDs fall into the class of sedatives, stimulants, antibiotics, cardiovascular drugs, vitamins, and nutritional supplements.^3,6 Some medications that have been reported to cause PPDs include acetaminophen, aspirin, carbamazepine, diltiazem, furosemide, glipizide, hydralazine, infliximab, isotretinoin, lorazepam, minocycline, nitroglycerine, and sildenafil.^3,7-15

Although the mechanism of drug-induced PPD is not completely understood, it is thought that the ingested substance leads to an immunologic response in the capillary endothelium, which results in a cell-mediated immune response causing vascular damage.³ The ingested substance may act as a hapten, stimulating antibody formation and immune-mediated injury, leading to the clinical presentation of nonblanching, symmetric, purpuric, telangiectatic, and atrophic patches at the site of injury.^1,3

Levofloxacin is a broad-spectrum antibiotic that has activity against both gram-positive and gram-negative bacteria. It inhibits the enzymes DNA gyrase and topoisomerase IV, preventing bacteria from undergoing proper DNA synthesis.¹⁶ Our patient’s rash began shortly after a 2-week course of levofloxacin and faded within a few weeks of discontinuing the drug; the clinical presentation, time course, and histologic appearance of the lesions were consistent with the diagnosis of drug-induced PPD. Of note, solar capillaritis has been reported following a phototoxic reaction induced by levofloxacin.¹⁷ Our case differs in that our patient had annular lesions on both photoprotected and photoexposed skin.

The first-line interventions for the treatment of PPDs are nonpharmacologic, such as discontinuation of an offending drug or allergen or wearing supportive stockings if there are signs of venous stasis. Other interventions include the use of a medium- or high-potency topical corticosteroid once to twice daily to affected areas for 4 to 6 weeks.¹⁸ Some case series also have shown improvement with narrowband UVB treatment after 24 to 28 treatment sessions or with psoralen plus UVA phototherapy within 7 to 20 treatments.^19,20 If the above measures are unsuccessful in resolving symptoms, other treatment alternatives may include pentoxifylline, griseofulvin, colchicine, cyclosporine, and methotrexate. The potential benefit of treatment must be weighed against the side-effect profile of these medications.^2,21-24 Of note, oral rutoside (50 mg twice daily) and ascorbic acid (500 mg twice daily) were administered to 3 patients with chronic progressive pigmented purpura. At the end of the 4-week treatment period, complete clearance of skin lesions was seen in all patients with no adverse reactions noted.²⁵

Despite these treatment options, PATM does not necessitate treatment given its benign course and often self-resolving nature.²⁶ In cases of drug-induced PPD such as in our patient, discontinuation of the offending drug often may lead to resolution.

In summary, PATM is a PPD that has been associated with different etiologic factors. If PATM is suspected to be caused by a drug, discontinuation of the offending agent usually results in resolution of symptoms, as it did in our case with fading of lesions within a few weeks after the patient was no longer taking levofloxacin.

A long-term safety study of crisaborole showed few safety concerns, suggesting that the therapy has the potential to treat atopic dermatitis without the side effects of the current topical treatments, said Lawrence F. Eichenfield, MD, of Rady Children’s Hospital, San Diego, and his associates.

The multicenter, long-term, open-label safety study of 48 weeks assessed 517 patients with mild to moderate atopic dermatitis after they had finished a 28-day phase 3 study of 2% crisaborole ointment. The patients in the extension study were told to apply crisaborole twice daily for 28 days, with an off-treatment period initiated if their disease severity was clear or almost clear after the 28 days. They were told to stop the treatment if they had no improvement in their Investigator’s Static Global Assessment score after three consecutive treatment periods.

aniaostudio/Thinkstock

[email protected]

A long-term safety study of crisaborole showed few safety concerns, suggesting that the therapy has the potential to treat atopic dermatitis without the side effects of the current topical treatments, said Lawrence F. Eichenfield, MD, of Rady Children’s Hospital, San Diego, and his associates.

The multicenter, long-term, open-label safety study of 48 weeks assessed 517 patients with mild to moderate atopic dermatitis after they had finished a 28-day phase 3 study of 2% crisaborole ointment. The patients in the extension study were told to apply crisaborole twice daily for 28 days, with an off-treatment period initiated if their disease severity was clear or almost clear after the 28 days. They were told to stop the treatment if they had no improvement in their Investigator’s Static Global Assessment score after three consecutive treatment periods.

aniaostudio/Thinkstock

[email protected]

A long-term safety study of crisaborole showed few safety concerns, suggesting that the therapy has the potential to treat atopic dermatitis without the side effects of the current topical treatments, said Lawrence F. Eichenfield, MD, of Rady Children’s Hospital, San Diego, and his associates.

The multicenter, long-term, open-label safety study of 48 weeks assessed 517 patients with mild to moderate atopic dermatitis after they had finished a 28-day phase 3 study of 2% crisaborole ointment. The patients in the extension study were told to apply crisaborole twice daily for 28 days, with an off-treatment period initiated if their disease severity was clear or almost clear after the 28 days. They were told to stop the treatment if they had no improvement in their Investigator’s Static Global Assessment score after three consecutive treatment periods.

aniaostudio/Thinkstock

[email protected]

Much has been written over the past year about the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA), and its primary vehicle, the Merit-Based Incentive System (MIPS); but many small practices seem reluctant to take it seriously, despite the fact that it puts yet another significant percentage of our Medicare reimbursements at risk.

Those much-publicized attempts to “repeal and replace” the Affordable Care Act earlier this year undoubtedly contributed to the apathy; but the ACA is apparently here to stay, and the first MIPS “performance period” ends on Dec. 31, so now would be an excellent time to get up to speed. Herewith, the basics:

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

Much has been written over the past year about the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA), and its primary vehicle, the Merit-Based Incentive System (MIPS); but many small practices seem reluctant to take it seriously, despite the fact that it puts yet another significant percentage of our Medicare reimbursements at risk.

Those much-publicized attempts to “repeal and replace” the Affordable Care Act earlier this year undoubtedly contributed to the apathy; but the ACA is apparently here to stay, and the first MIPS “performance period” ends on Dec. 31, so now would be an excellent time to get up to speed. Herewith, the basics:

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

Much has been written over the past year about the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA), and its primary vehicle, the Merit-Based Incentive System (MIPS); but many small practices seem reluctant to take it seriously, despite the fact that it puts yet another significant percentage of our Medicare reimbursements at risk.

Those much-publicized attempts to “repeal and replace” the Affordable Care Act earlier this year undoubtedly contributed to the apathy; but the ACA is apparently here to stay, and the first MIPS “performance period” ends on Dec. 31, so now would be an excellent time to get up to speed. Herewith, the basics:

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

To the Editor:

A 69-year-old woman with no history of immunodeficiency presented 1 month after a thorn from her locally grown Madagascar palm plant (Pachypodium lamerei) pierced the skin. The patient developed a painful nodule at the site on the left elbow (Figure 1). An excisional biopsy by an outside dermatologist was performed, which showed granulomatous inflammation within the dermis with epidermal hyperplasia and the presence of golden brown spherules (medlar bodies). The diagnosis was a dermal fungal infection consistent with chromoblastomycosis. A curative surgical excision was performed, and medlar bodies were seen adjacent to a polarizable foreign body consistent with plant material on histology (Figure 2). Because the lesion was localized, adjuvant medical treatment was not deemed necessary. The patient has not had any recurrence in the last 1.5 years since the resection.

The categorization of chromoblastomycosis includes a chronic fungal infection of the cutaneous and subcutaneous tissues by dematiaceous (pigmented) fungi. This definition is such that there are a multitude of organisms that can be the primary cause of this diagnosis. Generally, infection follows a traumatic permeation of the skin by a foreign body contaminated by the causative organism in agricultural workers. The most common dematiaceous pathogens are Fonsecaea pedrosoi, Phialophora verrucosa, and Cladosporium carrionii; however, the specific causative organism varies heavily on geographic location. With inoculation by a foreign body, a small papule develops at the site of the lesion. Several years after the primary infection, nodules and verrucous erythematous plaques develop in the same area, and patients present with concerns of pain and pruritus.¹ Lesions usually are localized to the initial area of inoculation, generally a break in the skin by the offending foreign body, on the legs, arms, or hands, but hematogenous or lymphatic dissemination with distant transmission due to scratching also can occur. Ulceration due to secondary bacterial infection is another possible manifestation, resulting in a foul odor and less commonly lymphedema. Rarely, squamous cell carcinoma is a complication.²

RELATED ARTICLE: Fungal Foes: Presentations of Chromoblastomycosis Post–Hurricane Ike

On histopathology, thick-walled sclerotic bodies termed medlar bodies or copper pennies are pathognomonic for chromoblastomycosis and represent the fungal elements. Grossly, black dots can be seen on the skin in the affected areas from the transepidermal elimination of the fungi.^1,2 However, there is no specificity for determining the causative organism in this manner, or even with culture, as it is difficult to differentiate the species morphologically. More advanced tests can help, such as polymerase chain reaction or enzyme-linked immunosorbent assay, where available.² Hematoxylin and eosin stain also shows epidermal hyperplasia and dermal mononuclear infiltrate.

Treatment modalities include surgical excision, cryotherapy, pharmacologic treatment, and combination therapy. Localized lesions often can be resected, but more severe infections can require pharmacologic treatment. Unfortunately, there tends to be a high risk for relapse with most antifungal modalities. The combination of itraconazole and terbinafine has been shown to offer the best medical therapy with lower risk for refractoriness to treatment by producing a synergistic effect between the 2 antifungals.^2,3 Many surgical treatments often are combined with oral antifungals to try to attain complete eradication in deep or extensive lesions, as seen in a case in which oral terbinafine was used prior to surgery to reduce the size of the lesion, followed by complete resection.⁴ With localized lesions that are resectable, a wide and deep incision often can be curative. Cryotherapy also may be coupled with surgical excision or pharmacologic therapy. Most literature suggests that cryotherapy or the use of antifungals prior to excision offers improved outcomes.^2,5 Prognosis tends to be good for chromoblastomycoses, particularly with smaller lesions. Complete eradication varies greatly on the size and depth of the lesion, independent of the causative pathogen.

Our patient’s presentation with chromoblastomycosis is unique because of the source of infection, which was a plant grown from seeds in a local nursery in South Florida and then sold to the patient. The majority of chromoblastomycosis infections occur in agricultural workers, typically in tropical climates such as South and Central America, the Caribbean, and Mexico.^1,2 Historically, infections in the United States have been uncommon, with the majority presenting in patients on prolonged corticosteroid therapy or with other immunosuppressive conditions.^6,7 This presentation of a chromoblastomycosis infection in a 69-year-old woman with no history of immunosuppression or chronic disease can serve as a teaching point about atypical presentations of the disease. The Madagascar palm plant that was responsible for the initial lesion in our case is a member of the Pachypodium species of plant that is endemic to Madagascar, one of the few regions outside of Latin America that has displayed numerous cases of chromoblastomycosis. In this fashion, a domestic gardener can now become exposed to dematiaceous pathogens that normally are not found in the continental United States, and knowledge of this possible exposure source can be crucial in the diagnosis and management of similar patients.

To the Editor:

A 69-year-old woman with no history of immunodeficiency presented 1 month after a thorn from her locally grown Madagascar palm plant (Pachypodium lamerei) pierced the skin. The patient developed a painful nodule at the site on the left elbow (Figure 1). An excisional biopsy by an outside dermatologist was performed, which showed granulomatous inflammation within the dermis with epidermal hyperplasia and the presence of golden brown spherules (medlar bodies). The diagnosis was a dermal fungal infection consistent with chromoblastomycosis. A curative surgical excision was performed, and medlar bodies were seen adjacent to a polarizable foreign body consistent with plant material on histology (Figure 2). Because the lesion was localized, adjuvant medical treatment was not deemed necessary. The patient has not had any recurrence in the last 1.5 years since the resection.

The categorization of chromoblastomycosis includes a chronic fungal infection of the cutaneous and subcutaneous tissues by dematiaceous (pigmented) fungi. This definition is such that there are a multitude of organisms that can be the primary cause of this diagnosis. Generally, infection follows a traumatic permeation of the skin by a foreign body contaminated by the causative organism in agricultural workers. The most common dematiaceous pathogens are Fonsecaea pedrosoi, Phialophora verrucosa, and Cladosporium carrionii; however, the specific causative organism varies heavily on geographic location. With inoculation by a foreign body, a small papule develops at the site of the lesion. Several years after the primary infection, nodules and verrucous erythematous plaques develop in the same area, and patients present with concerns of pain and pruritus.¹ Lesions usually are localized to the initial area of inoculation, generally a break in the skin by the offending foreign body, on the legs, arms, or hands, but hematogenous or lymphatic dissemination with distant transmission due to scratching also can occur. Ulceration due to secondary bacterial infection is another possible manifestation, resulting in a foul odor and less commonly lymphedema. Rarely, squamous cell carcinoma is a complication.²

RELATED ARTICLE: Fungal Foes: Presentations of Chromoblastomycosis Post–Hurricane Ike

On histopathology, thick-walled sclerotic bodies termed medlar bodies or copper pennies are pathognomonic for chromoblastomycosis and represent the fungal elements. Grossly, black dots can be seen on the skin in the affected areas from the transepidermal elimination of the fungi.^1,2 However, there is no specificity for determining the causative organism in this manner, or even with culture, as it is difficult to differentiate the species morphologically. More advanced tests can help, such as polymerase chain reaction or enzyme-linked immunosorbent assay, where available.² Hematoxylin and eosin stain also shows epidermal hyperplasia and dermal mononuclear infiltrate.

Treatment modalities include surgical excision, cryotherapy, pharmacologic treatment, and combination therapy. Localized lesions often can be resected, but more severe infections can require pharmacologic treatment. Unfortunately, there tends to be a high risk for relapse with most antifungal modalities. The combination of itraconazole and terbinafine has been shown to offer the best medical therapy with lower risk for refractoriness to treatment by producing a synergistic effect between the 2 antifungals.^2,3 Many surgical treatments often are combined with oral antifungals to try to attain complete eradication in deep or extensive lesions, as seen in a case in which oral terbinafine was used prior to surgery to reduce the size of the lesion, followed by complete resection.⁴ With localized lesions that are resectable, a wide and deep incision often can be curative. Cryotherapy also may be coupled with surgical excision or pharmacologic therapy. Most literature suggests that cryotherapy or the use of antifungals prior to excision offers improved outcomes.^2,5 Prognosis tends to be good for chromoblastomycoses, particularly with smaller lesions. Complete eradication varies greatly on the size and depth of the lesion, independent of the causative pathogen.

Our patient’s presentation with chromoblastomycosis is unique because of the source of infection, which was a plant grown from seeds in a local nursery in South Florida and then sold to the patient. The majority of chromoblastomycosis infections occur in agricultural workers, typically in tropical climates such as South and Central America, the Caribbean, and Mexico.^1,2 Historically, infections in the United States have been uncommon, with the majority presenting in patients on prolonged corticosteroid therapy or with other immunosuppressive conditions.^6,7 This presentation of a chromoblastomycosis infection in a 69-year-old woman with no history of immunosuppression or chronic disease can serve as a teaching point about atypical presentations of the disease. The Madagascar palm plant that was responsible for the initial lesion in our case is a member of the Pachypodium species of plant that is endemic to Madagascar, one of the few regions outside of Latin America that has displayed numerous cases of chromoblastomycosis. In this fashion, a domestic gardener can now become exposed to dematiaceous pathogens that normally are not found in the continental United States, and knowledge of this possible exposure source can be crucial in the diagnosis and management of similar patients.

To the Editor:

A 69-year-old woman with no history of immunodeficiency presented 1 month after a thorn from her locally grown Madagascar palm plant (Pachypodium lamerei) pierced the skin. The patient developed a painful nodule at the site on the left elbow (Figure 1). An excisional biopsy by an outside dermatologist was performed, which showed granulomatous inflammation within the dermis with epidermal hyperplasia and the presence of golden brown spherules (medlar bodies). The diagnosis was a dermal fungal infection consistent with chromoblastomycosis. A curative surgical excision was performed, and medlar bodies were seen adjacent to a polarizable foreign body consistent with plant material on histology (Figure 2). Because the lesion was localized, adjuvant medical treatment was not deemed necessary. The patient has not had any recurrence in the last 1.5 years since the resection.

The categorization of chromoblastomycosis includes a chronic fungal infection of the cutaneous and subcutaneous tissues by dematiaceous (pigmented) fungi. This definition is such that there are a multitude of organisms that can be the primary cause of this diagnosis. Generally, infection follows a traumatic permeation of the skin by a foreign body contaminated by the causative organism in agricultural workers. The most common dematiaceous pathogens are Fonsecaea pedrosoi, Phialophora verrucosa, and Cladosporium carrionii; however, the specific causative organism varies heavily on geographic location. With inoculation by a foreign body, a small papule develops at the site of the lesion. Several years after the primary infection, nodules and verrucous erythematous plaques develop in the same area, and patients present with concerns of pain and pruritus.¹ Lesions usually are localized to the initial area of inoculation, generally a break in the skin by the offending foreign body, on the legs, arms, or hands, but hematogenous or lymphatic dissemination with distant transmission due to scratching also can occur. Ulceration due to secondary bacterial infection is another possible manifestation, resulting in a foul odor and less commonly lymphedema. Rarely, squamous cell carcinoma is a complication.²

RELATED ARTICLE: Fungal Foes: Presentations of Chromoblastomycosis Post–Hurricane Ike

On histopathology, thick-walled sclerotic bodies termed medlar bodies or copper pennies are pathognomonic for chromoblastomycosis and represent the fungal elements. Grossly, black dots can be seen on the skin in the affected areas from the transepidermal elimination of the fungi.^1,2 However, there is no specificity for determining the causative organism in this manner, or even with culture, as it is difficult to differentiate the species morphologically. More advanced tests can help, such as polymerase chain reaction or enzyme-linked immunosorbent assay, where available.² Hematoxylin and eosin stain also shows epidermal hyperplasia and dermal mononuclear infiltrate.

Treatment modalities include surgical excision, cryotherapy, pharmacologic treatment, and combination therapy. Localized lesions often can be resected, but more severe infections can require pharmacologic treatment. Unfortunately, there tends to be a high risk for relapse with most antifungal modalities. The combination of itraconazole and terbinafine has been shown to offer the best medical therapy with lower risk for refractoriness to treatment by producing a synergistic effect between the 2 antifungals.^2,3 Many surgical treatments often are combined with oral antifungals to try to attain complete eradication in deep or extensive lesions, as seen in a case in which oral terbinafine was used prior to surgery to reduce the size of the lesion, followed by complete resection.⁴ With localized lesions that are resectable, a wide and deep incision often can be curative. Cryotherapy also may be coupled with surgical excision or pharmacologic therapy. Most literature suggests that cryotherapy or the use of antifungals prior to excision offers improved outcomes.^2,5 Prognosis tends to be good for chromoblastomycoses, particularly with smaller lesions. Complete eradication varies greatly on the size and depth of the lesion, independent of the causative pathogen.

Our patient’s presentation with chromoblastomycosis is unique because of the source of infection, which was a plant grown from seeds in a local nursery in South Florida and then sold to the patient. The majority of chromoblastomycosis infections occur in agricultural workers, typically in tropical climates such as South and Central America, the Caribbean, and Mexico.^1,2 Historically, infections in the United States have been uncommon, with the majority presenting in patients on prolonged corticosteroid therapy or with other immunosuppressive conditions.^6,7 This presentation of a chromoblastomycosis infection in a 69-year-old woman with no history of immunosuppression or chronic disease can serve as a teaching point about atypical presentations of the disease. The Madagascar palm plant that was responsible for the initial lesion in our case is a member of the Pachypodium species of plant that is endemic to Madagascar, one of the few regions outside of Latin America that has displayed numerous cases of chromoblastomycosis. In this fashion, a domestic gardener can now become exposed to dematiaceous pathogens that normally are not found in the continental United States, and knowledge of this possible exposure source can be crucial in the diagnosis and management of similar patients.

Peripheral intravenous catheter (PIV) insertion is the fastest, simplest, and most cost-effective method to gain vascular access, and it is used for short-term intravenous (IV) fluids, medications, blood products, and contrast media.¹ It is the most common invasive device in hospitalized patients,² with up to 70% of hospital patients receiving a PIV.³ Unacceptable PIV failure rates have been reported as high as 69%.^4-7 Failure is most frequently due to phlebitis (vein wall irritation/inflammation), occlusion (blockage), infiltration or extravasation (IV fluids/vesicant therapy entering surrounding tissue), partial dislodgement or accidental removal, leakage, and infection.^4,6,8 These failures have important implications for patients, who endure the discomfort of PIV complications and catheter replacements, and healthcare staff and budgets.

To reduce the incidence of catheter failure and avoid preventable PIV replacements, a clear understanding of why catheters fail is required. Previous research has identified that catheter gauge,^9-11 insertion site,^12-14 and inserter skill^10,15 have an impact on PIV failure. Limitations of existing research are small study sizes,^16-18 retrospective design,¹⁹ or secondary analysis of an existing data set; all potentially introduce sampling bias.^10,20

To overcome these potential biases, we developed a data collection instrument based on the catheter-associated risk factors described in the literature,^9-11,13 and other potential insertion and maintenance risks for PIV failure (eg, multiple insertion attempts, medications administered), with data collected prospectively. The study aim was to improve patient outcomes by identifying PIV insertion and maintenance risk factors amenable to modification through education or alternative clinical interventions, such as catheter gauge selection or insertion site.

Study Design and Participants

We conducted this prospective cohort study in a large tertiary hospital in Queensland, Australia. Ethics committee approval was obtained from the hospital (HREC/14/QRBW/76) and Griffith University (NRS/26/14/HREC). The study was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000738527). Patients in medical and surgical wards were screened Monday, Wednesday, and Friday between October 2014 and December 2015. Patients over 18 years with a PIV (BD Insyte^TM Autoguard^TM BC; Becton Dickinson, Franklin Lakes, NJ) inserted within 24 hours, and who were able to provide written informed consent, were eligible and recruited sequentially. Patients classified as palliative by the treating clinical team were excluded.

Sample Size Calculation

The “10 events per variable” rule was used to determine the sample size required to study 50 potential risk factors.^21,22 This determined that 1000 patients, with an average of 1.5 PIVs each and an expected PIV failure of 30% (500 events), were required.

Data Collection

At recruitment, baseline patient information was collected by a research nurse (ReNs) (demographics, admitting diagnosis, comorbidities, skin type,²³ and vein condition) and entered into an electronic data platform supported by Research Electronic Data Capture (REDCap).²⁴ Baseline data also included catheter variables (eg, gauge, insertion site, catheterized vein) and insertion details (eg, department of insertion, inserting clinician, number of insertion attempts). We included every PIV the participant had during their admission until hospital discharge or insertion of a central venous access device. PIV sites were reviewed Monday, Wednesday, and Friday by ReNs for site complications (eg, redness, pain, swelling, palpable cord). Potential risk factors for failure were also recorded (eg, infusates and additives, antibiotic type and dosage, flushing regimen, number of times the PIV was accessed each day for administration of IV medications or fluids, dressing type and condition, securement method for the catheter and tubing, presence of extension tubing or 3-way taps, patient mobility status, and delirium). A project manager trained and supervised ReNs for protocol compliance and audited study data quality. We considered PIV failure to have occurred if the catheter had complications at removal identified by the ReNs assessment, from medical charts, or by speaking to the patient and beside nurse. We grouped the failures in 1 of 3 types: (1) occlusion or infiltration, defined as blockage, IV fluids moving into surrounding tissue, induration, or swelling greater than 1 cm from the insertion site at or within 24 hours of removal; (2) phlebitis, defined as per clinicians’ definitions or one or more of the following signs and symptoms: pain or tenderness scored at 2 or more on a 1 to 10 increasing severity pain scale, or redness or a palpable cord (either extending greater than 1 cm from the insertion site) at or within 24 hours of PIV removal; and (3) dislodgement (partial or complete). If multiple complications were present, all were recorded.

Statistical Analysis

Data were downloaded from REDcap to Stata 14.2 (StataCorp., College Station, TX) for data management and analysis. Missing data were not imputed. Nominal data observations were collapsed into a single observation per device. Patient and device variables were described as frequencies and proportions, means and standard deviations, or medians and interquartile ranges. Failure incidence rates were calculated, and a Kaplan-Meier survival curve was plotted. In general, Cox proportional hazards models were fitted (Efron method) to handle tied failures (clustering by patient). Variables significant at P < 0.20 on univariable analyses were subjected to multivariable regression. Generally, the largest category was set as referent. Correlations between variables were checked (Spearman’s rank for binary variables, R-squared value of linear regressions for continuous/categorical or continuous/continuous variables). Correlations were considered significant if r > 0.5 and the lower bound of the 95% confidence interval (CI) was >0.5 (where calculated). Covariate interactions were explored, and effects at P < 0.05 noted. The 4 steps of multivariable model building were (1) baseline covariates only with manual stepwise removal of covariates at P ≥ 0.05, (2) treatment covariates only with manual stepwise removal of covariates at P ≥ 0.05, (3) a combination of the derived models from (1) and (2) and manual stepwise removal of covariates at P ≥ 0.05, and (4) manual stepwise addition and removal (at P ≥ 0.05) of variables dropped during the previous steps and interaction testing. Final models were checked as follows: global proportional-hazards assumption test, concordance probability (that predictions and outcomes were in agreement), and Nelson-Aalen cumulative hazard function plotted against the Cox-Snell residuals.

Patient Characteristics

In total, 1000 patients with 1578 PIVs were recruited. The average age was 54 years and the majority were surgical patients (673; 67%). Almost half of patients (455; 46%) had 2 or more comorbidities, and 334 (33%) were obese (body mass index greater than 30). Sample characteristics are shown by the type of catheter failure in Table 1.

PIV Characteristics

All 1578 PIVs were followed until removal, with only 7 PIVs (0.44%) having missing data for the 3 outcomes of interest (these were coded as nonfailures for analysis). Sixty percent of participants had more than 1 PIV followed in the study. Doctors and physicians inserted 1278 (83%) catheters. A total of 550 (35%) were placed in the ward, with 428 (28%) inserted in the emergency department or ambulance. A third of the catheters (540; 34%) were 18-gauge or larger in diameter, and 1000 (64%) were located in the cubital fossa or hand. Multiple insertion attempts were required to place 315 (23%) PIVs. No PIVs were inserted with ultrasound, as this is rarely used in this hospital. The flushing policy was for the administration of 9% sodium chloride every 8 hours if no IV medications or fluids were ordered. Table 2 contains further details of device-related characteristics. Although the hospital policy was for catheter removal by 72 hours, dwell time ranged from <1 to 14 days, with an average of 2.4 days.

PIV Complications

Catheter failure (any cause) occurred in 512 (32%) catheters, which is a failure rate of 136 per 1000 catheter days (95% CI, 125-148). A total of 346 patients out of 1000 (35%) had at least 1 failed PIV during the study. Failures were 267 phlebitis (17%), 228 occlusion/infiltration (14%), and/or 154 dislodgement (10%; Figure), with some PIVs exhibiting multiple concurrent complications (Table 2).

Multivariable AnalysisOcclusion/Infiltration

The multivariable analysis (Table 3) showed occlusion or infiltration was statistically significantly associated with female patients (hazard ratio [HR], 1.48; 95% CI, 1.10-2.00), with a 22-gauge catheter (HR, 1.43; 95% CI, 1.02-2.00), IV flucloxacillin (HR, 1.98; 95% CI, 1.19-3.31), and with frequent PIV access (HR, 1.12; 95% CI, 1.04-1.21; ie, with each increase of 1 in the mean medications/fluids administrations per day, relative PIV failure increased 112%). Less occlusion and infiltration were statistically significantly associated with securement by using additional nonsterile tape (HR, 0.46; 95% CI, 0.33-0.63), elasticized tubular bandages (HR, 0.49; 95% CI, 0.35-0.70 ), or other types of additional securement for the PIV (HR, 0.35; 95% CI, 0.26-0.47).

Phlebitis

Phlebitis was statistically significantly associated with female patients (HR, 1.81; 95% CI, 1.40-2.35), bruising at the insertion site (HR, 2.16; 95% CI, 1.26-3.71), insertion in patients’ dominant side (HR, 1.39; 95% CI, 1.09-1.77), IV flucloxicillin (HR, 2.01; 95% CI, 1.26-3.21), or with frequent PIV access (HR, 1.14; 95% CI, 1.08-1.21). Older age, (HR, 0.99; 95% CI, 0.98-0.99; ie, each year older was associated with 1% less phlebitis), securement with additional nonsterile tape (HR, 0.63; 95% CI, 0.48-0.82) or with any other additional securement (HR, 0.53; 95% CI, 0.39-0.70), or the administration of IV cephazolin (HR, 0.63; 95% CI, 0.44-0.89) were associated with lower phlebitis risk.

Dislodgement

Statistically significant predictors associated with an increased risk of PIV dislodgement included paramedic insertion (HR, 1.78; 95% CI, 1.03-3.06) and frequent PIV access (HR, 1.11; 95% CI, 1.03-1.20). A decreased risk was associated with the additional securement of the PIV, including nonsterile tape (HR, 0.44; 95% CI, 0.31-0.63) or other forms of additional securement (HR, 0.32; 95% CI, 0.22-0.46).

One in 3 PIVs failed in this study, with phlebitis as the most common cause of PIV failure. The 17% phlebitis rate reflected clinician-reported phlebitis or phlebitis observed by research staff using a 1-criteria definition because any sign or symptom can trigger PIV removal (eg, pain), even if other signs or symptoms are not present. Reported phlebitis rates are lower if definitions require 2 signs or symptoms.^4,6 With over 71 different phlebitis assessment scales in use, and none well validated, the best method for diagnosing phlebitis remains unclear and explains the variation in reported rates.²⁵ Occlusion/infiltration and dislodgement were also highly prevalent forms of PIV failure at 14% and 10%, respectively. Occlusion and infiltration were combined because clinical staff use these terms interchangeably, and differential diagnostic tools are not used in practice. Both result in the same outcome (therapy interruption and PIV removal), and this combination of outcomes has been used previously.²³ No PIV-associated bloodstream infections occurred, despite the heightened awareness of these infections in the literature.³

Females had significantly more occlusion/infiltration and phlebitis than males, in keeping with previous studies.^7,9,10 This could be because of females’ smaller vein caliber, although the effect remained after adjustment for PIV gauge.^7,26 The effect of aging on vascular endothelium and structural integrity may explain the observed decrease in phlebitis of 1% with each older year of age.²⁷ However, gender and age effects could be explained by psychosocial factors (eg, older people may be less likely to admit pain, or we may question them less sympathetically), but, regardless, women and younger patients should be monitored more closely.

We found 22-gauge catheters were more likely to fail from occlusion/infiltration than other sizes. This confirms similar findings from Abolfotouh et al.⁹ PIV gauge selection for this study was made at the inserter’s discretion and may be confounded by smaller vein size, which was not measured. In addition, risk may be because of smaller gauge alone or also more influenced by the shorter length of the studied 22-gauge (25 mm) than the <20-gauge catheters (30 mm). These results question international guidelines, which currently recommend the smallest gauge peripheral catheter possible,^28,29 and randomized trials are needed. Although practice varies between inserters, some preferentially cannulate the nondominant limb. We are not aware of previous studies on this practice; however, our results support this approach.

Flucloxacillin was associated with a 2-fold increase in occlusion/infiltration and phlebitis. Although multiple studies have reported IV medications^9,11 and IV antibiotics^10,30,31 as risk factors for PIV failure, none have identified flucloxacillin as an independent risk factor. IV flucloxacillin is recommended for reconstitution as 1 g in 15 mL to 20 mL of sterile water, and injection over 3 to 4 minutes, although this may not be adhered to in practice. Alternative administration regimes or improved adherence to current policy may be needed. An exception to the relationship between IV antibiotics and catheter failure was IV cephazolin, associated with 40% relatively less phlebitis. This may be a spurious finding because the administration, pH, and osmolality of cephazolin are similar to other IV antibiotics.

The more PIVs that were accessed per day, whether for infusions or medications, the more failure occurred from occlusion/infiltration, phlebitis, and dislodgement. This suggests that peripheral veins are easily damaged and/or inflamed by the influx of fluids or medications. Lower injection pressures or the timely transfer to oral medications may limit this problem. Flushing regimens may also assist because practice varies greatly, and questions on whether slow continuous flush infusion or intermittent manual flushing are more vein-protective, and the optimal flush volume, frequency, and technique (eg, pulsatile) remain.^32,33 Manual handling for frequent access may loosen dressings and securement, thus explaining the observed association between frequent access and catheter dislodgement. Finally, the association between use and failure may indicate that many of these patients were not suitable for a PIV, and different approaches (eg, ultrasound-guided insertion) or a midline may have been a superior option. There is growing emphasis on the need for better preinsertion assessment and selection of the most appropriate device for the patient and the IV treatment required.³⁴

Suboptimal dressings or securements are not unusual in hospitals.³⁵ Despite our policy of PIV securement with bordered transparent dressings, we found 4 dressing types in use. In addition, we found almost 50% of PIVs had an additional (secondary) securement, and this was associated with significantly less PIV failure of all 3 types. This suggests that 1 or more of nonsterile tape, elasticized tubular bandages, or other securement (eg, bandage or second transparent dressing) can reduce PIV failure, although a randomized trial is lacking.³⁶ Whether the dressing was failing and required reinforcement or hospital staff lacked confidence in the dressing and placed additional securement preventatively is unclear. Both PIV failure and PIV dressing failure are common, and further research into superior PIV products and practices is urgently needed. Paramedic insertions had a higher risk of dislodgement, suggesting that the increased emphasis on securement should start in the prehospital setting.

While multiple or difficult insertion attempts were not associated with PIV failure, insertions were not directly observed, and clinicians may have underreported attempts. In contrast, insertion-related bruising (a surrogate for difficult insertion) was associated with more than double the incidence of phlebitis. The long-term implications of multiple insertion attempts on patient’s vasculature are unclear, but we believe first time PIV insertion is important to patients and of interest to clinicians. A recent systematic review of strategies associated with first attempt PIV insertion success in an emergency department found little evidence for effective strategies and recommended further research.³⁷

The overall PIV failure rate in our study was 32%, lower than the 35% to 40% failure observed in our previous randomized controlled trials, which had more stringent inclusion and exclusion criteria (eg, longer predicted duration of therapy).^6,38 The implications for patients and costs to the organization of frequent catheter replacement demonstrate urgent need for further research in this area of practice.³⁹ A strength of this study is that all PIVs, regardless of the expected length of dwell time or reason for insertion, were eligible for inclusion, providing more generalizable results. The PIV failure rate of 32% is concerning because these failures trigger treatment delays and replacement insertions, with significant increased labor and equipment costs. The mean cost of PIV replacement has been costed at AUD $69.30 or US $51.92 (as per 2010 $ value) per episode of IV treatment.⁴⁰ For our hospital, which uses 200,000 PIVs per year, the current level of PIV failure suggests almost AU $5.5 (US $4.1) million in waste annually at this site alone.

The additional strengths of this study include the extensive information collected prospectively about PIV insertion and maintenance, including information on who inserted the PIV, IV medications administered, and PIV dressings used. Limitations were the population of surgical and medical patients in 1 tertiary hospital, which may not be generalizable to other settings.

Our study confirms the high rate of catheter failure in acute care hospitals, validates existing evidence related to PIV failure, and identifies new, potentially modifiable risk factors to improve PIV insertion and management. Implications for future research were also identified.

Acknowledgments

The researchers acknowledge and thank the nurses and patients involved in this study. The authors would also like to acknowledge Becton Dickinson for partly funding this study in the form of an unrestricted grant-in-aid paid to Griffith University. Becton Dickinson did not design the study protocol, collect or analyze data, and did not prepare or review the manuscript.

Disclosure

 On behalf of NM and CMR, Griffith University has received unrestricted educational and research grants and consultancy payment for lectures from 3M and Becton Dickinson. On behalf of NM, MC, and CMR, Griffith University has received unrestricted investigator-initiated research grants from Centurion Medical Products and Entrotech Lifesciences (manufacturers of PIV dressings) and Becton Dickinson (manufacturer of PIVs). On behalf of MC, Griffith University has received a consultancy payment to develop education material from Baxter. On behalf of CMR, Griffith University has received unrestricted donations or investigator initiated research grants unrelated to this research from Adhezion, Angiodynamics, Baxter, Carefusion, Cook Medical, Hospira, Mayo, Smiths Medical, and Vygon. On behalf of CMR, Griffith University has received consultancy payments for educational lectures or professional opinion from B. Braun, Bard, Carefusion, Mayo, ResQDevices, and Smiths Medical. On behalf of EL, Griffith University has received consultancy payments for educational lecture from 3M. On behalf of MC, Griffith University has received a consultancy payment to develop education material from Baxter. As this was an observational study, no products were trialed in this study. JW and GM have no conflicts of interest.

Peripheral intravenous catheter (PIV) insertion is the fastest, simplest, and most cost-effective method to gain vascular access, and it is used for short-term intravenous (IV) fluids, medications, blood products, and contrast media.¹ It is the most common invasive device in hospitalized patients,² with up to 70% of hospital patients receiving a PIV.³ Unacceptable PIV failure rates have been reported as high as 69%.^4-7 Failure is most frequently due to phlebitis (vein wall irritation/inflammation), occlusion (blockage), infiltration or extravasation (IV fluids/vesicant therapy entering surrounding tissue), partial dislodgement or accidental removal, leakage, and infection.^4,6,8 These failures have important implications for patients, who endure the discomfort of PIV complications and catheter replacements, and healthcare staff and budgets.

To reduce the incidence of catheter failure and avoid preventable PIV replacements, a clear understanding of why catheters fail is required. Previous research has identified that catheter gauge,^9-11 insertion site,^12-14 and inserter skill^10,15 have an impact on PIV failure. Limitations of existing research are small study sizes,^16-18 retrospective design,¹⁹ or secondary analysis of an existing data set; all potentially introduce sampling bias.^10,20

To overcome these potential biases, we developed a data collection instrument based on the catheter-associated risk factors described in the literature,^9-11,13 and other potential insertion and maintenance risks for PIV failure (eg, multiple insertion attempts, medications administered), with data collected prospectively. The study aim was to improve patient outcomes by identifying PIV insertion and maintenance risk factors amenable to modification through education or alternative clinical interventions, such as catheter gauge selection or insertion site.

Study Design and Participants

We conducted this prospective cohort study in a large tertiary hospital in Queensland, Australia. Ethics committee approval was obtained from the hospital (HREC/14/QRBW/76) and Griffith University (NRS/26/14/HREC). The study was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000738527). Patients in medical and surgical wards were screened Monday, Wednesday, and Friday between October 2014 and December 2015. Patients over 18 years with a PIV (BD Insyte^TM Autoguard^TM BC; Becton Dickinson, Franklin Lakes, NJ) inserted within 24 hours, and who were able to provide written informed consent, were eligible and recruited sequentially. Patients classified as palliative by the treating clinical team were excluded.

Sample Size Calculation

The “10 events per variable” rule was used to determine the sample size required to study 50 potential risk factors.^21,22 This determined that 1000 patients, with an average of 1.5 PIVs each and an expected PIV failure of 30% (500 events), were required.

Data Collection

At recruitment, baseline patient information was collected by a research nurse (ReNs) (demographics, admitting diagnosis, comorbidities, skin type,²³ and vein condition) and entered into an electronic data platform supported by Research Electronic Data Capture (REDCap).²⁴ Baseline data also included catheter variables (eg, gauge, insertion site, catheterized vein) and insertion details (eg, department of insertion, inserting clinician, number of insertion attempts). We included every PIV the participant had during their admission until hospital discharge or insertion of a central venous access device. PIV sites were reviewed Monday, Wednesday, and Friday by ReNs for site complications (eg, redness, pain, swelling, palpable cord). Potential risk factors for failure were also recorded (eg, infusates and additives, antibiotic type and dosage, flushing regimen, number of times the PIV was accessed each day for administration of IV medications or fluids, dressing type and condition, securement method for the catheter and tubing, presence of extension tubing or 3-way taps, patient mobility status, and delirium). A project manager trained and supervised ReNs for protocol compliance and audited study data quality. We considered PIV failure to have occurred if the catheter had complications at removal identified by the ReNs assessment, from medical charts, or by speaking to the patient and beside nurse. We grouped the failures in 1 of 3 types: (1) occlusion or infiltration, defined as blockage, IV fluids moving into surrounding tissue, induration, or swelling greater than 1 cm from the insertion site at or within 24 hours of removal; (2) phlebitis, defined as per clinicians’ definitions or one or more of the following signs and symptoms: pain or tenderness scored at 2 or more on a 1 to 10 increasing severity pain scale, or redness or a palpable cord (either extending greater than 1 cm from the insertion site) at or within 24 hours of PIV removal; and (3) dislodgement (partial or complete). If multiple complications were present, all were recorded.

Statistical Analysis

Data were downloaded from REDcap to Stata 14.2 (StataCorp., College Station, TX) for data management and analysis. Missing data were not imputed. Nominal data observations were collapsed into a single observation per device. Patient and device variables were described as frequencies and proportions, means and standard deviations, or medians and interquartile ranges. Failure incidence rates were calculated, and a Kaplan-Meier survival curve was plotted. In general, Cox proportional hazards models were fitted (Efron method) to handle tied failures (clustering by patient). Variables significant at P < 0.20 on univariable analyses were subjected to multivariable regression. Generally, the largest category was set as referent. Correlations between variables were checked (Spearman’s rank for binary variables, R-squared value of linear regressions for continuous/categorical or continuous/continuous variables). Correlations were considered significant if r > 0.5 and the lower bound of the 95% confidence interval (CI) was >0.5 (where calculated). Covariate interactions were explored, and effects at P < 0.05 noted. The 4 steps of multivariable model building were (1) baseline covariates only with manual stepwise removal of covariates at P ≥ 0.05, (2) treatment covariates only with manual stepwise removal of covariates at P ≥ 0.05, (3) a combination of the derived models from (1) and (2) and manual stepwise removal of covariates at P ≥ 0.05, and (4) manual stepwise addition and removal (at P ≥ 0.05) of variables dropped during the previous steps and interaction testing. Final models were checked as follows: global proportional-hazards assumption test, concordance probability (that predictions and outcomes were in agreement), and Nelson-Aalen cumulative hazard function plotted against the Cox-Snell residuals.

Patient Characteristics

In total, 1000 patients with 1578 PIVs were recruited. The average age was 54 years and the majority were surgical patients (673; 67%). Almost half of patients (455; 46%) had 2 or more comorbidities, and 334 (33%) were obese (body mass index greater than 30). Sample characteristics are shown by the type of catheter failure in Table 1.

PIV Characteristics

All 1578 PIVs were followed until removal, with only 7 PIVs (0.44%) having missing data for the 3 outcomes of interest (these were coded as nonfailures for analysis). Sixty percent of participants had more than 1 PIV followed in the study. Doctors and physicians inserted 1278 (83%) catheters. A total of 550 (35%) were placed in the ward, with 428 (28%) inserted in the emergency department or ambulance. A third of the catheters (540; 34%) were 18-gauge or larger in diameter, and 1000 (64%) were located in the cubital fossa or hand. Multiple insertion attempts were required to place 315 (23%) PIVs. No PIVs were inserted with ultrasound, as this is rarely used in this hospital. The flushing policy was for the administration of 9% sodium chloride every 8 hours if no IV medications or fluids were ordered. Table 2 contains further details of device-related characteristics. Although the hospital policy was for catheter removal by 72 hours, dwell time ranged from <1 to 14 days, with an average of 2.4 days.

PIV Complications

Catheter failure (any cause) occurred in 512 (32%) catheters, which is a failure rate of 136 per 1000 catheter days (95% CI, 125-148). A total of 346 patients out of 1000 (35%) had at least 1 failed PIV during the study. Failures were 267 phlebitis (17%), 228 occlusion/infiltration (14%), and/or 154 dislodgement (10%; Figure), with some PIVs exhibiting multiple concurrent complications (Table 2).

Multivariable AnalysisOcclusion/Infiltration

The multivariable analysis (Table 3) showed occlusion or infiltration was statistically significantly associated with female patients (hazard ratio [HR], 1.48; 95% CI, 1.10-2.00), with a 22-gauge catheter (HR, 1.43; 95% CI, 1.02-2.00), IV flucloxacillin (HR, 1.98; 95% CI, 1.19-3.31), and with frequent PIV access (HR, 1.12; 95% CI, 1.04-1.21; ie, with each increase of 1 in the mean medications/fluids administrations per day, relative PIV failure increased 112%). Less occlusion and infiltration were statistically significantly associated with securement by using additional nonsterile tape (HR, 0.46; 95% CI, 0.33-0.63), elasticized tubular bandages (HR, 0.49; 95% CI, 0.35-0.70 ), or other types of additional securement for the PIV (HR, 0.35; 95% CI, 0.26-0.47).

Phlebitis

Phlebitis was statistically significantly associated with female patients (HR, 1.81; 95% CI, 1.40-2.35), bruising at the insertion site (HR, 2.16; 95% CI, 1.26-3.71), insertion in patients’ dominant side (HR, 1.39; 95% CI, 1.09-1.77), IV flucloxicillin (HR, 2.01; 95% CI, 1.26-3.21), or with frequent PIV access (HR, 1.14; 95% CI, 1.08-1.21). Older age, (HR, 0.99; 95% CI, 0.98-0.99; ie, each year older was associated with 1% less phlebitis), securement with additional nonsterile tape (HR, 0.63; 95% CI, 0.48-0.82) or with any other additional securement (HR, 0.53; 95% CI, 0.39-0.70), or the administration of IV cephazolin (HR, 0.63; 95% CI, 0.44-0.89) were associated with lower phlebitis risk.

Dislodgement

Statistically significant predictors associated with an increased risk of PIV dislodgement included paramedic insertion (HR, 1.78; 95% CI, 1.03-3.06) and frequent PIV access (HR, 1.11; 95% CI, 1.03-1.20). A decreased risk was associated with the additional securement of the PIV, including nonsterile tape (HR, 0.44; 95% CI, 0.31-0.63) or other forms of additional securement (HR, 0.32; 95% CI, 0.22-0.46).

One in 3 PIVs failed in this study, with phlebitis as the most common cause of PIV failure. The 17% phlebitis rate reflected clinician-reported phlebitis or phlebitis observed by research staff using a 1-criteria definition because any sign or symptom can trigger PIV removal (eg, pain), even if other signs or symptoms are not present. Reported phlebitis rates are lower if definitions require 2 signs or symptoms.^4,6 With over 71 different phlebitis assessment scales in use, and none well validated, the best method for diagnosing phlebitis remains unclear and explains the variation in reported rates.²⁵ Occlusion/infiltration and dislodgement were also highly prevalent forms of PIV failure at 14% and 10%, respectively. Occlusion and infiltration were combined because clinical staff use these terms interchangeably, and differential diagnostic tools are not used in practice. Both result in the same outcome (therapy interruption and PIV removal), and this combination of outcomes has been used previously.²³ No PIV-associated bloodstream infections occurred, despite the heightened awareness of these infections in the literature.³

Females had significantly more occlusion/infiltration and phlebitis than males, in keeping with previous studies.^7,9,10 This could be because of females’ smaller vein caliber, although the effect remained after adjustment for PIV gauge.^7,26 The effect of aging on vascular endothelium and structural integrity may explain the observed decrease in phlebitis of 1% with each older year of age.²⁷ However, gender and age effects could be explained by psychosocial factors (eg, older people may be less likely to admit pain, or we may question them less sympathetically), but, regardless, women and younger patients should be monitored more closely.

We found 22-gauge catheters were more likely to fail from occlusion/infiltration than other sizes. This confirms similar findings from Abolfotouh et al.⁹ PIV gauge selection for this study was made at the inserter’s discretion and may be confounded by smaller vein size, which was not measured. In addition, risk may be because of smaller gauge alone or also more influenced by the shorter length of the studied 22-gauge (25 mm) than the <20-gauge catheters (30 mm). These results question international guidelines, which currently recommend the smallest gauge peripheral catheter possible,^28,29 and randomized trials are needed. Although practice varies between inserters, some preferentially cannulate the nondominant limb. We are not aware of previous studies on this practice; however, our results support this approach.

Flucloxacillin was associated with a 2-fold increase in occlusion/infiltration and phlebitis. Although multiple studies have reported IV medications^9,11 and IV antibiotics^10,30,31 as risk factors for PIV failure, none have identified flucloxacillin as an independent risk factor. IV flucloxacillin is recommended for reconstitution as 1 g in 15 mL to 20 mL of sterile water, and injection over 3 to 4 minutes, although this may not be adhered to in practice. Alternative administration regimes or improved adherence to current policy may be needed. An exception to the relationship between IV antibiotics and catheter failure was IV cephazolin, associated with 40% relatively less phlebitis. This may be a spurious finding because the administration, pH, and osmolality of cephazolin are similar to other IV antibiotics.

The more PIVs that were accessed per day, whether for infusions or medications, the more failure occurred from occlusion/infiltration, phlebitis, and dislodgement. This suggests that peripheral veins are easily damaged and/or inflamed by the influx of fluids or medications. Lower injection pressures or the timely transfer to oral medications may limit this problem. Flushing regimens may also assist because practice varies greatly, and questions on whether slow continuous flush infusion or intermittent manual flushing are more vein-protective, and the optimal flush volume, frequency, and technique (eg, pulsatile) remain.^32,33 Manual handling for frequent access may loosen dressings and securement, thus explaining the observed association between frequent access and catheter dislodgement. Finally, the association between use and failure may indicate that many of these patients were not suitable for a PIV, and different approaches (eg, ultrasound-guided insertion) or a midline may have been a superior option. There is growing emphasis on the need for better preinsertion assessment and selection of the most appropriate device for the patient and the IV treatment required.³⁴

Suboptimal dressings or securements are not unusual in hospitals.³⁵ Despite our policy of PIV securement with bordered transparent dressings, we found 4 dressing types in use. In addition, we found almost 50% of PIVs had an additional (secondary) securement, and this was associated with significantly less PIV failure of all 3 types. This suggests that 1 or more of nonsterile tape, elasticized tubular bandages, or other securement (eg, bandage or second transparent dressing) can reduce PIV failure, although a randomized trial is lacking.³⁶ Whether the dressing was failing and required reinforcement or hospital staff lacked confidence in the dressing and placed additional securement preventatively is unclear. Both PIV failure and PIV dressing failure are common, and further research into superior PIV products and practices is urgently needed. Paramedic insertions had a higher risk of dislodgement, suggesting that the increased emphasis on securement should start in the prehospital setting.

While multiple or difficult insertion attempts were not associated with PIV failure, insertions were not directly observed, and clinicians may have underreported attempts. In contrast, insertion-related bruising (a surrogate for difficult insertion) was associated with more than double the incidence of phlebitis. The long-term implications of multiple insertion attempts on patient’s vasculature are unclear, but we believe first time PIV insertion is important to patients and of interest to clinicians. A recent systematic review of strategies associated with first attempt PIV insertion success in an emergency department found little evidence for effective strategies and recommended further research.³⁷

The overall PIV failure rate in our study was 32%, lower than the 35% to 40% failure observed in our previous randomized controlled trials, which had more stringent inclusion and exclusion criteria (eg, longer predicted duration of therapy).^6,38 The implications for patients and costs to the organization of frequent catheter replacement demonstrate urgent need for further research in this area of practice.³⁹ A strength of this study is that all PIVs, regardless of the expected length of dwell time or reason for insertion, were eligible for inclusion, providing more generalizable results. The PIV failure rate of 32% is concerning because these failures trigger treatment delays and replacement insertions, with significant increased labor and equipment costs. The mean cost of PIV replacement has been costed at AUD $69.30 or US $51.92 (as per 2010 $ value) per episode of IV treatment.⁴⁰ For our hospital, which uses 200,000 PIVs per year, the current level of PIV failure suggests almost AU $5.5 (US $4.1) million in waste annually at this site alone.

The additional strengths of this study include the extensive information collected prospectively about PIV insertion and maintenance, including information on who inserted the PIV, IV medications administered, and PIV dressings used. Limitations were the population of surgical and medical patients in 1 tertiary hospital, which may not be generalizable to other settings.

Our study confirms the high rate of catheter failure in acute care hospitals, validates existing evidence related to PIV failure, and identifies new, potentially modifiable risk factors to improve PIV insertion and management. Implications for future research were also identified.

Acknowledgments

The researchers acknowledge and thank the nurses and patients involved in this study. The authors would also like to acknowledge Becton Dickinson for partly funding this study in the form of an unrestricted grant-in-aid paid to Griffith University. Becton Dickinson did not design the study protocol, collect or analyze data, and did not prepare or review the manuscript.

Disclosure

 On behalf of NM and CMR, Griffith University has received unrestricted educational and research grants and consultancy payment for lectures from 3M and Becton Dickinson. On behalf of NM, MC, and CMR, Griffith University has received unrestricted investigator-initiated research grants from Centurion Medical Products and Entrotech Lifesciences (manufacturers of PIV dressings) and Becton Dickinson (manufacturer of PIVs). On behalf of MC, Griffith University has received a consultancy payment to develop education material from Baxter. On behalf of CMR, Griffith University has received unrestricted donations or investigator initiated research grants unrelated to this research from Adhezion, Angiodynamics, Baxter, Carefusion, Cook Medical, Hospira, Mayo, Smiths Medical, and Vygon. On behalf of CMR, Griffith University has received consultancy payments for educational lectures or professional opinion from B. Braun, Bard, Carefusion, Mayo, ResQDevices, and Smiths Medical. On behalf of EL, Griffith University has received consultancy payments for educational lecture from 3M. On behalf of MC, Griffith University has received a consultancy payment to develop education material from Baxter. As this was an observational study, no products were trialed in this study. JW and GM have no conflicts of interest.

Peripheral intravenous catheter (PIV) insertion is the fastest, simplest, and most cost-effective method to gain vascular access, and it is used for short-term intravenous (IV) fluids, medications, blood products, and contrast media.¹ It is the most common invasive device in hospitalized patients,² with up to 70% of hospital patients receiving a PIV.³ Unacceptable PIV failure rates have been reported as high as 69%.^4-7 Failure is most frequently due to phlebitis (vein wall irritation/inflammation), occlusion (blockage), infiltration or extravasation (IV fluids/vesicant therapy entering surrounding tissue), partial dislodgement or accidental removal, leakage, and infection.^4,6,8 These failures have important implications for patients, who endure the discomfort of PIV complications and catheter replacements, and healthcare staff and budgets.

To reduce the incidence of catheter failure and avoid preventable PIV replacements, a clear understanding of why catheters fail is required. Previous research has identified that catheter gauge,^9-11 insertion site,^12-14 and inserter skill^10,15 have an impact on PIV failure. Limitations of existing research are small study sizes,^16-18 retrospective design,¹⁹ or secondary analysis of an existing data set; all potentially introduce sampling bias.^10,20

To overcome these potential biases, we developed a data collection instrument based on the catheter-associated risk factors described in the literature,^9-11,13 and other potential insertion and maintenance risks for PIV failure (eg, multiple insertion attempts, medications administered), with data collected prospectively. The study aim was to improve patient outcomes by identifying PIV insertion and maintenance risk factors amenable to modification through education or alternative clinical interventions, such as catheter gauge selection or insertion site.

Study Design and Participants

We conducted this prospective cohort study in a large tertiary hospital in Queensland, Australia. Ethics committee approval was obtained from the hospital (HREC/14/QRBW/76) and Griffith University (NRS/26/14/HREC). The study was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000738527). Patients in medical and surgical wards were screened Monday, Wednesday, and Friday between October 2014 and December 2015. Patients over 18 years with a PIV (BD Insyte^TM Autoguard^TM BC; Becton Dickinson, Franklin Lakes, NJ) inserted within 24 hours, and who were able to provide written informed consent, were eligible and recruited sequentially. Patients classified as palliative by the treating clinical team were excluded.

Sample Size Calculation

The “10 events per variable” rule was used to determine the sample size required to study 50 potential risk factors.^21,22 This determined that 1000 patients, with an average of 1.5 PIVs each and an expected PIV failure of 30% (500 events), were required.

Data Collection

At recruitment, baseline patient information was collected by a research nurse (ReNs) (demographics, admitting diagnosis, comorbidities, skin type,²³ and vein condition) and entered into an electronic data platform supported by Research Electronic Data Capture (REDCap).²⁴ Baseline data also included catheter variables (eg, gauge, insertion site, catheterized vein) and insertion details (eg, department of insertion, inserting clinician, number of insertion attempts). We included every PIV the participant had during their admission until hospital discharge or insertion of a central venous access device. PIV sites were reviewed Monday, Wednesday, and Friday by ReNs for site complications (eg, redness, pain, swelling, palpable cord). Potential risk factors for failure were also recorded (eg, infusates and additives, antibiotic type and dosage, flushing regimen, number of times the PIV was accessed each day for administration of IV medications or fluids, dressing type and condition, securement method for the catheter and tubing, presence of extension tubing or 3-way taps, patient mobility status, and delirium). A project manager trained and supervised ReNs for protocol compliance and audited study data quality. We considered PIV failure to have occurred if the catheter had complications at removal identified by the ReNs assessment, from medical charts, or by speaking to the patient and beside nurse. We grouped the failures in 1 of 3 types: (1) occlusion or infiltration, defined as blockage, IV fluids moving into surrounding tissue, induration, or swelling greater than 1 cm from the insertion site at or within 24 hours of removal; (2) phlebitis, defined as per clinicians’ definitions or one or more of the following signs and symptoms: pain or tenderness scored at 2 or more on a 1 to 10 increasing severity pain scale, or redness or a palpable cord (either extending greater than 1 cm from the insertion site) at or within 24 hours of PIV removal; and (3) dislodgement (partial or complete). If multiple complications were present, all were recorded.

Statistical Analysis

Data were downloaded from REDcap to Stata 14.2 (StataCorp., College Station, TX) for data management and analysis. Missing data were not imputed. Nominal data observations were collapsed into a single observation per device. Patient and device variables were described as frequencies and proportions, means and standard deviations, or medians and interquartile ranges. Failure incidence rates were calculated, and a Kaplan-Meier survival curve was plotted. In general, Cox proportional hazards models were fitted (Efron method) to handle tied failures (clustering by patient). Variables significant at P < 0.20 on univariable analyses were subjected to multivariable regression. Generally, the largest category was set as referent. Correlations between variables were checked (Spearman’s rank for binary variables, R-squared value of linear regressions for continuous/categorical or continuous/continuous variables). Correlations were considered significant if r > 0.5 and the lower bound of the 95% confidence interval (CI) was >0.5 (where calculated). Covariate interactions were explored, and effects at P < 0.05 noted. The 4 steps of multivariable model building were (1) baseline covariates only with manual stepwise removal of covariates at P ≥ 0.05, (2) treatment covariates only with manual stepwise removal of covariates at P ≥ 0.05, (3) a combination of the derived models from (1) and (2) and manual stepwise removal of covariates at P ≥ 0.05, and (4) manual stepwise addition and removal (at P ≥ 0.05) of variables dropped during the previous steps and interaction testing. Final models were checked as follows: global proportional-hazards assumption test, concordance probability (that predictions and outcomes were in agreement), and Nelson-Aalen cumulative hazard function plotted against the Cox-Snell residuals.

Patient Characteristics

In total, 1000 patients with 1578 PIVs were recruited. The average age was 54 years and the majority were surgical patients (673; 67%). Almost half of patients (455; 46%) had 2 or more comorbidities, and 334 (33%) were obese (body mass index greater than 30). Sample characteristics are shown by the type of catheter failure in Table 1.

PIV Characteristics

All 1578 PIVs were followed until removal, with only 7 PIVs (0.44%) having missing data for the 3 outcomes of interest (these were coded as nonfailures for analysis). Sixty percent of participants had more than 1 PIV followed in the study. Doctors and physicians inserted 1278 (83%) catheters. A total of 550 (35%) were placed in the ward, with 428 (28%) inserted in the emergency department or ambulance. A third of the catheters (540; 34%) were 18-gauge or larger in diameter, and 1000 (64%) were located in the cubital fossa or hand. Multiple insertion attempts were required to place 315 (23%) PIVs. No PIVs were inserted with ultrasound, as this is rarely used in this hospital. The flushing policy was for the administration of 9% sodium chloride every 8 hours if no IV medications or fluids were ordered. Table 2 contains further details of device-related characteristics. Although the hospital policy was for catheter removal by 72 hours, dwell time ranged from <1 to 14 days, with an average of 2.4 days.

PIV Complications

Catheter failure (any cause) occurred in 512 (32%) catheters, which is a failure rate of 136 per 1000 catheter days (95% CI, 125-148). A total of 346 patients out of 1000 (35%) had at least 1 failed PIV during the study. Failures were 267 phlebitis (17%), 228 occlusion/infiltration (14%), and/or 154 dislodgement (10%; Figure), with some PIVs exhibiting multiple concurrent complications (Table 2).

Multivariable AnalysisOcclusion/Infiltration

The multivariable analysis (Table 3) showed occlusion or infiltration was statistically significantly associated with female patients (hazard ratio [HR], 1.48; 95% CI, 1.10-2.00), with a 22-gauge catheter (HR, 1.43; 95% CI, 1.02-2.00), IV flucloxacillin (HR, 1.98; 95% CI, 1.19-3.31), and with frequent PIV access (HR, 1.12; 95% CI, 1.04-1.21; ie, with each increase of 1 in the mean medications/fluids administrations per day, relative PIV failure increased 112%). Less occlusion and infiltration were statistically significantly associated with securement by using additional nonsterile tape (HR, 0.46; 95% CI, 0.33-0.63), elasticized tubular bandages (HR, 0.49; 95% CI, 0.35-0.70 ), or other types of additional securement for the PIV (HR, 0.35; 95% CI, 0.26-0.47).

Phlebitis

Phlebitis was statistically significantly associated with female patients (HR, 1.81; 95% CI, 1.40-2.35), bruising at the insertion site (HR, 2.16; 95% CI, 1.26-3.71), insertion in patients’ dominant side (HR, 1.39; 95% CI, 1.09-1.77), IV flucloxicillin (HR, 2.01; 95% CI, 1.26-3.21), or with frequent PIV access (HR, 1.14; 95% CI, 1.08-1.21). Older age, (HR, 0.99; 95% CI, 0.98-0.99; ie, each year older was associated with 1% less phlebitis), securement with additional nonsterile tape (HR, 0.63; 95% CI, 0.48-0.82) or with any other additional securement (HR, 0.53; 95% CI, 0.39-0.70), or the administration of IV cephazolin (HR, 0.63; 95% CI, 0.44-0.89) were associated with lower phlebitis risk.

Dislodgement

Statistically significant predictors associated with an increased risk of PIV dislodgement included paramedic insertion (HR, 1.78; 95% CI, 1.03-3.06) and frequent PIV access (HR, 1.11; 95% CI, 1.03-1.20). A decreased risk was associated with the additional securement of the PIV, including nonsterile tape (HR, 0.44; 95% CI, 0.31-0.63) or other forms of additional securement (HR, 0.32; 95% CI, 0.22-0.46).

One in 3 PIVs failed in this study, with phlebitis as the most common cause of PIV failure. The 17% phlebitis rate reflected clinician-reported phlebitis or phlebitis observed by research staff using a 1-criteria definition because any sign or symptom can trigger PIV removal (eg, pain), even if other signs or symptoms are not present. Reported phlebitis rates are lower if definitions require 2 signs or symptoms.^4,6 With over 71 different phlebitis assessment scales in use, and none well validated, the best method for diagnosing phlebitis remains unclear and explains the variation in reported rates.²⁵ Occlusion/infiltration and dislodgement were also highly prevalent forms of PIV failure at 14% and 10%, respectively. Occlusion and infiltration were combined because clinical staff use these terms interchangeably, and differential diagnostic tools are not used in practice. Both result in the same outcome (therapy interruption and PIV removal), and this combination of outcomes has been used previously.²³ No PIV-associated bloodstream infections occurred, despite the heightened awareness of these infections in the literature.³

Females had significantly more occlusion/infiltration and phlebitis than males, in keeping with previous studies.^7,9,10 This could be because of females’ smaller vein caliber, although the effect remained after adjustment for PIV gauge.^7,26 The effect of aging on vascular endothelium and structural integrity may explain the observed decrease in phlebitis of 1% with each older year of age.²⁷ However, gender and age effects could be explained by psychosocial factors (eg, older people may be less likely to admit pain, or we may question them less sympathetically), but, regardless, women and younger patients should be monitored more closely.

We found 22-gauge catheters were more likely to fail from occlusion/infiltration than other sizes. This confirms similar findings from Abolfotouh et al.⁹ PIV gauge selection for this study was made at the inserter’s discretion and may be confounded by smaller vein size, which was not measured. In addition, risk may be because of smaller gauge alone or also more influenced by the shorter length of the studied 22-gauge (25 mm) than the <20-gauge catheters (30 mm). These results question international guidelines, which currently recommend the smallest gauge peripheral catheter possible,^28,29 and randomized trials are needed. Although practice varies between inserters, some preferentially cannulate the nondominant limb. We are not aware of previous studies on this practice; however, our results support this approach.

Flucloxacillin was associated with a 2-fold increase in occlusion/infiltration and phlebitis. Although multiple studies have reported IV medications^9,11 and IV antibiotics^10,30,31 as risk factors for PIV failure, none have identified flucloxacillin as an independent risk factor. IV flucloxacillin is recommended for reconstitution as 1 g in 15 mL to 20 mL of sterile water, and injection over 3 to 4 minutes, although this may not be adhered to in practice. Alternative administration regimes or improved adherence to current policy may be needed. An exception to the relationship between IV antibiotics and catheter failure was IV cephazolin, associated with 40% relatively less phlebitis. This may be a spurious finding because the administration, pH, and osmolality of cephazolin are similar to other IV antibiotics.

The more PIVs that were accessed per day, whether for infusions or medications, the more failure occurred from occlusion/infiltration, phlebitis, and dislodgement. This suggests that peripheral veins are easily damaged and/or inflamed by the influx of fluids or medications. Lower injection pressures or the timely transfer to oral medications may limit this problem. Flushing regimens may also assist because practice varies greatly, and questions on whether slow continuous flush infusion or intermittent manual flushing are more vein-protective, and the optimal flush volume, frequency, and technique (eg, pulsatile) remain.^32,33 Manual handling for frequent access may loosen dressings and securement, thus explaining the observed association between frequent access and catheter dislodgement. Finally, the association between use and failure may indicate that many of these patients were not suitable for a PIV, and different approaches (eg, ultrasound-guided insertion) or a midline may have been a superior option. There is growing emphasis on the need for better preinsertion assessment and selection of the most appropriate device for the patient and the IV treatment required.³⁴

Suboptimal dressings or securements are not unusual in hospitals.³⁵ Despite our policy of PIV securement with bordered transparent dressings, we found 4 dressing types in use. In addition, we found almost 50% of PIVs had an additional (secondary) securement, and this was associated with significantly less PIV failure of all 3 types. This suggests that 1 or more of nonsterile tape, elasticized tubular bandages, or other securement (eg, bandage or second transparent dressing) can reduce PIV failure, although a randomized trial is lacking.³⁶ Whether the dressing was failing and required reinforcement or hospital staff lacked confidence in the dressing and placed additional securement preventatively is unclear. Both PIV failure and PIV dressing failure are common, and further research into superior PIV products and practices is urgently needed. Paramedic insertions had a higher risk of dislodgement, suggesting that the increased emphasis on securement should start in the prehospital setting.

While multiple or difficult insertion attempts were not associated with PIV failure, insertions were not directly observed, and clinicians may have underreported attempts. In contrast, insertion-related bruising (a surrogate for difficult insertion) was associated with more than double the incidence of phlebitis. The long-term implications of multiple insertion attempts on patient’s vasculature are unclear, but we believe first time PIV insertion is important to patients and of interest to clinicians. A recent systematic review of strategies associated with first attempt PIV insertion success in an emergency department found little evidence for effective strategies and recommended further research.³⁷

The overall PIV failure rate in our study was 32%, lower than the 35% to 40% failure observed in our previous randomized controlled trials, which had more stringent inclusion and exclusion criteria (eg, longer predicted duration of therapy).^6,38 The implications for patients and costs to the organization of frequent catheter replacement demonstrate urgent need for further research in this area of practice.³⁹ A strength of this study is that all PIVs, regardless of the expected length of dwell time or reason for insertion, were eligible for inclusion, providing more generalizable results. The PIV failure rate of 32% is concerning because these failures trigger treatment delays and replacement insertions, with significant increased labor and equipment costs. The mean cost of PIV replacement has been costed at AUD $69.30 or US $51.92 (as per 2010 $ value) per episode of IV treatment.⁴⁰ For our hospital, which uses 200,000 PIVs per year, the current level of PIV failure suggests almost AU $5.5 (US $4.1) million in waste annually at this site alone.

The additional strengths of this study include the extensive information collected prospectively about PIV insertion and maintenance, including information on who inserted the PIV, IV medications administered, and PIV dressings used. Limitations were the population of surgical and medical patients in 1 tertiary hospital, which may not be generalizable to other settings.

Our study confirms the high rate of catheter failure in acute care hospitals, validates existing evidence related to PIV failure, and identifies new, potentially modifiable risk factors to improve PIV insertion and management. Implications for future research were also identified.

Acknowledgments

The researchers acknowledge and thank the nurses and patients involved in this study. The authors would also like to acknowledge Becton Dickinson for partly funding this study in the form of an unrestricted grant-in-aid paid to Griffith University. Becton Dickinson did not design the study protocol, collect or analyze data, and did not prepare or review the manuscript.

Disclosure

 On behalf of NM and CMR, Griffith University has received unrestricted educational and research grants and consultancy payment for lectures from 3M and Becton Dickinson. On behalf of NM, MC, and CMR, Griffith University has received unrestricted investigator-initiated research grants from Centurion Medical Products and Entrotech Lifesciences (manufacturers of PIV dressings) and Becton Dickinson (manufacturer of PIVs). On behalf of MC, Griffith University has received a consultancy payment to develop education material from Baxter. On behalf of CMR, Griffith University has received unrestricted donations or investigator initiated research grants unrelated to this research from Adhezion, Angiodynamics, Baxter, Carefusion, Cook Medical, Hospira, Mayo, Smiths Medical, and Vygon. On behalf of CMR, Griffith University has received consultancy payments for educational lectures or professional opinion from B. Braun, Bard, Carefusion, Mayo, ResQDevices, and Smiths Medical. On behalf of EL, Griffith University has received consultancy payments for educational lecture from 3M. On behalf of MC, Griffith University has received a consultancy payment to develop education material from Baxter. As this was an observational study, no products were trialed in this study. JW and GM have no conflicts of interest.

The United States is facing an epidemic of prescription opioid and heroin use, which has been linked to the escalating prescribing of opioid analgesics. Though opioid prescriptions appear to be reaching a plateau, estimates suggest there are at least 900,000 active heroin users in the United States, and this number continues to grow.¹ One response to this epidemic (through state legislation and medical society guidelines) has been a move to reduce opioid prescribing in order to diminish the potential for diversion and misuse.² However, the treatment of pain is not the sole driver of heroin epidemiology, and new strategies are also needed to better engage patients with existing opioid use disorders (OUDs) to begin treatment. These patients are increasingly hospitalized for infectious comorbidities of injection drug use, trauma, or pregnancy, and this may present a unique opportunity to initiate these patients on maintenance opioid agonist therapy, the most effective option for medication-assisted treatment (MAT) for addiction.

Patients with OUDs comprise an estimated 2% to 4% of hospitalized patients, representing a disproportionately large number of inpatients.^3-6 According to a recent analysis of data from the National (Nationwide) Inpatient Sample, the estimated annual number of hospitalizations associated with OUDs in the United States increased from approximately 300,000 to more than 500,000 in the decade from 2002 to 2012.⁷ Severe bacterial infections associated with intravenous administration of opioids (including endocarditis, osteomyelitis, septic arthritis, and epidural abscess) increased substantially at an estimated cost of more than $700 million in 2012.⁷ Over a similar period, the prevalence of opioid use among women in labor increased from 13.7 to 22.0 per 10,000 live births,⁸ and there was a corresponding rise in admissions to neonatal intensive care units for neonatal abstinence syndrome.⁹ As the prevalence of prescription drug and heroin dependence continues to rise across the United States, hospitals and clinicians find themselves on the front lines of this epidemic, creating potential opportunities to engage patients in recovery, a “treatable moment” for this vulnerable population.¹⁰

Currently, a common approach in the hospitalized patient is to attempt medically assisted withdrawal using a rapid taper of long-acting opioids. This process may appeal to healthcare providers who hope to guide their patients in transitioning to opioid abstinence. However, tapering an opioid regimen, even over a period of months, results in unacceptably high rates of relapse (as high as 70% to 90% in some studies), especially when a patient is acutely ill and symptomatic from a concurrent medical issue.^11-13 In the hospital setting, this treatment failure can manifest as pain and undertreated withdrawal symptoms (such as agitation, arthralgias, and gastrointestinal distress), which may hinder some patients from completing their treatment or drive some to leave against medical advice.¹⁴ Further harm may occur when an inpatient rapid taper is accomplished, putting patients at increased risk of a fatal relapse after discharge due to loss of tolerance.¹⁵Maintenance opioid agonist therapy with buprenorphine or methadone, in which a long-acting opioid is titrated until craving and withdrawal symptoms are well controlled, is the first-line modality for MAT among patients with OUDs in outpatient settings and is associated with reduced risk of fatal overdose and all-cause mortality.¹⁶ Initiation and dose stabilization of agonist therapy with these agents during acute medical hospitalization has been shown to be feasible in a variety of inpatient settings.^17-20 In one trial, patients randomized to buprenorphine induction and linkage to office-based therapy during their inpatient stay were more than 5 times as likely to enter and remain in treatment after discharge when compared with those in whom buprenorphine was tapered.²⁰ International guidelines support the use of maintenance agonist therapy in this context, but this remains an underutilized strategy in recent efforts to treat OUDs in the United States.^21,22 A few key barriers currently prevent this strategy from being applied broadly within our healthcare system.

First, there is a common misconception that regulations prohibit the use of methadone and buprenorphine for opioid agonist therapy by inpatient medical providers without special certification. Title 42 of the Code of Federal Regulations (CFR) provides extensive guidance regarding the use of opioid medications by registered outpatient opioid treatment programs. However, it also contains an exemption from these rules for hospitals treating patients with emergent medical needs (21 CFR § 1306.07[c]) allowing hospital-based clinicians “to maintain or detoxify a person as an incidental adjunct to medical or surgical treatment of conditions other than addiction” without restriction. According to guidelines from the Substance Abuse and Mental Health Services Administration, this exemption applies to the use of both methadone and buprenorphine.²³

Many clinicians and hospital pharmacy departments interpret this law to limit the use of maintenance therapy in patients already enrolled in outpatient programs or to require a rapid taper over the first 3 days of hospitalization. However, these interpretations may in part be rooted in confusion with an adjacent section of the regulations (21 CFR § 1306.07[b]) directed at outpatient physicians providing time-limited, emergency treatment for withdrawal in an office setting. The application of this time limit to hospitalized patients has not been supported by communication from the Drug Enforcement Agency.²⁴ There is no case law or other regulation requiring an opioid regimen to be time limited for patients during medical hospitalization, and hospital policies need not place undue constraints on the ability of clinicians to stabilize patients on maintenance therapy and transition them to outpatient treatment.

Second, the limited capacity of existing opioid maintenance programs can lead to a gap in treatment upon hospital discharge for patients in whom methadone or buprenorphine is initiated. Health delivery systems can play a role in mitigating the impact of this resource gap. Integrating the model of screening, brief intervention, and referral to treatment into hospital admission processes and engaging social workers, addiction consult services (where available), and other supports early in the course of hospitalization can help facilitate appropriate follow-up care.^25,26 Hospitals may also be eligible for federal funding to strengthen local referral networks for outpatient MAT programs under Section 103 of the Comprehensive Addiction and Recovery Act passed into law in July 2016. Innovative delivery models designed to enhance integration across community stakeholders in healthcare, social services, and criminal justice have recently been developed, such as Vermont’s “Hub and Spoke” model,²⁷ Boston Medical Center’s Faster Paths opioid urgent care center,²⁸ and the police-led Angel Program in Gloucester, Massachusetts.²⁹ Implementation science studies will be needed to identify the most effective ways to engage inpatient medical teams in such efforts.

Currently, individual providers can already play a central role in providing a bridge for patients in whom a delay in beginning MAT cannot be avoided upon discharge. Interim buprenorphine maintenance treatment has been shown to dramatically decrease the use of illicit opioids among those awaiting initiation of comprehensive MAT programs and substantially increase retention in long-term treatment.^20,30,31 With the recent expansion of the limits on buprenorphine prescriptions to 275 patients per provider (part of the waiver required under the Drug Addiction Treatment Act [DATA] of 2000 to provide outpatient buprenorphine treatment, also known as a DATA waiver), this may be an increasingly promising option for hospital discharge.

Obtaining a waiver to prescribe buprenorphine is not required for the inpatient initiation of buprenorphine therapy. However, doing so is relatively simple (requiring an online, 8-hour training [https://www.samhsa.gov/medication-assisted-treatment/training-resources/buprenorphine-physician-training]) and allows hospital-based providers not only to ensure optimal management of OUDs during hospitalization but also to help their patients with the next steps toward recovery after discharge. The use of buprenorphine may be challenging in some patients with significant pain as a component of their medical condition. For these patients, methadone will likely be better tolerated.

Additional funding is also urgently needed to expand the capacity of existing opioid treatment programs and create specialized discharge-transition clinics that can provide structured interim opioid therapy while patients are on waitlists for traditional MAT programs. Requiring patients who are not ready or able to begin long-term maintenance agonist therapy to rapidly taper an inpatient opioid regimen unnecessarily puts them at risk for overdose after discharge.¹⁵ Regardless of the available resources for long-term treatment within the community, hospital discharge planning should include a naloxone prescription and brief training for patients and their loved ones.³² The long-acting opioid antagonist, depot naltrexone, is another effective, alternative MAT option and is increasingly used in community settings among patients who are motivated to achieve opioid abstinence.^33,34 It has not yet been studied among hospitalized patients, and further research is needed to determine if it could be a viable option for discharge. However, the requirement that a patient be abstinent from opioids for 7 to 10 days prior to administering the first dose of depot naltrexone may serve as a significant barrier to its use for most hospitalized patients.

Finally, healthcare providers must be trained in the appropriate use of opioid agonist therapy. Medical schools, residency programs, and schools of pharmacy and nursing should develop curricula to expand the capacity of nonspecialists to care for patients with OUDs and to focus on judicious analgesic prescribing to prevent chronic opioid use. This curriculum should address the appropriate titration of methadone and buprenorphine for agonist therapy and address the stigma faced by patients with substance use disorders. Other important topics include the management of overdose and withdrawal symptoms, structured approaches to pain management in patients with OUDs, harm-reduction methods, and multidisciplinary care for the psychosocial and psychiatric comorbidities of addiction. Though international guidelines have been developed for the inpatient management of patients with OUDs,^21,22 hospitals and professional societies should take a leadership role in facilitating continuing education to disseminate them among current medical providers.

There is great potential for the leadership and front-line staff of hospital systems, with a few key changes in policy and practice, to become advocates for patients with OUDs to access treatment. As perspectives about opioid prescribing change amid efforts to limit the escalation of the current heroin epidemic, it is vital to identify opportunities to reduce opioid exposure for opioid-naïve patients and enhance the engagement of patients diagnosed with OUDs in treatment.

Disclosure

 The authors have no conflicts of interest to declare.

The United States is facing an epidemic of prescription opioid and heroin use, which has been linked to the escalating prescribing of opioid analgesics. Though opioid prescriptions appear to be reaching a plateau, estimates suggest there are at least 900,000 active heroin users in the United States, and this number continues to grow.¹ One response to this epidemic (through state legislation and medical society guidelines) has been a move to reduce opioid prescribing in order to diminish the potential for diversion and misuse.² However, the treatment of pain is not the sole driver of heroin epidemiology, and new strategies are also needed to better engage patients with existing opioid use disorders (OUDs) to begin treatment. These patients are increasingly hospitalized for infectious comorbidities of injection drug use, trauma, or pregnancy, and this may present a unique opportunity to initiate these patients on maintenance opioid agonist therapy, the most effective option for medication-assisted treatment (MAT) for addiction.

Patients with OUDs comprise an estimated 2% to 4% of hospitalized patients, representing a disproportionately large number of inpatients.^3-6 According to a recent analysis of data from the National (Nationwide) Inpatient Sample, the estimated annual number of hospitalizations associated with OUDs in the United States increased from approximately 300,000 to more than 500,000 in the decade from 2002 to 2012.⁷ Severe bacterial infections associated with intravenous administration of opioids (including endocarditis, osteomyelitis, septic arthritis, and epidural abscess) increased substantially at an estimated cost of more than $700 million in 2012.⁷ Over a similar period, the prevalence of opioid use among women in labor increased from 13.7 to 22.0 per 10,000 live births,⁸ and there was a corresponding rise in admissions to neonatal intensive care units for neonatal abstinence syndrome.⁹ As the prevalence of prescription drug and heroin dependence continues to rise across the United States, hospitals and clinicians find themselves on the front lines of this epidemic, creating potential opportunities to engage patients in recovery, a “treatable moment” for this vulnerable population.¹⁰

Currently, a common approach in the hospitalized patient is to attempt medically assisted withdrawal using a rapid taper of long-acting opioids. This process may appeal to healthcare providers who hope to guide their patients in transitioning to opioid abstinence. However, tapering an opioid regimen, even over a period of months, results in unacceptably high rates of relapse (as high as 70% to 90% in some studies), especially when a patient is acutely ill and symptomatic from a concurrent medical issue.^11-13 In the hospital setting, this treatment failure can manifest as pain and undertreated withdrawal symptoms (such as agitation, arthralgias, and gastrointestinal distress), which may hinder some patients from completing their treatment or drive some to leave against medical advice.¹⁴ Further harm may occur when an inpatient rapid taper is accomplished, putting patients at increased risk of a fatal relapse after discharge due to loss of tolerance.¹⁵Maintenance opioid agonist therapy with buprenorphine or methadone, in which a long-acting opioid is titrated until craving and withdrawal symptoms are well controlled, is the first-line modality for MAT among patients with OUDs in outpatient settings and is associated with reduced risk of fatal overdose and all-cause mortality.¹⁶ Initiation and dose stabilization of agonist therapy with these agents during acute medical hospitalization has been shown to be feasible in a variety of inpatient settings.^17-20 In one trial, patients randomized to buprenorphine induction and linkage to office-based therapy during their inpatient stay were more than 5 times as likely to enter and remain in treatment after discharge when compared with those in whom buprenorphine was tapered.²⁰ International guidelines support the use of maintenance agonist therapy in this context, but this remains an underutilized strategy in recent efforts to treat OUDs in the United States.^21,22 A few key barriers currently prevent this strategy from being applied broadly within our healthcare system.

First, there is a common misconception that regulations prohibit the use of methadone and buprenorphine for opioid agonist therapy by inpatient medical providers without special certification. Title 42 of the Code of Federal Regulations (CFR) provides extensive guidance regarding the use of opioid medications by registered outpatient opioid treatment programs. However, it also contains an exemption from these rules for hospitals treating patients with emergent medical needs (21 CFR § 1306.07[c]) allowing hospital-based clinicians “to maintain or detoxify a person as an incidental adjunct to medical or surgical treatment of conditions other than addiction” without restriction. According to guidelines from the Substance Abuse and Mental Health Services Administration, this exemption applies to the use of both methadone and buprenorphine.²³

Many clinicians and hospital pharmacy departments interpret this law to limit the use of maintenance therapy in patients already enrolled in outpatient programs or to require a rapid taper over the first 3 days of hospitalization. However, these interpretations may in part be rooted in confusion with an adjacent section of the regulations (21 CFR § 1306.07[b]) directed at outpatient physicians providing time-limited, emergency treatment for withdrawal in an office setting. The application of this time limit to hospitalized patients has not been supported by communication from the Drug Enforcement Agency.²⁴ There is no case law or other regulation requiring an opioid regimen to be time limited for patients during medical hospitalization, and hospital policies need not place undue constraints on the ability of clinicians to stabilize patients on maintenance therapy and transition them to outpatient treatment.

Second, the limited capacity of existing opioid maintenance programs can lead to a gap in treatment upon hospital discharge for patients in whom methadone or buprenorphine is initiated. Health delivery systems can play a role in mitigating the impact of this resource gap. Integrating the model of screening, brief intervention, and referral to treatment into hospital admission processes and engaging social workers, addiction consult services (where available), and other supports early in the course of hospitalization can help facilitate appropriate follow-up care.^25,26 Hospitals may also be eligible for federal funding to strengthen local referral networks for outpatient MAT programs under Section 103 of the Comprehensive Addiction and Recovery Act passed into law in July 2016. Innovative delivery models designed to enhance integration across community stakeholders in healthcare, social services, and criminal justice have recently been developed, such as Vermont’s “Hub and Spoke” model,²⁷ Boston Medical Center’s Faster Paths opioid urgent care center,²⁸ and the police-led Angel Program in Gloucester, Massachusetts.²⁹ Implementation science studies will be needed to identify the most effective ways to engage inpatient medical teams in such efforts.

Currently, individual providers can already play a central role in providing a bridge for patients in whom a delay in beginning MAT cannot be avoided upon discharge. Interim buprenorphine maintenance treatment has been shown to dramatically decrease the use of illicit opioids among those awaiting initiation of comprehensive MAT programs and substantially increase retention in long-term treatment.^20,30,31 With the recent expansion of the limits on buprenorphine prescriptions to 275 patients per provider (part of the waiver required under the Drug Addiction Treatment Act [DATA] of 2000 to provide outpatient buprenorphine treatment, also known as a DATA waiver), this may be an increasingly promising option for hospital discharge.

Obtaining a waiver to prescribe buprenorphine is not required for the inpatient initiation of buprenorphine therapy. However, doing so is relatively simple (requiring an online, 8-hour training [https://www.samhsa.gov/medication-assisted-treatment/training-resources/buprenorphine-physician-training]) and allows hospital-based providers not only to ensure optimal management of OUDs during hospitalization but also to help their patients with the next steps toward recovery after discharge. The use of buprenorphine may be challenging in some patients with significant pain as a component of their medical condition. For these patients, methadone will likely be better tolerated.

Additional funding is also urgently needed to expand the capacity of existing opioid treatment programs and create specialized discharge-transition clinics that can provide structured interim opioid therapy while patients are on waitlists for traditional MAT programs. Requiring patients who are not ready or able to begin long-term maintenance agonist therapy to rapidly taper an inpatient opioid regimen unnecessarily puts them at risk for overdose after discharge.¹⁵ Regardless of the available resources for long-term treatment within the community, hospital discharge planning should include a naloxone prescription and brief training for patients and their loved ones.³² The long-acting opioid antagonist, depot naltrexone, is another effective, alternative MAT option and is increasingly used in community settings among patients who are motivated to achieve opioid abstinence.^33,34 It has not yet been studied among hospitalized patients, and further research is needed to determine if it could be a viable option for discharge. However, the requirement that a patient be abstinent from opioids for 7 to 10 days prior to administering the first dose of depot naltrexone may serve as a significant barrier to its use for most hospitalized patients.

Finally, healthcare providers must be trained in the appropriate use of opioid agonist therapy. Medical schools, residency programs, and schools of pharmacy and nursing should develop curricula to expand the capacity of nonspecialists to care for patients with OUDs and to focus on judicious analgesic prescribing to prevent chronic opioid use. This curriculum should address the appropriate titration of methadone and buprenorphine for agonist therapy and address the stigma faced by patients with substance use disorders. Other important topics include the management of overdose and withdrawal symptoms, structured approaches to pain management in patients with OUDs, harm-reduction methods, and multidisciplinary care for the psychosocial and psychiatric comorbidities of addiction. Though international guidelines have been developed for the inpatient management of patients with OUDs,^21,22 hospitals and professional societies should take a leadership role in facilitating continuing education to disseminate them among current medical providers.

There is great potential for the leadership and front-line staff of hospital systems, with a few key changes in policy and practice, to become advocates for patients with OUDs to access treatment. As perspectives about opioid prescribing change amid efforts to limit the escalation of the current heroin epidemic, it is vital to identify opportunities to reduce opioid exposure for opioid-naïve patients and enhance the engagement of patients diagnosed with OUDs in treatment.

Disclosure

 The authors have no conflicts of interest to declare.

The United States is facing an epidemic of prescription opioid and heroin use, which has been linked to the escalating prescribing of opioid analgesics. Though opioid prescriptions appear to be reaching a plateau, estimates suggest there are at least 900,000 active heroin users in the United States, and this number continues to grow.¹ One response to this epidemic (through state legislation and medical society guidelines) has been a move to reduce opioid prescribing in order to diminish the potential for diversion and misuse.² However, the treatment of pain is not the sole driver of heroin epidemiology, and new strategies are also needed to better engage patients with existing opioid use disorders (OUDs) to begin treatment. These patients are increasingly hospitalized for infectious comorbidities of injection drug use, trauma, or pregnancy, and this may present a unique opportunity to initiate these patients on maintenance opioid agonist therapy, the most effective option for medication-assisted treatment (MAT) for addiction.

Patients with OUDs comprise an estimated 2% to 4% of hospitalized patients, representing a disproportionately large number of inpatients.^3-6 According to a recent analysis of data from the National (Nationwide) Inpatient Sample, the estimated annual number of hospitalizations associated with OUDs in the United States increased from approximately 300,000 to more than 500,000 in the decade from 2002 to 2012.⁷ Severe bacterial infections associated with intravenous administration of opioids (including endocarditis, osteomyelitis, septic arthritis, and epidural abscess) increased substantially at an estimated cost of more than $700 million in 2012.⁷ Over a similar period, the prevalence of opioid use among women in labor increased from 13.7 to 22.0 per 10,000 live births,⁸ and there was a corresponding rise in admissions to neonatal intensive care units for neonatal abstinence syndrome.⁹ As the prevalence of prescription drug and heroin dependence continues to rise across the United States, hospitals and clinicians find themselves on the front lines of this epidemic, creating potential opportunities to engage patients in recovery, a “treatable moment” for this vulnerable population.¹⁰

Currently, a common approach in the hospitalized patient is to attempt medically assisted withdrawal using a rapid taper of long-acting opioids. This process may appeal to healthcare providers who hope to guide their patients in transitioning to opioid abstinence. However, tapering an opioid regimen, even over a period of months, results in unacceptably high rates of relapse (as high as 70% to 90% in some studies), especially when a patient is acutely ill and symptomatic from a concurrent medical issue.^11-13 In the hospital setting, this treatment failure can manifest as pain and undertreated withdrawal symptoms (such as agitation, arthralgias, and gastrointestinal distress), which may hinder some patients from completing their treatment or drive some to leave against medical advice.¹⁴ Further harm may occur when an inpatient rapid taper is accomplished, putting patients at increased risk of a fatal relapse after discharge due to loss of tolerance.¹⁵Maintenance opioid agonist therapy with buprenorphine or methadone, in which a long-acting opioid is titrated until craving and withdrawal symptoms are well controlled, is the first-line modality for MAT among patients with OUDs in outpatient settings and is associated with reduced risk of fatal overdose and all-cause mortality.¹⁶ Initiation and dose stabilization of agonist therapy with these agents during acute medical hospitalization has been shown to be feasible in a variety of inpatient settings.^17-20 In one trial, patients randomized to buprenorphine induction and linkage to office-based therapy during their inpatient stay were more than 5 times as likely to enter and remain in treatment after discharge when compared with those in whom buprenorphine was tapered.²⁰ International guidelines support the use of maintenance agonist therapy in this context, but this remains an underutilized strategy in recent efforts to treat OUDs in the United States.^21,22 A few key barriers currently prevent this strategy from being applied broadly within our healthcare system.

First, there is a common misconception that regulations prohibit the use of methadone and buprenorphine for opioid agonist therapy by inpatient medical providers without special certification. Title 42 of the Code of Federal Regulations (CFR) provides extensive guidance regarding the use of opioid medications by registered outpatient opioid treatment programs. However, it also contains an exemption from these rules for hospitals treating patients with emergent medical needs (21 CFR § 1306.07[c]) allowing hospital-based clinicians “to maintain or detoxify a person as an incidental adjunct to medical or surgical treatment of conditions other than addiction” without restriction. According to guidelines from the Substance Abuse and Mental Health Services Administration, this exemption applies to the use of both methadone and buprenorphine.²³

Many clinicians and hospital pharmacy departments interpret this law to limit the use of maintenance therapy in patients already enrolled in outpatient programs or to require a rapid taper over the first 3 days of hospitalization. However, these interpretations may in part be rooted in confusion with an adjacent section of the regulations (21 CFR § 1306.07[b]) directed at outpatient physicians providing time-limited, emergency treatment for withdrawal in an office setting. The application of this time limit to hospitalized patients has not been supported by communication from the Drug Enforcement Agency.²⁴ There is no case law or other regulation requiring an opioid regimen to be time limited for patients during medical hospitalization, and hospital policies need not place undue constraints on the ability of clinicians to stabilize patients on maintenance therapy and transition them to outpatient treatment.

Second, the limited capacity of existing opioid maintenance programs can lead to a gap in treatment upon hospital discharge for patients in whom methadone or buprenorphine is initiated. Health delivery systems can play a role in mitigating the impact of this resource gap. Integrating the model of screening, brief intervention, and referral to treatment into hospital admission processes and engaging social workers, addiction consult services (where available), and other supports early in the course of hospitalization can help facilitate appropriate follow-up care.^25,26 Hospitals may also be eligible for federal funding to strengthen local referral networks for outpatient MAT programs under Section 103 of the Comprehensive Addiction and Recovery Act passed into law in July 2016. Innovative delivery models designed to enhance integration across community stakeholders in healthcare, social services, and criminal justice have recently been developed, such as Vermont’s “Hub and Spoke” model,²⁷ Boston Medical Center’s Faster Paths opioid urgent care center,²⁸ and the police-led Angel Program in Gloucester, Massachusetts.²⁹ Implementation science studies will be needed to identify the most effective ways to engage inpatient medical teams in such efforts.

Currently, individual providers can already play a central role in providing a bridge for patients in whom a delay in beginning MAT cannot be avoided upon discharge. Interim buprenorphine maintenance treatment has been shown to dramatically decrease the use of illicit opioids among those awaiting initiation of comprehensive MAT programs and substantially increase retention in long-term treatment.^20,30,31 With the recent expansion of the limits on buprenorphine prescriptions to 275 patients per provider (part of the waiver required under the Drug Addiction Treatment Act [DATA] of 2000 to provide outpatient buprenorphine treatment, also known as a DATA waiver), this may be an increasingly promising option for hospital discharge.

Obtaining a waiver to prescribe buprenorphine is not required for the inpatient initiation of buprenorphine therapy. However, doing so is relatively simple (requiring an online, 8-hour training [https://www.samhsa.gov/medication-assisted-treatment/training-resources/buprenorphine-physician-training]) and allows hospital-based providers not only to ensure optimal management of OUDs during hospitalization but also to help their patients with the next steps toward recovery after discharge. The use of buprenorphine may be challenging in some patients with significant pain as a component of their medical condition. For these patients, methadone will likely be better tolerated.

Additional funding is also urgently needed to expand the capacity of existing opioid treatment programs and create specialized discharge-transition clinics that can provide structured interim opioid therapy while patients are on waitlists for traditional MAT programs. Requiring patients who are not ready or able to begin long-term maintenance agonist therapy to rapidly taper an inpatient opioid regimen unnecessarily puts them at risk for overdose after discharge.¹⁵ Regardless of the available resources for long-term treatment within the community, hospital discharge planning should include a naloxone prescription and brief training for patients and their loved ones.³² The long-acting opioid antagonist, depot naltrexone, is another effective, alternative MAT option and is increasingly used in community settings among patients who are motivated to achieve opioid abstinence.^33,34 It has not yet been studied among hospitalized patients, and further research is needed to determine if it could be a viable option for discharge. However, the requirement that a patient be abstinent from opioids for 7 to 10 days prior to administering the first dose of depot naltrexone may serve as a significant barrier to its use for most hospitalized patients.

Finally, healthcare providers must be trained in the appropriate use of opioid agonist therapy. Medical schools, residency programs, and schools of pharmacy and nursing should develop curricula to expand the capacity of nonspecialists to care for patients with OUDs and to focus on judicious analgesic prescribing to prevent chronic opioid use. This curriculum should address the appropriate titration of methadone and buprenorphine for agonist therapy and address the stigma faced by patients with substance use disorders. Other important topics include the management of overdose and withdrawal symptoms, structured approaches to pain management in patients with OUDs, harm-reduction methods, and multidisciplinary care for the psychosocial and psychiatric comorbidities of addiction. Though international guidelines have been developed for the inpatient management of patients with OUDs,^21,22 hospitals and professional societies should take a leadership role in facilitating continuing education to disseminate them among current medical providers.

There is great potential for the leadership and front-line staff of hospital systems, with a few key changes in policy and practice, to become advocates for patients with OUDs to access treatment. As perspectives about opioid prescribing change amid efforts to limit the escalation of the current heroin epidemic, it is vital to identify opportunities to reduce opioid exposure for opioid-naïve patients and enhance the engagement of patients diagnosed with OUDs in treatment.

Disclosure

 The authors have no conflicts of interest to declare.