Purpuric Lesions of the Scalp, Axillae, and Groin of an Infant

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The Diagnosis: Langerhans Cell Histiocytosis 

Langerhans cell histiocytosis (LCH) is a clonal proliferative disorder of Langerhans cells that can affect any organ, most commonly the skin and bones. It typically develops in children aged 1 to 3 years, with a male to female ratio of 2 to 1.1 Skin manifestations include purpuric papules, pustules, vesicles, erosions, and fissuring distributed predominantly on the scalp and flexural sites. Mucosal sites, particularly the oral mucosa, may be involved and usually present as erosions associated with underlying bone lesions.1 Langerhans cell histiocytosis should be considered in the differential diagnosis of recalcitrant diaper dermatitis in an infant, especially when there is purpura and erosions, as seen in our patient. Common conditions in infants such as cutaneous candidiasis (intense erythema with superficial erosions, peripheral scale and satellite pustules on flexural areas, potassium hydroxide microscopy revealing yeast forms and pseudohyphae) and seborrheic dermatitis (well-defined pink to red, moist, and often scaly patches favoring the folds) may be distinguished clinically from Hailey-Hailey disease (malodorous plaques with fissures and erosions favoring the folds), which is rare in infancy, and acrodermatitis enteropathica (erythema and erosions with scale-crust and desquamation on periorificial, acral, and intertriginous skin).

Histopathologic evaluation is instrumental in diagnosing the skin lesions of LCH. Further evaluation for systemic involvement is necessary once the diagnosis is made. Skin biopsy of the scalp and right inguinal fold revealed a wedge-shaped infiltrate of histiocytes with slightly folded nuclear contours in our patient (Figure 1). CD1a (Figure 2) and S-100 stains were markedly positive, which is characteristic of LCH. Complete blood cell count, renal function, liver function, urinalysis, and flow cytometry results were within reference range. A skeletal survey and echocardiogram were unremarkable; however, mild hepatosplenomegaly was noted on abdominal ultrasonography.

Figure 1. Langerhans cell histiocytosis. Histopathologic evaluation of the scalp specimen revealed a dense dermal histiocytic infiltrate with irregularly contoured nuclei (A and B)(H&E, original magnifications ×20 and ×40).

Figure 2. Langerhans cell histiocytosis. CD1a staining was markedly positive (original magnification ×40).

Treatment of LCH varies based on the extent of organ involvement. For isolated cutaneous disease, topical steroids, topical nitrogen mustard, phototherapy, and thalidomide may be employed.2 Multisystem disease requires chemotherapeutic agents including vinblastine and prednisone.2,3 Because more than half of patients with LCH have oncogenic BRAF V600E mutations,4 vemurafenib may have a therapeutic role in treatment. Rare case reports have documented disease response in patients with LCH and Erdheim-Chester disease.5,6 

Prognosis varies based on age and extent of systemic involvement. Children younger than 2 years with multiorgan involvement have a poor prognosis (35%-55% mortality rate) compared to older children without hematopoietic, hepatosplenic, or lung involvement (100% survival rate). Additionally, response to treatment affects prognosis, as there is a 66% mortality rate in those who do not respond to treatment after 6 weeks.3 Long-term sequelae of LCH include endocrine dysfunction (ie, diabetes insipidus, growth hormone deficiencies), hearing impairment, orthopedic impairment, and neuropsychological disease; thus, multidisciplinary care often is neccessary.7

Given the multisystem involvement in our patient, he was treated with vinblastine, 6-mercaptopurine, and prednisolone with only partial and transient disease response. He was then treated with clofarabine with dramatic resolution of the mediastinal mass on follow-up positron emission tomography. The cutaneous lesions persisted and were managed with topical corticosteroids.

References
  1. Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed. Philadelphia, PA: Elsevier; 2012.
  2. Haupt R, Minkov M, Astigarraga I, et al; Euro Histio Network. Langerhans cell histiocytosis (LCH): guidelines for diagnosis, clinical work‐up, and treatment for patients till the age of 18 years [published online October 25, 2012]. Pediatr Blood Cancer. 2013;60:175-184.
  3. Gadner H, Grois N, Arico M, et al; Histiocyte Society. A randomized trial of treatment for multisystem Langerhans' cell histiocytosis. J Pediatr. 2001;138:728-734.
  4. Badalian-Very G, Vergilio JA, Degar BA, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. 2010;116:1919-1923.
  5. Haroche J, Cohen-Aubart F, Emile JF, et al. Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood. 2013;121:1495-1500.
  6. Charles J, Beani JC, Fiandrino G, et al. Major response to vemurafenib in patient with severe cutaneous Langerhans cell histiocytosis harboring BRAF V600E mutation. J Am Acad Dermatol. 2014;71:E97-E99.
  7. Martin A, Macmillan S, Murphy D, et al. Langerhans cell histiocytosis: 23 years' paediatric experience highlights severe long-term sequelae. Scott Med J. 2014;59:149-157.
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From Yale University School of Medicine, New Haven, Connecticut. Dr. Khurana is from the Department of Internal Medicine, and Drs. Leventhal, Levy, McNiff, and Antaya are from the Department of Dermatology.

The authors report no conflict of interest.

Correspondence: Jonathan S. Leventhal, MD, 15 York St, LMP 5040, New Haven, CT 06510 (jonathan.leventhal@yale.edu).

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From Yale University School of Medicine, New Haven, Connecticut. Dr. Khurana is from the Department of Internal Medicine, and Drs. Leventhal, Levy, McNiff, and Antaya are from the Department of Dermatology.

The authors report no conflict of interest.

Correspondence: Jonathan S. Leventhal, MD, 15 York St, LMP 5040, New Haven, CT 06510 (jonathan.leventhal@yale.edu).

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From Yale University School of Medicine, New Haven, Connecticut. Dr. Khurana is from the Department of Internal Medicine, and Drs. Leventhal, Levy, McNiff, and Antaya are from the Department of Dermatology.

The authors report no conflict of interest.

Correspondence: Jonathan S. Leventhal, MD, 15 York St, LMP 5040, New Haven, CT 06510 (jonathan.leventhal@yale.edu).

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The Diagnosis: Langerhans Cell Histiocytosis 

Langerhans cell histiocytosis (LCH) is a clonal proliferative disorder of Langerhans cells that can affect any organ, most commonly the skin and bones. It typically develops in children aged 1 to 3 years, with a male to female ratio of 2 to 1.1 Skin manifestations include purpuric papules, pustules, vesicles, erosions, and fissuring distributed predominantly on the scalp and flexural sites. Mucosal sites, particularly the oral mucosa, may be involved and usually present as erosions associated with underlying bone lesions.1 Langerhans cell histiocytosis should be considered in the differential diagnosis of recalcitrant diaper dermatitis in an infant, especially when there is purpura and erosions, as seen in our patient. Common conditions in infants such as cutaneous candidiasis (intense erythema with superficial erosions, peripheral scale and satellite pustules on flexural areas, potassium hydroxide microscopy revealing yeast forms and pseudohyphae) and seborrheic dermatitis (well-defined pink to red, moist, and often scaly patches favoring the folds) may be distinguished clinically from Hailey-Hailey disease (malodorous plaques with fissures and erosions favoring the folds), which is rare in infancy, and acrodermatitis enteropathica (erythema and erosions with scale-crust and desquamation on periorificial, acral, and intertriginous skin).

Histopathologic evaluation is instrumental in diagnosing the skin lesions of LCH. Further evaluation for systemic involvement is necessary once the diagnosis is made. Skin biopsy of the scalp and right inguinal fold revealed a wedge-shaped infiltrate of histiocytes with slightly folded nuclear contours in our patient (Figure 1). CD1a (Figure 2) and S-100 stains were markedly positive, which is characteristic of LCH. Complete blood cell count, renal function, liver function, urinalysis, and flow cytometry results were within reference range. A skeletal survey and echocardiogram were unremarkable; however, mild hepatosplenomegaly was noted on abdominal ultrasonography.

Figure 1. Langerhans cell histiocytosis. Histopathologic evaluation of the scalp specimen revealed a dense dermal histiocytic infiltrate with irregularly contoured nuclei (A and B)(H&E, original magnifications ×20 and ×40).

Figure 2. Langerhans cell histiocytosis. CD1a staining was markedly positive (original magnification ×40).

Treatment of LCH varies based on the extent of organ involvement. For isolated cutaneous disease, topical steroids, topical nitrogen mustard, phototherapy, and thalidomide may be employed.2 Multisystem disease requires chemotherapeutic agents including vinblastine and prednisone.2,3 Because more than half of patients with LCH have oncogenic BRAF V600E mutations,4 vemurafenib may have a therapeutic role in treatment. Rare case reports have documented disease response in patients with LCH and Erdheim-Chester disease.5,6 

Prognosis varies based on age and extent of systemic involvement. Children younger than 2 years with multiorgan involvement have a poor prognosis (35%-55% mortality rate) compared to older children without hematopoietic, hepatosplenic, or lung involvement (100% survival rate). Additionally, response to treatment affects prognosis, as there is a 66% mortality rate in those who do not respond to treatment after 6 weeks.3 Long-term sequelae of LCH include endocrine dysfunction (ie, diabetes insipidus, growth hormone deficiencies), hearing impairment, orthopedic impairment, and neuropsychological disease; thus, multidisciplinary care often is neccessary.7

Given the multisystem involvement in our patient, he was treated with vinblastine, 6-mercaptopurine, and prednisolone with only partial and transient disease response. He was then treated with clofarabine with dramatic resolution of the mediastinal mass on follow-up positron emission tomography. The cutaneous lesions persisted and were managed with topical corticosteroids.

The Diagnosis: Langerhans Cell Histiocytosis 

Langerhans cell histiocytosis (LCH) is a clonal proliferative disorder of Langerhans cells that can affect any organ, most commonly the skin and bones. It typically develops in children aged 1 to 3 years, with a male to female ratio of 2 to 1.1 Skin manifestations include purpuric papules, pustules, vesicles, erosions, and fissuring distributed predominantly on the scalp and flexural sites. Mucosal sites, particularly the oral mucosa, may be involved and usually present as erosions associated with underlying bone lesions.1 Langerhans cell histiocytosis should be considered in the differential diagnosis of recalcitrant diaper dermatitis in an infant, especially when there is purpura and erosions, as seen in our patient. Common conditions in infants such as cutaneous candidiasis (intense erythema with superficial erosions, peripheral scale and satellite pustules on flexural areas, potassium hydroxide microscopy revealing yeast forms and pseudohyphae) and seborrheic dermatitis (well-defined pink to red, moist, and often scaly patches favoring the folds) may be distinguished clinically from Hailey-Hailey disease (malodorous plaques with fissures and erosions favoring the folds), which is rare in infancy, and acrodermatitis enteropathica (erythema and erosions with scale-crust and desquamation on periorificial, acral, and intertriginous skin).

Histopathologic evaluation is instrumental in diagnosing the skin lesions of LCH. Further evaluation for systemic involvement is necessary once the diagnosis is made. Skin biopsy of the scalp and right inguinal fold revealed a wedge-shaped infiltrate of histiocytes with slightly folded nuclear contours in our patient (Figure 1). CD1a (Figure 2) and S-100 stains were markedly positive, which is characteristic of LCH. Complete blood cell count, renal function, liver function, urinalysis, and flow cytometry results were within reference range. A skeletal survey and echocardiogram were unremarkable; however, mild hepatosplenomegaly was noted on abdominal ultrasonography.

Figure 1. Langerhans cell histiocytosis. Histopathologic evaluation of the scalp specimen revealed a dense dermal histiocytic infiltrate with irregularly contoured nuclei (A and B)(H&E, original magnifications ×20 and ×40).

Figure 2. Langerhans cell histiocytosis. CD1a staining was markedly positive (original magnification ×40).

Treatment of LCH varies based on the extent of organ involvement. For isolated cutaneous disease, topical steroids, topical nitrogen mustard, phototherapy, and thalidomide may be employed.2 Multisystem disease requires chemotherapeutic agents including vinblastine and prednisone.2,3 Because more than half of patients with LCH have oncogenic BRAF V600E mutations,4 vemurafenib may have a therapeutic role in treatment. Rare case reports have documented disease response in patients with LCH and Erdheim-Chester disease.5,6 

Prognosis varies based on age and extent of systemic involvement. Children younger than 2 years with multiorgan involvement have a poor prognosis (35%-55% mortality rate) compared to older children without hematopoietic, hepatosplenic, or lung involvement (100% survival rate). Additionally, response to treatment affects prognosis, as there is a 66% mortality rate in those who do not respond to treatment after 6 weeks.3 Long-term sequelae of LCH include endocrine dysfunction (ie, diabetes insipidus, growth hormone deficiencies), hearing impairment, orthopedic impairment, and neuropsychological disease; thus, multidisciplinary care often is neccessary.7

Given the multisystem involvement in our patient, he was treated with vinblastine, 6-mercaptopurine, and prednisolone with only partial and transient disease response. He was then treated with clofarabine with dramatic resolution of the mediastinal mass on follow-up positron emission tomography. The cutaneous lesions persisted and were managed with topical corticosteroids.

References
  1. Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed. Philadelphia, PA: Elsevier; 2012.
  2. Haupt R, Minkov M, Astigarraga I, et al; Euro Histio Network. Langerhans cell histiocytosis (LCH): guidelines for diagnosis, clinical work‐up, and treatment for patients till the age of 18 years [published online October 25, 2012]. Pediatr Blood Cancer. 2013;60:175-184.
  3. Gadner H, Grois N, Arico M, et al; Histiocyte Society. A randomized trial of treatment for multisystem Langerhans' cell histiocytosis. J Pediatr. 2001;138:728-734.
  4. Badalian-Very G, Vergilio JA, Degar BA, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. 2010;116:1919-1923.
  5. Haroche J, Cohen-Aubart F, Emile JF, et al. Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood. 2013;121:1495-1500.
  6. Charles J, Beani JC, Fiandrino G, et al. Major response to vemurafenib in patient with severe cutaneous Langerhans cell histiocytosis harboring BRAF V600E mutation. J Am Acad Dermatol. 2014;71:E97-E99.
  7. Martin A, Macmillan S, Murphy D, et al. Langerhans cell histiocytosis: 23 years' paediatric experience highlights severe long-term sequelae. Scott Med J. 2014;59:149-157.
References
  1. Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed. Philadelphia, PA: Elsevier; 2012.
  2. Haupt R, Minkov M, Astigarraga I, et al; Euro Histio Network. Langerhans cell histiocytosis (LCH): guidelines for diagnosis, clinical work‐up, and treatment for patients till the age of 18 years [published online October 25, 2012]. Pediatr Blood Cancer. 2013;60:175-184.
  3. Gadner H, Grois N, Arico M, et al; Histiocyte Society. A randomized trial of treatment for multisystem Langerhans' cell histiocytosis. J Pediatr. 2001;138:728-734.
  4. Badalian-Very G, Vergilio JA, Degar BA, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. 2010;116:1919-1923.
  5. Haroche J, Cohen-Aubart F, Emile JF, et al. Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood. 2013;121:1495-1500.
  6. Charles J, Beani JC, Fiandrino G, et al. Major response to vemurafenib in patient with severe cutaneous Langerhans cell histiocytosis harboring BRAF V600E mutation. J Am Acad Dermatol. 2014;71:E97-E99.
  7. Martin A, Macmillan S, Murphy D, et al. Langerhans cell histiocytosis: 23 years' paediatric experience highlights severe long-term sequelae. Scott Med J. 2014;59:149-157.
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A 7-month-old boy admitted to the hospital with new-onset respiratory stridor was found to have a rash of the scalp, axillae, and groin of 1 month's duration that was unresponsive to treatment with mineral oil. Bronchoscopy revealed tracheal compression, and urgent magnetic resonance imaging of the chest demonstrated an anterior mediastinal mass. Prior to presentation, the patient was otherwise healthy with normal growth and development. On physical examination, scattered red-brown and purpuric papules with hemorrhagic crust were noted on the scalp. There were well-defined pink erosive patches and purpuric papules in the inguinal folds bilaterally and similar erosive patches in the axillae. Numerous punched out ulcerations were noted on the lower gingiva. There was no palpable lymphadenopathy. The hands, feet, penis, scrotum, and perianal area were spared. Biopsies of the skin and mediastinal mass were performed.
 

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VIDEO: Immunotherapy ups disease control rate in relapsed mesothelioma

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– Early data from a phase II trial of immune checkpoint inhibitors to treat relapsed mesothelioma give hope that immunotherapy may be an effective therapeutic option for the rapidly progressive, currently incurable cancer.

Reporting on 12 weeks of data from the randomized multicenter trial, Arnaud Scherpereel, MD, the study’s first author, said in a video interview, “We were very pleased to see that we were able to increase ... the disease control rate to 44% with nivolumab, and 50% with nivolumab plus ipilimumab. This was translated into a overall survival gain for these patients.” The best previous disease control rate seen with other therapies was less than 30%, said Dr. Scherpereel at the annual meeting of the American Society of Clinical Oncology.

Discussing the early results in a video interview, Dr. Scherpereel, head of the pulmonary and thoracic oncology department at the University Hospital of Lille, France noted that the median overall survival for the nivolumab patients was 10.4 months, and has not yet been reached for the nivolumab plus ipilimumab patients. Further, he said in a press briefing, “Tumors shrunk in 18% of patients treated with nivolumab and 26% of those treated with nivolumab plus ipilimumab.”

The French MAPS-2 study has enrolled 125 adult patients with malignant pleural mesothelioma who had measurable disease progression after one or two prior lines of chemotherapy, including pemetrexed/platinum doublet. Patients were randomized 1:1 to receive either nivolumab or nivolumab plus ipilimumab, until disease control or unacceptable toxicity was reached, for a maximum of 2 years. Patients were mostly (80%) male, with a median age of 71.8 years, and most had the epithelioid malignant pleural mesothelioma subtype.

In commentary at the press briefing announcing the findings, ASCO expert Michael Sabel, MD, said, “I need to emphasize that this is amazing, in that we are seeing [the use of] checkpoint inhibitors expanding beyond melanoma, to other cancers that we thought were not amenable to immunotherapy approaches.”

“This is a great example of how basic cancer research in one field can expand across others,” said Dr. Sabel of the departments of surgery and surgical oncology at the University of Michigan, Ann Arbor.

Most side effects were not severe, but there were three potentially drug-related deaths in the nivolumab-ipilimumab combo arm: one patient died of fulminant hepatitis, one from metabolic encephalitis, and one from acute renal failure. “There is no identified factor that is predictive” in terms of which patients will have the more significant known adverse effects of checkpoint inhibitors, said Dr. Scherpereel. Patients, caregivers, and health care professionals all need to be alert to the possibility of adverse events and act promptly if concerning symptoms crop up, he said.

Dr. Scherpereel said that though his study group has not yet reported the quality of life findings from MAPS-2, he sees that his patients who are study participants are doing better. “In my patients, they have a very good tolerance to this treatment compared to chemotherapy. They have less dyspnea, less chest pain. Clearly, we hope to get these drugs into the routine very quickly for them.”

Bristol-Myers Squibb manufactures both nivolumab and ipilimumab and provided the study drugs. Dr. Sabel disclosed a financial relationship with Merck. Dr. Scherpereel has no relevant financial disclosures.

The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
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– Early data from a phase II trial of immune checkpoint inhibitors to treat relapsed mesothelioma give hope that immunotherapy may be an effective therapeutic option for the rapidly progressive, currently incurable cancer.

Reporting on 12 weeks of data from the randomized multicenter trial, Arnaud Scherpereel, MD, the study’s first author, said in a video interview, “We were very pleased to see that we were able to increase ... the disease control rate to 44% with nivolumab, and 50% with nivolumab plus ipilimumab. This was translated into a overall survival gain for these patients.” The best previous disease control rate seen with other therapies was less than 30%, said Dr. Scherpereel at the annual meeting of the American Society of Clinical Oncology.

Discussing the early results in a video interview, Dr. Scherpereel, head of the pulmonary and thoracic oncology department at the University Hospital of Lille, France noted that the median overall survival for the nivolumab patients was 10.4 months, and has not yet been reached for the nivolumab plus ipilimumab patients. Further, he said in a press briefing, “Tumors shrunk in 18% of patients treated with nivolumab and 26% of those treated with nivolumab plus ipilimumab.”

The French MAPS-2 study has enrolled 125 adult patients with malignant pleural mesothelioma who had measurable disease progression after one or two prior lines of chemotherapy, including pemetrexed/platinum doublet. Patients were randomized 1:1 to receive either nivolumab or nivolumab plus ipilimumab, until disease control or unacceptable toxicity was reached, for a maximum of 2 years. Patients were mostly (80%) male, with a median age of 71.8 years, and most had the epithelioid malignant pleural mesothelioma subtype.

In commentary at the press briefing announcing the findings, ASCO expert Michael Sabel, MD, said, “I need to emphasize that this is amazing, in that we are seeing [the use of] checkpoint inhibitors expanding beyond melanoma, to other cancers that we thought were not amenable to immunotherapy approaches.”

“This is a great example of how basic cancer research in one field can expand across others,” said Dr. Sabel of the departments of surgery and surgical oncology at the University of Michigan, Ann Arbor.

Most side effects were not severe, but there were three potentially drug-related deaths in the nivolumab-ipilimumab combo arm: one patient died of fulminant hepatitis, one from metabolic encephalitis, and one from acute renal failure. “There is no identified factor that is predictive” in terms of which patients will have the more significant known adverse effects of checkpoint inhibitors, said Dr. Scherpereel. Patients, caregivers, and health care professionals all need to be alert to the possibility of adverse events and act promptly if concerning symptoms crop up, he said.

Dr. Scherpereel said that though his study group has not yet reported the quality of life findings from MAPS-2, he sees that his patients who are study participants are doing better. “In my patients, they have a very good tolerance to this treatment compared to chemotherapy. They have less dyspnea, less chest pain. Clearly, we hope to get these drugs into the routine very quickly for them.”

Bristol-Myers Squibb manufactures both nivolumab and ipilimumab and provided the study drugs. Dr. Sabel disclosed a financial relationship with Merck. Dr. Scherpereel has no relevant financial disclosures.

The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel

 

– Early data from a phase II trial of immune checkpoint inhibitors to treat relapsed mesothelioma give hope that immunotherapy may be an effective therapeutic option for the rapidly progressive, currently incurable cancer.

Reporting on 12 weeks of data from the randomized multicenter trial, Arnaud Scherpereel, MD, the study’s first author, said in a video interview, “We were very pleased to see that we were able to increase ... the disease control rate to 44% with nivolumab, and 50% with nivolumab plus ipilimumab. This was translated into a overall survival gain for these patients.” The best previous disease control rate seen with other therapies was less than 30%, said Dr. Scherpereel at the annual meeting of the American Society of Clinical Oncology.

Discussing the early results in a video interview, Dr. Scherpereel, head of the pulmonary and thoracic oncology department at the University Hospital of Lille, France noted that the median overall survival for the nivolumab patients was 10.4 months, and has not yet been reached for the nivolumab plus ipilimumab patients. Further, he said in a press briefing, “Tumors shrunk in 18% of patients treated with nivolumab and 26% of those treated with nivolumab plus ipilimumab.”

The French MAPS-2 study has enrolled 125 adult patients with malignant pleural mesothelioma who had measurable disease progression after one or two prior lines of chemotherapy, including pemetrexed/platinum doublet. Patients were randomized 1:1 to receive either nivolumab or nivolumab plus ipilimumab, until disease control or unacceptable toxicity was reached, for a maximum of 2 years. Patients were mostly (80%) male, with a median age of 71.8 years, and most had the epithelioid malignant pleural mesothelioma subtype.

In commentary at the press briefing announcing the findings, ASCO expert Michael Sabel, MD, said, “I need to emphasize that this is amazing, in that we are seeing [the use of] checkpoint inhibitors expanding beyond melanoma, to other cancers that we thought were not amenable to immunotherapy approaches.”

“This is a great example of how basic cancer research in one field can expand across others,” said Dr. Sabel of the departments of surgery and surgical oncology at the University of Michigan, Ann Arbor.

Most side effects were not severe, but there were three potentially drug-related deaths in the nivolumab-ipilimumab combo arm: one patient died of fulminant hepatitis, one from metabolic encephalitis, and one from acute renal failure. “There is no identified factor that is predictive” in terms of which patients will have the more significant known adverse effects of checkpoint inhibitors, said Dr. Scherpereel. Patients, caregivers, and health care professionals all need to be alert to the possibility of adverse events and act promptly if concerning symptoms crop up, he said.

Dr. Scherpereel said that though his study group has not yet reported the quality of life findings from MAPS-2, he sees that his patients who are study participants are doing better. “In my patients, they have a very good tolerance to this treatment compared to chemotherapy. They have less dyspnea, less chest pain. Clearly, we hope to get these drugs into the routine very quickly for them.”

Bristol-Myers Squibb manufactures both nivolumab and ipilimumab and provided the study drugs. Dr. Sabel disclosed a financial relationship with Merck. Dr. Scherpereel has no relevant financial disclosures.

The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
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Depressed, acutely ill elders benefit from short-term CBT

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Short-term cognitive-behavioral therapy is an effective intervention for geriatric patients with comorbid acute illness and depression, judging from the findings of a trial of 155 patients.

“The results presented here confirm the interaction of depression with cognitive and functional performance in this vulnerable study population,” wrote Jana Hummel, MD. “However, the extent of the effect on almost all levels of health was unexpected.”

CBT previously had not been used as a treatment for older patients with acute physical illness and comorbid depression, according to Dr. Hummel and her associates (JAMDA. 2017;18:341-9).

The authors recruited patients aged 82 years, plus or minus 6 years, from a 170-bed hospital that served as the Center for Geriatric Medicine at the University of Heidelberg, Germany. Patients who had been admitted to the hospital had a Hospital Anxiety and Depression Scale (HADS) score of greater than 7. Those with dementia or a life expectancy of less than 1 year were excluded from the study, reported Dr. Hummel of the Geriatric and Gerontopsychotherapeutic Practice in Mannheim, Germany, and her associates.

After the patients were discharged, the clinicians began the active intervention. The investigators randomized 56 people into the CBT intervention, a 15-session, manualized program designed for elderly patients who were based at home. The program included several group sessions held at the hospital’s day clinic and two individual sessions conducted by psychotherapists with expertise in gerontology.

The control group was made up of 99 people. Patients in both groups received antidepressants and other medication, the authors reported in the Journal of the American Medical Directors Association.

Four months after discharge, the patients’ severity of depression as measured by HADS scores was significantly lower among the patients in the psychotherapy group than in the usual care group (1.56 plus or minus 1.4, compared with 3.13 plus or minus 1; P less than .001). Likewise, patients in the psychotherapy group also scored lower on the Hamilton Rating Scale for Depression than did those in the control group (10.57 plus or minus 6.4, compared with 21.47 plus or minus 6.9; P less than .001).

In order for CBT to be effective for this population, arrangements might need to be made to transport patients to intervention sites, according to Dr. Hummel and her associates. Alternatively, the treatment could be administered in nursing homes. Ultimately, the authors said, “the interventions have to be tailored to the individual needs, severity of depression, and health situation.”

One limitation of the study is that the cognitive function of some elderly patients could prevent them from benefiting from CBT. However, Dr. Hummel and her associates said they are optimistic about such interventions for other geriatric patients.

“CBT provides psychological benefit to older patients with depressive symptoms, and it also can reverse some of the functional and cognitive decline associated with depression, they wrote. “It may prove to be an important tool in the treatment of depression in old age and multimorbidity.”

The study was funded with grants from the Robert Bosch Foundation and the Dietmar Hopp Foundation. Dr, Hummel and her associates declared no conflicts of interest.

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Short-term cognitive-behavioral therapy is an effective intervention for geriatric patients with comorbid acute illness and depression, judging from the findings of a trial of 155 patients.

“The results presented here confirm the interaction of depression with cognitive and functional performance in this vulnerable study population,” wrote Jana Hummel, MD. “However, the extent of the effect on almost all levels of health was unexpected.”

CBT previously had not been used as a treatment for older patients with acute physical illness and comorbid depression, according to Dr. Hummel and her associates (JAMDA. 2017;18:341-9).

The authors recruited patients aged 82 years, plus or minus 6 years, from a 170-bed hospital that served as the Center for Geriatric Medicine at the University of Heidelberg, Germany. Patients who had been admitted to the hospital had a Hospital Anxiety and Depression Scale (HADS) score of greater than 7. Those with dementia or a life expectancy of less than 1 year were excluded from the study, reported Dr. Hummel of the Geriatric and Gerontopsychotherapeutic Practice in Mannheim, Germany, and her associates.

After the patients were discharged, the clinicians began the active intervention. The investigators randomized 56 people into the CBT intervention, a 15-session, manualized program designed for elderly patients who were based at home. The program included several group sessions held at the hospital’s day clinic and two individual sessions conducted by psychotherapists with expertise in gerontology.

The control group was made up of 99 people. Patients in both groups received antidepressants and other medication, the authors reported in the Journal of the American Medical Directors Association.

Four months after discharge, the patients’ severity of depression as measured by HADS scores was significantly lower among the patients in the psychotherapy group than in the usual care group (1.56 plus or minus 1.4, compared with 3.13 plus or minus 1; P less than .001). Likewise, patients in the psychotherapy group also scored lower on the Hamilton Rating Scale for Depression than did those in the control group (10.57 plus or minus 6.4, compared with 21.47 plus or minus 6.9; P less than .001).

In order for CBT to be effective for this population, arrangements might need to be made to transport patients to intervention sites, according to Dr. Hummel and her associates. Alternatively, the treatment could be administered in nursing homes. Ultimately, the authors said, “the interventions have to be tailored to the individual needs, severity of depression, and health situation.”

One limitation of the study is that the cognitive function of some elderly patients could prevent them from benefiting from CBT. However, Dr. Hummel and her associates said they are optimistic about such interventions for other geriatric patients.

“CBT provides psychological benefit to older patients with depressive symptoms, and it also can reverse some of the functional and cognitive decline associated with depression, they wrote. “It may prove to be an important tool in the treatment of depression in old age and multimorbidity.”

The study was funded with grants from the Robert Bosch Foundation and the Dietmar Hopp Foundation. Dr, Hummel and her associates declared no conflicts of interest.

 

Short-term cognitive-behavioral therapy is an effective intervention for geriatric patients with comorbid acute illness and depression, judging from the findings of a trial of 155 patients.

“The results presented here confirm the interaction of depression with cognitive and functional performance in this vulnerable study population,” wrote Jana Hummel, MD. “However, the extent of the effect on almost all levels of health was unexpected.”

CBT previously had not been used as a treatment for older patients with acute physical illness and comorbid depression, according to Dr. Hummel and her associates (JAMDA. 2017;18:341-9).

The authors recruited patients aged 82 years, plus or minus 6 years, from a 170-bed hospital that served as the Center for Geriatric Medicine at the University of Heidelberg, Germany. Patients who had been admitted to the hospital had a Hospital Anxiety and Depression Scale (HADS) score of greater than 7. Those with dementia or a life expectancy of less than 1 year were excluded from the study, reported Dr. Hummel of the Geriatric and Gerontopsychotherapeutic Practice in Mannheim, Germany, and her associates.

After the patients were discharged, the clinicians began the active intervention. The investigators randomized 56 people into the CBT intervention, a 15-session, manualized program designed for elderly patients who were based at home. The program included several group sessions held at the hospital’s day clinic and two individual sessions conducted by psychotherapists with expertise in gerontology.

The control group was made up of 99 people. Patients in both groups received antidepressants and other medication, the authors reported in the Journal of the American Medical Directors Association.

Four months after discharge, the patients’ severity of depression as measured by HADS scores was significantly lower among the patients in the psychotherapy group than in the usual care group (1.56 plus or minus 1.4, compared with 3.13 plus or minus 1; P less than .001). Likewise, patients in the psychotherapy group also scored lower on the Hamilton Rating Scale for Depression than did those in the control group (10.57 plus or minus 6.4, compared with 21.47 plus or minus 6.9; P less than .001).

In order for CBT to be effective for this population, arrangements might need to be made to transport patients to intervention sites, according to Dr. Hummel and her associates. Alternatively, the treatment could be administered in nursing homes. Ultimately, the authors said, “the interventions have to be tailored to the individual needs, severity of depression, and health situation.”

One limitation of the study is that the cognitive function of some elderly patients could prevent them from benefiting from CBT. However, Dr. Hummel and her associates said they are optimistic about such interventions for other geriatric patients.

“CBT provides psychological benefit to older patients with depressive symptoms, and it also can reverse some of the functional and cognitive decline associated with depression, they wrote. “It may prove to be an important tool in the treatment of depression in old age and multimorbidity.”

The study was funded with grants from the Robert Bosch Foundation and the Dietmar Hopp Foundation. Dr, Hummel and her associates declared no conflicts of interest.

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Weight gain in pregnancy: Too much and too little can be harmful

How to combat the ‘eating for two’ message
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Both high and low gestational weight gain, compared with the recommended weight gain, are associated with increased risks of adverse perinatal outcomes, according to a systematic review and meta-analysis.

Stephanie Horrocks/iStockphoto
Gestational weight gain was below 2009 Institute of Medicine guidelines in 23% of these pregnancies, within recommended guidelines in 30%, and above recommended guidelines in 47%, said Rebecca F. Goldstein, MBBS, of Monash University, Victoria, Australia, and her associates.

Compared with the recommended gestational weight gain, low weight gain was associated with a 5% higher risk of a small-for-gestational-age (SGA) neonate and a 5% higher risk of preterm birth. However, low weight gain reduced the risks of a large-for-gestational-age (LGA) neonate and macrosomia.

Compared with the recommended gestational weight gain, high weight gain was associated with a 4% higher risk of cesarean delivery, a 4% higher risk of a LGA neonate, and a 6% higher risk of macrosomia. However, high weight gain reduced the risk of an SGA neonate by 3% and that of preterm birth by 2%, the researchers reported (JAMA. 2017;317[21]:2207-25).

These increases and decreases in risks remained consistent regardless of the mother’s prepregnancy BMI, they noted.

The effect of either high or low gestational weight gain on the risk of gestational diabetes could not be determined because of inconsistencies across the 23 cohort studies concerning definitions and treatments.

The Australian Department of Education and Training and the Australian National Health and Medical Research Council supported the study. Dr. Goldstein reported having no relevant financial disclosures; one of her associates reported serving on the Women’s Health Global Advisory Board for Pfizer.

Body

 

The findings by Goldstein et al. raise the question: Can clinicians change the amount of weight women gain in pregnancy?

Behavioral economics has demonstrated that loss avoidance is a stronger motivator than the promise of a gain. So rather than positive incentives for adherent behavior, emphasizing how a pregnant woman’s nonadherent behavior will lead to greater harm to her developing baby may be more effective in changing behavior. Sending a message that gaining too much weight could potentially lead to an increased risk of obesity in her child and that gaining too little weight could lead to growth restriction in the child may be better than a simple positive message that eating well leads to greater health for both the mother and infant.

Given the overwhelming environment of constant advertising of high-caloric foods that pregnant women are exposed to, such reminders need to be delivered persistently and frequently – perhaps with the enhanced messaging capacity of social media and public health campaigns.

Aaron B. Caughey, MD, PhD, is in the department of ob.gyn. at Oregon Health & Science University, Portland. He reported having no relevant financial disclosures. These remarks are adapted from an accompanying editorial (JAMA 2017;317[21]:2175-6).

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The findings by Goldstein et al. raise the question: Can clinicians change the amount of weight women gain in pregnancy?

Behavioral economics has demonstrated that loss avoidance is a stronger motivator than the promise of a gain. So rather than positive incentives for adherent behavior, emphasizing how a pregnant woman’s nonadherent behavior will lead to greater harm to her developing baby may be more effective in changing behavior. Sending a message that gaining too much weight could potentially lead to an increased risk of obesity in her child and that gaining too little weight could lead to growth restriction in the child may be better than a simple positive message that eating well leads to greater health for both the mother and infant.

Given the overwhelming environment of constant advertising of high-caloric foods that pregnant women are exposed to, such reminders need to be delivered persistently and frequently – perhaps with the enhanced messaging capacity of social media and public health campaigns.

Aaron B. Caughey, MD, PhD, is in the department of ob.gyn. at Oregon Health & Science University, Portland. He reported having no relevant financial disclosures. These remarks are adapted from an accompanying editorial (JAMA 2017;317[21]:2175-6).

Body

 

The findings by Goldstein et al. raise the question: Can clinicians change the amount of weight women gain in pregnancy?

Behavioral economics has demonstrated that loss avoidance is a stronger motivator than the promise of a gain. So rather than positive incentives for adherent behavior, emphasizing how a pregnant woman’s nonadherent behavior will lead to greater harm to her developing baby may be more effective in changing behavior. Sending a message that gaining too much weight could potentially lead to an increased risk of obesity in her child and that gaining too little weight could lead to growth restriction in the child may be better than a simple positive message that eating well leads to greater health for both the mother and infant.

Given the overwhelming environment of constant advertising of high-caloric foods that pregnant women are exposed to, such reminders need to be delivered persistently and frequently – perhaps with the enhanced messaging capacity of social media and public health campaigns.

Aaron B. Caughey, MD, PhD, is in the department of ob.gyn. at Oregon Health & Science University, Portland. He reported having no relevant financial disclosures. These remarks are adapted from an accompanying editorial (JAMA 2017;317[21]:2175-6).

Title
How to combat the ‘eating for two’ message
How to combat the ‘eating for two’ message

 

Both high and low gestational weight gain, compared with the recommended weight gain, are associated with increased risks of adverse perinatal outcomes, according to a systematic review and meta-analysis.

Stephanie Horrocks/iStockphoto
Gestational weight gain was below 2009 Institute of Medicine guidelines in 23% of these pregnancies, within recommended guidelines in 30%, and above recommended guidelines in 47%, said Rebecca F. Goldstein, MBBS, of Monash University, Victoria, Australia, and her associates.

Compared with the recommended gestational weight gain, low weight gain was associated with a 5% higher risk of a small-for-gestational-age (SGA) neonate and a 5% higher risk of preterm birth. However, low weight gain reduced the risks of a large-for-gestational-age (LGA) neonate and macrosomia.

Compared with the recommended gestational weight gain, high weight gain was associated with a 4% higher risk of cesarean delivery, a 4% higher risk of a LGA neonate, and a 6% higher risk of macrosomia. However, high weight gain reduced the risk of an SGA neonate by 3% and that of preterm birth by 2%, the researchers reported (JAMA. 2017;317[21]:2207-25).

These increases and decreases in risks remained consistent regardless of the mother’s prepregnancy BMI, they noted.

The effect of either high or low gestational weight gain on the risk of gestational diabetes could not be determined because of inconsistencies across the 23 cohort studies concerning definitions and treatments.

The Australian Department of Education and Training and the Australian National Health and Medical Research Council supported the study. Dr. Goldstein reported having no relevant financial disclosures; one of her associates reported serving on the Women’s Health Global Advisory Board for Pfizer.

 

Both high and low gestational weight gain, compared with the recommended weight gain, are associated with increased risks of adverse perinatal outcomes, according to a systematic review and meta-analysis.

Stephanie Horrocks/iStockphoto
Gestational weight gain was below 2009 Institute of Medicine guidelines in 23% of these pregnancies, within recommended guidelines in 30%, and above recommended guidelines in 47%, said Rebecca F. Goldstein, MBBS, of Monash University, Victoria, Australia, and her associates.

Compared with the recommended gestational weight gain, low weight gain was associated with a 5% higher risk of a small-for-gestational-age (SGA) neonate and a 5% higher risk of preterm birth. However, low weight gain reduced the risks of a large-for-gestational-age (LGA) neonate and macrosomia.

Compared with the recommended gestational weight gain, high weight gain was associated with a 4% higher risk of cesarean delivery, a 4% higher risk of a LGA neonate, and a 6% higher risk of macrosomia. However, high weight gain reduced the risk of an SGA neonate by 3% and that of preterm birth by 2%, the researchers reported (JAMA. 2017;317[21]:2207-25).

These increases and decreases in risks remained consistent regardless of the mother’s prepregnancy BMI, they noted.

The effect of either high or low gestational weight gain on the risk of gestational diabetes could not be determined because of inconsistencies across the 23 cohort studies concerning definitions and treatments.

The Australian Department of Education and Training and the Australian National Health and Medical Research Council supported the study. Dr. Goldstein reported having no relevant financial disclosures; one of her associates reported serving on the Women’s Health Global Advisory Board for Pfizer.

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Key clinical point: Both high and low gestational weight gain are associated with increased risks of adverse perinatal outcomes.

Major finding: Low gestational weight gain was associated with a 5% higher risk of an SGA neonate and a 5% higher risk of preterm birth, while high weight gain was associated with a 4% higher risk of cesarean delivery, a 4% higher risk of an LGA neonate, and a 6% higher risk of macrosomia.

Data source: A systematic review and meta-analysis of 23 studies involving 1,309,136 pregnancies from diverse international cohorts.

Disclosures: The Australian Department of Education and Training and the Australian National Health and Medical Research Council supported the study. Dr. Goldstein reported having no relevant financial disclosures; one of her associates reported serving on the Women’s Health Global Advisory Board for Pfizer.

Does Preoperative Pneumonia Affect Complications of Geriatric Hip Fracture Surgery?

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Does Preoperative Pneumonia Affect Complications of Geriatric Hip Fracture Surgery?

Take-Home Points

  • The prevalence of preoperative pneumonia is 1.2% among hip fracture patients aged >65 years.
  • Preoperative pneumonia is an independent risk factor for mortality and adverse events including renal failure, prolonged ventilator dependence, and prolonged altered mental status after geriatric hip fracture surgery.
  • Underweight BMI (<18.5 kg/m2) was associated with higher mortality within 30 days among hip fracture patients admitted with pneumonia.
  • The mortality rate normalized to that of patients without pneumonia within 2 weeks of hip fracture surgery.
  • Time from admission to surgery was not associated with adverse events or mortality among hip fracture patients admitted with pneumonia.

Preoperative pneumonia remains relatively unexplored as a risk factor for adverse outcomes in geriatric hip fracture surgery. Dated studies report a 0.3% to 3.2% prevalence of “recent pneumonia” in patients presenting with hip fracture but provide neither a definition of pneumonia based on clinical criteria nor a subset analysis of outcomes in the pneumonia group.1-3 Although active pneumonia has been identified as a preoperative optimization target in the management guidelines for geriatric hip fracture,4 we are unaware of any studies that have reported on differences in demographics, comorbidities, delay to surgery, or adverse outcomes between hip fracture patients with and without preoperative pneumonia.

This paucity of information on the effect of preoperative pneumonia in the hip fracture population may be related to low prevalence of preoperative pneumonia and a cadre of variable definitions, which limit identification of a cohort of patients with preoperative pneumonia large enough from which to draw meaningful results. Database studies, especially those using surgical registries rather than administrative or reimbursement data, offer particular advantages for investigation of such rare clinical entities.5Medical care of patients with pneumonia alone is known to be facilitated by assessments of mortality risk from clinical and laboratory data. The modified British Thoracic Society rule/CURB-65 (confusion, urea, respiratory rate, blood pressure) score is strongly predictive of mortality in hospitalized adults with pneumonia (odds ratio [OR], 4.59; 95% confidence interval [CI], 1.42-14.85; P = .011) and may guide antibiotic therapy, laboratory investigations, and the decision to intubate in a patient with pneumonia.6-8 This score is predictive of adverse events (AEs), hospital length of stay, and use of intensive care services.6,7,9-13 We hypothesized that preoperative clinical indicators assessed by pneumonia severity scores as well as patient demographics and baseline comorbidities may also have prognostic value for risk of AEs in a cohort of geriatric hip fracture surgery patients with preoperative pneumonia.

In this article, we first describe the prevalence of preoperative pneumonia in geriatric hip fracture surgery patients as well as demographic and operative differences between patients with and without the disease. We then ask 3 questions: Is preoperative pneumonia an independent risk factor for mortality and adverse outcomes in geriatric hip fracture surgery? Is there a postoperative interval during which the unadjusted mortality rate is higher among patients with preoperative pneumonia? In patients with preoperative pneumonia, what are the predictors of morbidity and mortality?

Methods

Yale University’s Human Investigations Committee approved this retrospective cohort study, which used the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database for the period 2005 to 2012. ACS-NSQIP is a prospective, multi-institutional outcomes program that collects data on preoperative comorbidities, intraoperative variables, and 30-day postoperative outcomes for patients undergoing surgical procedures in inpatient and outpatient settings.14

Unlike administrative databases, which are based on reimbursement data, ACS-NSQIP data are collected by trained surgical clinical reviewers for the purposes of quality improvement and clinical research, and data quality is ensured with routine auditing.15 The program has gained a high degree of respect as a powerful and valid data source in both general16 and orthopedic17 surgery literature. The database offers a particular advantage with respect to the study of preoperative pneumonia: Only patients with new or recently diagnosed pneumonia on antibiotic therapy who meet strict criteria for characteristic findings on chest radiography, clinical signs and symptoms of respiratory illness, and positive cultures are coded as having actively treated pneumonia at time of surgery.15

To identify hip fracture patients over the age of 65 years who underwent operative fixation of a hip fracture, we used Current Procedural Terminology (CPT) hip fracture codes, including 27235 (percutaneous screw fixation), 27236 or 27244 (plate-and-screw fixation), and 27245 (intramedullary device), as well as 27125 (hemiarthroplasty) and 27130 (arthroplasty) for patients with a postoperative International Classification of Disease, Ninth Revision (ICD-9) diagnosis code (820.x, 820.2x, or 820.8) consistent with acute hip fracture.18,19 Procedure type, anesthesia type, and delay from admission to surgery were captured for all procedures.

Preoperative demographics included age, sex, transfer origin, functional status, and body mass index (BMI) category. Binary comorbidities were classified as preoperative anemia (hematocrit, <0.41 for men, <0.36 for women), confusion, dyspnea at rest, uremia (blood urea nitrogen, >6.8 mmol/L), history of cardiovascular disease (congestive heart failure, myocardial infarction, percutaneous coronary intervention, angina pectoris, medically treated hypertension, peripheral vascular disease, or resting claudication), chronic obstructive pulmonary disease, diabetes, renal disease (renal failure or dialysis), and cigarette use in preceding 12 months.20,21 Although preoperative hypotension and respiratory rate are often considered in patients with pneumonia, these variables were not available from the ACS-NSQIP data.6,22Pearson χ2 test for categorical variables was used to compare baseline demographics and operative characteristics between patients with and without pneumonia, and Student t test was used to compare intervals from hospital admission to hip fracture surgery, surgery start to surgery stop, and surgery to discharge between patients with and without preoperative pneumonia.

Binary outcome measures were compared between patients with and without preoperative pneumonia. “Any AE” included any serious AE (SAE) or any minor AE. SAEs included death, acute renal failure, ventilator use >48 hours, unplanned intubation, septic shock, sepsis, return to operating room, coma >24 hours, cardiac arrest requiring cardiopulmonary resuscitation, myocardial infarction, thromboembolic event (deep vein thrombosis or pulmonary embolism), and stroke/cerebrovascular accident. Minor AEs included progressive renal insufficiency, urinary tract infection, organ/space infection, superficial surgical-site infection, deep surgical-site infection, and wound dehiscence. Other binary outcome measures included discharge destination and unplanned readmission within 30 days after hip fracture surgery.23Poisson regression with robust error variance as described by Zou24 was used to compare the rates of any, minor, and individual AEs, and any SAEs, between patients with and without pneumonia. Multivariate analysis accounted for the baseline variables in Table 1. AEs that occurred more than once in each group were included in the analyses.



Kaplan-Meier survival analysis was performed for postoperative mortality within 30 days. Within the preoperative pneumonia group, covariates from Table 1 were identified as predictors of any AE, SAE, or death within 30 days after hip fracture surgery by stepwise multivariate Poisson regression with robust error variance. When interval from admission to surgery was longer than 24, 48, 72, or 96 hours, it was also included as a covariate. Variables that did not show an association with AEs at the P < .20 level were not included in the final regression model. All analyses were performed with Stata/SE Version 12.0 statistical software (StataCorp).

 

 

Results

Of the 7128 geriatric hip fracture patients in this study, 82 (1.2%) had active pneumonia at time of surgery (Table 1). Age, BMI, preoperative uremia, history of cardiovascular disease, diabetes, renal disease, and smoking were similar between groups. In addition, there was no difference in anesthesia type or fixation procedure between the pneumonia and no-pneumonia groups. Patients with preoperative pneumonia differed significantly with respect to sex, transfer from facility, preoperative functional dependence, anemia, confusion, dyspnea at rest, and history of chronic obstructive pulmonary disease (Table 1).

Interval from admission to surgery was longer (P < .001) for geriatric hip fracture patients with preoperative pneumonia (mean, 6.8 days; 95% CI, 2.5-11.1 days) than for those without pneumonia (mean, 1.5 days; CI, 1.4-1.5 days). There was no difference (P = .124) in operative time between the pneumonia group (mean, 72.8 min; CI, 64.0-81.5 min) and the no-pneumonia group (mean, 66.1 min; CI, 61.2-67.0 min). Interval from surgery to discharge was longer (P < .001) for patients with preoperative pneumonia (mean, 10.1 days; CI, 6.9-13.4 days) than for those without pneumonia (mean, 6.3 days; CI, 6.1-6.4 days).

Adverse outcomes of geriatric hip fracture surgery are listed in Table 2. In the multivariate analysis, preoperative pneumonia was significantly associated with any AE (relative risk [RR]) = 1.44) and any SAE (RR = 1.79).

Specific AEs were also assessed. In terms of SAEs, patients with pneumonia were more likely to die (RR = 2.08), develop acute renal failure (RR = 14.61), become comatose for more than 24 hours (RR = 7.31), and require mechanical ventilation for more than 48 hours after surgery (RR = 6.48). In terms of minor AEs, there were no significant differences between patients with and without pneumonia.

Survival patterns diverged between patients with and without preoperative pneumonia (Figure). The unadjusted mortality rate was qualitatively higher in patients with preoperative pneumonia than in patients without pneumonia during the first days after hip fracture (slopes of unadjusted mortality curves in Figure). Of note, no patient under age 75 years with pneumonia at time of surgery died within the 30-day study period.

Among geriatric hip fracture patients with preoperative pneumonia, multivariate analyses revealed no significant association of any preoperative comorbidity with any AE or any SAE. Given the gravity of the death complication, however, death within 30 days after surgery was analyzed separately, and was found to be significantly associated (RR = 4.67) with being underweight (BMI, <18.5 kg/m2) (Table 3). Admission-to-surgery interval longer than 24, 48, 72, or 96 hours did not reach significance at the P < 0.2 level in the stepwise regressions and therefore was not associated with a higher or lower risk of any AE, SAE, or death.

Discussion

In the general US population, pneumonia accounts for 1.4% of deaths in people 65 years to 74 years old, 2.1% in people 75 years to 84 years, and 3.1% in people 85 years or older. In total, 3.4% of hospital inpatient deaths are attributed to pneumonia.25 In hospitalized general orthopedic surgical patients as well as hip fracture patients, pneumonia is strongly associated with increased mortality.26,27

We identified a preoperative pneumonia prevalence of 1.2%, which is comparable to the rates reported in the literature (0.3%-3.2%).1-3 To our knowledge, our study represents the largest series of patients with preoperative pneumonia at time of hip fracture repair, and the first to independently associate preoperative pneumonia with increased incidence of AEs, including death.

This study had its limitations. First, the ACS-NSQIP morbidity and mortality data, which are limited to the first 30 postoperative days, may be skewed because AEs that occurred after that interval are not captured. Second, coding of pneumonia in ACS-NSQIP does not convey specific information about the disease and its severity—infectious organism(s) responsible; acquisition setting (healthcare or community); treatment given, including antibiotic(s) selection, steroid use, dosing, and duration; and measures of treatment efficacy—limiting interpretation of the difference in delay to surgery. We cannot say whether the longer interval in patients with pneumonia reflects medical optimization, or whether the delay itself or any interventions during that time positively or negatively affected outcomes. In addition, despite using a large national database, we obtained a relatively small sample of patients (82) who had pneumonia before surgical hip fracture repair.

Multivariate analysis controlling for baseline demographics and comorbidities revealed that multiple SAEs were independently associated with preoperative pneumonia (overall SAE, RR = 1.79). Postoperative use of ventilator support for longer than 48 hours (RR = 6.48) and coma longer than 24 hours (RR = 7.31) are expected given the severity of pulmonary compromise in the study cohort.28,29 Acute renal failure (RR = 14.61) can occur in both hip fracture patients and community-acquired pneumonia patients and may be a multifactorial complication of the pulmonary infection, of the anesthesia, or of the surgical intervention in this cohort.30-32Unadjusted mortality in hip fracture takes months to a year to normalize to that of age-matched controls.32-34 In our series, the unadjusted death rate in the pneumonia cohort (Figure) was transiently elevated during the first weeks after surgery but then drew nearer the rate in the nondiseased hip fracture cohort by the end of the first month. Early death in the pneumonia group likely was multifactorial, potentially influenced by the increased burden of comorbidities in the pneumonia group at baseline, and the longer delay to surgery,35-38 as well as by the natural history of treated pneumonia in hospital patients, who, compared with age-matched hospitalized controls, also exhibit higher mortality during only the first 2 to 4 months of hospitalization for pneumonia.39 We regret that quality improvement strategies in the treatment of geriatric hip fracture surgery with pneumonia cannot be extrapolated from these results.

Similarly, the utility of BMI <18.5 kg/m2 as an actionable preoperative finding cannot be assessed from these results. However, we propose that underweight geriatric hip fracture patients with pneumonia may benefit from more aggressive preoperative optimization that does not delay surgery. Higher acuity of postoperative care, including more intensive nursing care and early coordination of care with respiratory therapists and medical comanagement teams, may also be beneficial.

Anesthesia type did not differ between patients with and without preoperative pneumonia and was not associated with AEs in patients with preoperative pneumonia. Consistent with our findings, multiple studies have reported no significant differences in short-term outcomes of hip fracture repair between general and spinal anesthesia, though no other study has compared the benefits of general and spinal anesthesia for patients with preoperative pneumonia.40-44 Although spinal anesthesia (relative to general anesthesia) has been reported to have benefits in hip and knee arthroplasty, these benefits appear not to translate to hip fracture repair.45-50 The results of the present study suggest that general and spinal anesthesia may be equivalent in terms of risk for the geriatric hip fracture patient with preoperative pneumonia.43,44Our attempt to evaluate the CURB-65 pneumonia severity score as a prognosticator of AEs was thwarted by the absence of required variables in the ACS-NSQIP dataset (confusion, uremia, dyspnea, and age were available; hypotension and blood pressure were not). In our analysis, we did include, individually, variables previously found to predict AEs in the medical pneumonia population (confusion, uremia, dyspnea at rest, anemia).9-11,32 However, these clinical findings are nonspecific in hip fracture patients, who may become anemic, confused, dyspneic, or uremic from a multitude of factors related to their injury and unrelated to pneumonia, including but not limited to hemorrhage, muscle damage, renal injury, and pulmonary embolism. It is not surprising that confusion, uremia, dyspnea at rest, and anemia were not individually predictive of AEs or death within 30 days after surgery in the cohort of geriatric hip fracture patients with pneumonia.

There is no literature that argues for or against delaying hip fracture surgery in geriatric hip fracture patients with pneumonia. The surgical delay observed in this population is ostensibly related to medical optimization of the pneumonia and/or underlying comorbidities. However, we did not find a morbidity or mortality detriment or benefit in delaying surgery by 1 to 4 days in this population. Delay of surgery is a poor covariate, given extensive confounding by medical management and preoperative optimizing of comorbid conditions (reflected in our independent variable and covariates) as well as institutional and surgeon variations in policy and behavior and other unaccounted influences. Although some authors have found no difference in mortality or major AEs between hip fracture patients who had a surgical delay and those who did not,31,51-53 other series and meta-analyses have suggested a mortality detriment in a surgical delay of more than 2 days36,54 or 4 days55 from admission. Given our data, we cannot recommend against immediate hip fracture repair in the subpopulation of geriatric hip fracture patients with pneumonia.

Our study findings suggest that preoperative pneumonia is a rare independent risk factor for AEs after hip fracture surgery in geriatric patients. Underweight BMI is predictive of death in geriatric hip fracture surgery patients who present with pneumonia, whereas early surgical repair appears not to be associated with adverse outcomes. Further investigation is warranted to determine if such patients benefit from specific preoperative and postoperative strategies for optimizing medical and surgical care based on these findings.

Am J Orthop. 2017;46(3):E177-E185. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

References

1. Sexson SB, Lehner JT. Factors affecting hip fracture mortality. J Orthop Trauma. 1987;1(4):298-305.

2. Mullen JO, Mullen NL. Hip fracture mortality: a prospective, multifactorial study to predict and minimize death risk. Clin Orthop Relat Res. 1992;(280):214-222.

3. Kenzora JE, McCarthy RE, Lowell JD, Sledge CB. Hip fracture mortality. Relation to age, treatment, preoperative illness, time of surgery, and complications. Clin Orthop Relat Res. 1984;(186):45-56.

4. Auron-Gomez M, Michota F. Medical management of hip fracture. Clin Geriatr Med. 2008;24(4):701-719.

5. Bohl DD, Basques BA, Golinvaux NS, Baumgaertner MR, Grauer JN. Nationwide Inpatient Sample and National Surgical Quality Improvement Program give different results in hip fracture studies. Clin Orthop Relat Res. 2014;472(6):1672-1680.

6. Lim WS, van der Eerden MM, Laing R, et al. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax. 2003;58(5):377-382.

7. Myint PK, Kamath AV, Vowler SL, Maisey DN, Harrison BDW. The CURB (confusion, urea, respiratory rate and blood pressure) criteria in community-acquired pneumonia (CAP) in hospitalised elderly patients aged 65 years and over: a prospective observational cohort study. Age Ageing. 2005;34(1):75-77.

8. Wilkinson M, Woodhead MA. Guidelines for community-acquired pneumonia in the ICU. Curr Opin Crit Care. 2004;10(1):59-64.

9. Buising K, Thursky K, Black J, et al. A prospective comparison of severity scores for identifying patients with severe community acquired pneumonia: reconsidering what is meant by severe pneumonia. Thorax. 2006;61(5):419-424.

10. Ewig S, De Roux A, Bauer T, et al. Validation of predictive rules and indices of severity for community acquired pneumonia. Thorax. 2004;59(5):421-427.

11. Yandiola PP, Capelastegui A, Quintana J, et al. Prospective comparison of severity scores for predicting clinically relevant outcomes for patients hospitalized with community-acquired pneumonia. Chest. 2009;135(6):1572-1579.

12. Lim WS, Lewis S, Macfarlane JT. Severity prediction rules in community acquired pneumonia: a validation study. Thorax. 2000;55(3):219-223.

13. Bauer TT, Ewig S, Marre R, Suttorp N, Welte T; CAPNETZ Study Group. CRB‐65 predicts death from community‐acquired pneumonia. J Intern Med. 2006;260(1):93-101.

14. Khuri SF. The NSQIP: a new frontier in surgery. Surgery. 2005;138(5):837-843.

15. American College of Surgeons. User Guide for the 2012 ACS NSQIP Participant Use Data File: American College of Surgeons National Surgical Quality Improvement Program. https://www.facs.org/~/media/files/quality%20programs/nsqip/ug12.ashx. Published October 2013. Accessed October 8, 2014.

16. Ingraham AM, Richards KE, Hall BL, Ko CY. Quality improvement in surgery: the American College of Surgeons National Surgical Quality Improvement Program approach. Adv Surg. 2010;44(1):251-267.

17. Schilling PL, Hallstrom BR, Birkmeyer JD, Carpenter JE. Prioritizing perioperative quality improvement in orthopaedic surgery. J Bone Joint Surg Am. 2010;92(9):1884-1889.

18. Radcliff TA, Henderson WG, Stoner TJ, Khuri SF, Dohm M, Hutt E. Patient risk factors, operative care, and outcomes among older community-dwelling male veterans with hip fracture. J Bone Joint Surg Am. 2008;90(1):34-42.

19. Katzan I, Cebul R, Husak S, Dawson N, Baker D. The effect of pneumonia on mortality among patients hospitalized for acute stroke. Neurology. 2003;60(4):620-625.

20. Fisher MA, Matthei JD, Obirieze A, et al. Open reduction internal fixation versus hemiarthroplasty versus total hip arthroplasty in the elderly: a review of the National Surgical Quality Improvement Program database. J Surg Res. 2013;181(2):193-198.

21. Pugely AJ, Martin CT, Gao Y, Klocke NF, Callaghan JJ, Marsh JL. A risk calculator for short-term morbidity and mortality after hip fracture surgery. J Orthop Trauma. 2014;28(2):63-69.

22. Fine MJ, Smith MA, Carson CA, et al. Prognosis and outcomes of patients with community-acquired pneumonia: a meta-analysis. JAMA. 1996;275(2):134-141.

23. Donegan DJ, Gay AN, Baldwin K, Morales EE, Esterhai JL Jr, Mehta S. Use of medical comorbidities to predict complications after hip fracture surgery in the elderly. J Bone Joint Surg Am. 2010;92(4):807-813.

24. Zou G. A modified poisson regression approach to prospective studies with binary data. Am J Epidemiol. 2004:159(7):702-706.

25. Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2010. Natl Vital Stat Rep. 20138;61(4):1-117.

26. Bhattacharyya T, Iorio R, Healy WL. Rate of and risk factors for acute inpatient mortality after orthopaedic surgery. J Bone Joint Surg Am. 2002;84(4):562-572.

27. Myers AH, Robinson EG, Van Natta ML, Michelson JD, Collins K, Baker SP. Hip fractures among the elderly: factors associated with in-hospital mortality. Am J Epidemiol. 1991;134(10):1128-1137.

28. Mandell LA, Wunderink RG, Anzueto A, et al; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(suppl 2):S27-S72.

29. Leroy O, Santre C, Beuscart C, et al. A five-year study of severe community-acquired pneumonia with emphasis on prognosis in patients admitted to an intensive care unit. Intensive Care Med. 1995;21(1):24-31.

30. Urwin S, Parker M, Griffiths R. General versus regional anaesthesia for hip fracture surgery: a meta-analysis of randomized trials. Br J Anaesth. 2000;84(4):450-455.

31. Orosz GM, Magaziner J, Hannan EL, et al. Association of timing of surgery for hip fracture and patient outcomes. JAMA. 2004;291(14):1738-1743.

32. Niederman MS, Mandell LA, Anzueto A, et al; American Thoracic Society. Guidelines for the management of adults with community-acquired pneumonia: diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med. 2001;163(7):1730-1754.

33. Koval KJ, Skovron ML, Aharonoff GB, Zuckerman JD. Predictors of functional recovery after hip fracture in the elderly. Clin Orthop Relat Res. 1998;(348):22-28.

34. Doruk H, Mas MR, Yildiz C, Sonmez A, Kýrdemir V. The effect of the timing of hip fracture surgery on the activity of daily living and mortality in elderly. Arch Gerontol Geriatr. 2004;39(2):179-185.

35. George GH, Patel S. Secondary prevention of hip fracture. Rheumatology. 2000;39(4):346-349.

36. Bottle A, Aylin P. Mortality associated with delay in operation after hip fracture: observational study. BMJ. 2006;332(7547):947-951.

37. Grimes JP, Gregory PM, Noveck H, Butler MS, Carson JL. The effects of time-to-surgery on mortality and morbidity in patients following hip fracture. Am J Med. 2002;112(9):702-709.

38. Simunovic N, Devereaux P, Sprague S, et al. Effect of early surgery after hip fracture on mortality and complications: systematic review and meta-analysis. CMAJ. 2010;182(15):1609-1616.

 

 

39. Kaplan V, Clermont G, Griffin MF, et al. Pneumonia: still the old man’s friend? Arch Intern Med. 2003;163(3):317-323.

40. Parker MJ, Handoll HH, Griffiths R. Anaesthesia for hip fracture surgery in adults. Cochrane Database Syst Rev. 2004;(4):CD000521.

41. Chakladar A, White SM. Cost estimates of spinal versus general anaesthesia for fractured neck of femur surgery. Anaesthesia. 2010;65(8):810-814.

42. White SM, Moppett IK, Griffiths R. Outcome by mode of anaesthesia for hip fracture surgery. An observational audit of 65 535 patients in a national dataset. Anaesthesia. 2014;69(3):224-230.

43. Gilbert TB, Hawkes WG, Hebel JR, et al. Spinal anesthesia versus general anesthesia for hip fracture repair: a longitudinal observation of 741 elderly patients during 2-year follow-up. Am J Orthop. 2000;29(1):25-35.

44. O’Hara DA, Duff A, Berlin JA, et al. The effect of anesthetic technique on postoperative outcomes in hip fracture repair. Anesthesiology. 2000;92(4):947-957.

45. Hole A, Terjesen T, Breivik H. Epidural versus general anaesthesia for total hip arthroplasty in elderly patients. Acta Anaesthesiol Scand. 1980;24(4):279-287.

46. Rashiq S, Finegan BA. The effect of spinal anesthesia on blood transfusion rate in total joint arthroplasty. Can J Surg. 2006;49(6):391-396.

47. Chang CC, Lin HC, Lin HW, Lin HC. Anesthetic management and surgical site infections in total hip or knee replacement: a population-based study. Anesthesiology. 2010;113(2):279-284.

48. Mauermann WJ, Shilling AM, Zuo Z. A comparison of neuraxial block versus general anesthesia for elective total hip replacement: a meta-analysis. Anesth Analg. 2006;103(4):1018-1025.

49. Hu S, Zhang ZY, Hua YQ, Li J, Cai ZD. A comparison of regional and general anaesthesia for total replacement of the hip or knee: a meta-analysis. J Bone Joint Surg Br. 2009;91(7):935-942.

50. Pugely AJ, Martin CT, Gao Y, Mendoza-Lattes S, Callaghan JJ. Differences in short-term complications between spinal and general anesthesia for primary total knee arthroplasty. J Bone Joint Surg Am. 2013;95(3):193-199.

51. Khan SK, Kalra S, Khanna A, Thiruvengada MM, Parker MJ. Timing of surgery for hip fractures: a systematic review of 52 published studies involving 291,413 patients. Injury. 2009;40(7):692-697.

52. Majumdar SR, Beaupre LA, Johnston DW, Dick DA, Cinats JG, Jiang HX. Lack of association between mortality and timing of surgical fixation in elderly patients with hip fracture: results of a retrospective population-based cohort study. Med Care. 2006;44(6):552-559.

53. Moran CG, Wenn RT, Sikand M, Taylor AM. Early mortality after hip fracture: is delay before surgery important? J Bone Joint Surg Am. 2005;87(3):483-489.

54. Shiga T, Wajima Zi, Ohe Y. Is operative delay associated with increased mortality of hip fracture patients? Systematic review, meta-analysis, and meta-regression. Can J Anesth. 2008;55(3):146-154.

55. Streubel P, Ricci W, Wong A, Gardner M. Mortality after distal femur fractures in elderly patients. Clin Orthop Relat Res. 2011;469(4):1188-1196.

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Acknowledgments: The authors thank Jensa Morris, MD, and Nicholas S. Golinvaux, MD, for their advice regarding the design and scope of this study.

Authors’ Disclosure Statement: Dr. Grauer reports that he or an immediate family member receives consulting fees from Bioventus, Medtronic, and Stryker. The other authors report no actual or potential conflict of interest in relation to this article.

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Acknowledgments: The authors thank Jensa Morris, MD, and Nicholas S. Golinvaux, MD, for their advice regarding the design and scope of this study.

Authors’ Disclosure Statement: Dr. Grauer reports that he or an immediate family member receives consulting fees from Bioventus, Medtronic, and Stryker. The other authors report no actual or potential conflict of interest in relation to this article.

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Acknowledgments: The authors thank Jensa Morris, MD, and Nicholas S. Golinvaux, MD, for their advice regarding the design and scope of this study.

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Take-Home Points

  • The prevalence of preoperative pneumonia is 1.2% among hip fracture patients aged >65 years.
  • Preoperative pneumonia is an independent risk factor for mortality and adverse events including renal failure, prolonged ventilator dependence, and prolonged altered mental status after geriatric hip fracture surgery.
  • Underweight BMI (<18.5 kg/m2) was associated with higher mortality within 30 days among hip fracture patients admitted with pneumonia.
  • The mortality rate normalized to that of patients without pneumonia within 2 weeks of hip fracture surgery.
  • Time from admission to surgery was not associated with adverse events or mortality among hip fracture patients admitted with pneumonia.

Preoperative pneumonia remains relatively unexplored as a risk factor for adverse outcomes in geriatric hip fracture surgery. Dated studies report a 0.3% to 3.2% prevalence of “recent pneumonia” in patients presenting with hip fracture but provide neither a definition of pneumonia based on clinical criteria nor a subset analysis of outcomes in the pneumonia group.1-3 Although active pneumonia has been identified as a preoperative optimization target in the management guidelines for geriatric hip fracture,4 we are unaware of any studies that have reported on differences in demographics, comorbidities, delay to surgery, or adverse outcomes between hip fracture patients with and without preoperative pneumonia.

This paucity of information on the effect of preoperative pneumonia in the hip fracture population may be related to low prevalence of preoperative pneumonia and a cadre of variable definitions, which limit identification of a cohort of patients with preoperative pneumonia large enough from which to draw meaningful results. Database studies, especially those using surgical registries rather than administrative or reimbursement data, offer particular advantages for investigation of such rare clinical entities.5Medical care of patients with pneumonia alone is known to be facilitated by assessments of mortality risk from clinical and laboratory data. The modified British Thoracic Society rule/CURB-65 (confusion, urea, respiratory rate, blood pressure) score is strongly predictive of mortality in hospitalized adults with pneumonia (odds ratio [OR], 4.59; 95% confidence interval [CI], 1.42-14.85; P = .011) and may guide antibiotic therapy, laboratory investigations, and the decision to intubate in a patient with pneumonia.6-8 This score is predictive of adverse events (AEs), hospital length of stay, and use of intensive care services.6,7,9-13 We hypothesized that preoperative clinical indicators assessed by pneumonia severity scores as well as patient demographics and baseline comorbidities may also have prognostic value for risk of AEs in a cohort of geriatric hip fracture surgery patients with preoperative pneumonia.

In this article, we first describe the prevalence of preoperative pneumonia in geriatric hip fracture surgery patients as well as demographic and operative differences between patients with and without the disease. We then ask 3 questions: Is preoperative pneumonia an independent risk factor for mortality and adverse outcomes in geriatric hip fracture surgery? Is there a postoperative interval during which the unadjusted mortality rate is higher among patients with preoperative pneumonia? In patients with preoperative pneumonia, what are the predictors of morbidity and mortality?

Methods

Yale University’s Human Investigations Committee approved this retrospective cohort study, which used the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database for the period 2005 to 2012. ACS-NSQIP is a prospective, multi-institutional outcomes program that collects data on preoperative comorbidities, intraoperative variables, and 30-day postoperative outcomes for patients undergoing surgical procedures in inpatient and outpatient settings.14

Unlike administrative databases, which are based on reimbursement data, ACS-NSQIP data are collected by trained surgical clinical reviewers for the purposes of quality improvement and clinical research, and data quality is ensured with routine auditing.15 The program has gained a high degree of respect as a powerful and valid data source in both general16 and orthopedic17 surgery literature. The database offers a particular advantage with respect to the study of preoperative pneumonia: Only patients with new or recently diagnosed pneumonia on antibiotic therapy who meet strict criteria for characteristic findings on chest radiography, clinical signs and symptoms of respiratory illness, and positive cultures are coded as having actively treated pneumonia at time of surgery.15

To identify hip fracture patients over the age of 65 years who underwent operative fixation of a hip fracture, we used Current Procedural Terminology (CPT) hip fracture codes, including 27235 (percutaneous screw fixation), 27236 or 27244 (plate-and-screw fixation), and 27245 (intramedullary device), as well as 27125 (hemiarthroplasty) and 27130 (arthroplasty) for patients with a postoperative International Classification of Disease, Ninth Revision (ICD-9) diagnosis code (820.x, 820.2x, or 820.8) consistent with acute hip fracture.18,19 Procedure type, anesthesia type, and delay from admission to surgery were captured for all procedures.

Preoperative demographics included age, sex, transfer origin, functional status, and body mass index (BMI) category. Binary comorbidities were classified as preoperative anemia (hematocrit, <0.41 for men, <0.36 for women), confusion, dyspnea at rest, uremia (blood urea nitrogen, >6.8 mmol/L), history of cardiovascular disease (congestive heart failure, myocardial infarction, percutaneous coronary intervention, angina pectoris, medically treated hypertension, peripheral vascular disease, or resting claudication), chronic obstructive pulmonary disease, diabetes, renal disease (renal failure or dialysis), and cigarette use in preceding 12 months.20,21 Although preoperative hypotension and respiratory rate are often considered in patients with pneumonia, these variables were not available from the ACS-NSQIP data.6,22Pearson χ2 test for categorical variables was used to compare baseline demographics and operative characteristics between patients with and without pneumonia, and Student t test was used to compare intervals from hospital admission to hip fracture surgery, surgery start to surgery stop, and surgery to discharge between patients with and without preoperative pneumonia.

Binary outcome measures were compared between patients with and without preoperative pneumonia. “Any AE” included any serious AE (SAE) or any minor AE. SAEs included death, acute renal failure, ventilator use >48 hours, unplanned intubation, septic shock, sepsis, return to operating room, coma >24 hours, cardiac arrest requiring cardiopulmonary resuscitation, myocardial infarction, thromboembolic event (deep vein thrombosis or pulmonary embolism), and stroke/cerebrovascular accident. Minor AEs included progressive renal insufficiency, urinary tract infection, organ/space infection, superficial surgical-site infection, deep surgical-site infection, and wound dehiscence. Other binary outcome measures included discharge destination and unplanned readmission within 30 days after hip fracture surgery.23Poisson regression with robust error variance as described by Zou24 was used to compare the rates of any, minor, and individual AEs, and any SAEs, between patients with and without pneumonia. Multivariate analysis accounted for the baseline variables in Table 1. AEs that occurred more than once in each group were included in the analyses.



Kaplan-Meier survival analysis was performed for postoperative mortality within 30 days. Within the preoperative pneumonia group, covariates from Table 1 were identified as predictors of any AE, SAE, or death within 30 days after hip fracture surgery by stepwise multivariate Poisson regression with robust error variance. When interval from admission to surgery was longer than 24, 48, 72, or 96 hours, it was also included as a covariate. Variables that did not show an association with AEs at the P < .20 level were not included in the final regression model. All analyses were performed with Stata/SE Version 12.0 statistical software (StataCorp).

 

 

Results

Of the 7128 geriatric hip fracture patients in this study, 82 (1.2%) had active pneumonia at time of surgery (Table 1). Age, BMI, preoperative uremia, history of cardiovascular disease, diabetes, renal disease, and smoking were similar between groups. In addition, there was no difference in anesthesia type or fixation procedure between the pneumonia and no-pneumonia groups. Patients with preoperative pneumonia differed significantly with respect to sex, transfer from facility, preoperative functional dependence, anemia, confusion, dyspnea at rest, and history of chronic obstructive pulmonary disease (Table 1).

Interval from admission to surgery was longer (P < .001) for geriatric hip fracture patients with preoperative pneumonia (mean, 6.8 days; 95% CI, 2.5-11.1 days) than for those without pneumonia (mean, 1.5 days; CI, 1.4-1.5 days). There was no difference (P = .124) in operative time between the pneumonia group (mean, 72.8 min; CI, 64.0-81.5 min) and the no-pneumonia group (mean, 66.1 min; CI, 61.2-67.0 min). Interval from surgery to discharge was longer (P < .001) for patients with preoperative pneumonia (mean, 10.1 days; CI, 6.9-13.4 days) than for those without pneumonia (mean, 6.3 days; CI, 6.1-6.4 days).

Adverse outcomes of geriatric hip fracture surgery are listed in Table 2. In the multivariate analysis, preoperative pneumonia was significantly associated with any AE (relative risk [RR]) = 1.44) and any SAE (RR = 1.79).

Specific AEs were also assessed. In terms of SAEs, patients with pneumonia were more likely to die (RR = 2.08), develop acute renal failure (RR = 14.61), become comatose for more than 24 hours (RR = 7.31), and require mechanical ventilation for more than 48 hours after surgery (RR = 6.48). In terms of minor AEs, there were no significant differences between patients with and without pneumonia.

Survival patterns diverged between patients with and without preoperative pneumonia (Figure). The unadjusted mortality rate was qualitatively higher in patients with preoperative pneumonia than in patients without pneumonia during the first days after hip fracture (slopes of unadjusted mortality curves in Figure). Of note, no patient under age 75 years with pneumonia at time of surgery died within the 30-day study period.

Among geriatric hip fracture patients with preoperative pneumonia, multivariate analyses revealed no significant association of any preoperative comorbidity with any AE or any SAE. Given the gravity of the death complication, however, death within 30 days after surgery was analyzed separately, and was found to be significantly associated (RR = 4.67) with being underweight (BMI, <18.5 kg/m2) (Table 3). Admission-to-surgery interval longer than 24, 48, 72, or 96 hours did not reach significance at the P < 0.2 level in the stepwise regressions and therefore was not associated with a higher or lower risk of any AE, SAE, or death.

Discussion

In the general US population, pneumonia accounts for 1.4% of deaths in people 65 years to 74 years old, 2.1% in people 75 years to 84 years, and 3.1% in people 85 years or older. In total, 3.4% of hospital inpatient deaths are attributed to pneumonia.25 In hospitalized general orthopedic surgical patients as well as hip fracture patients, pneumonia is strongly associated with increased mortality.26,27

We identified a preoperative pneumonia prevalence of 1.2%, which is comparable to the rates reported in the literature (0.3%-3.2%).1-3 To our knowledge, our study represents the largest series of patients with preoperative pneumonia at time of hip fracture repair, and the first to independently associate preoperative pneumonia with increased incidence of AEs, including death.

This study had its limitations. First, the ACS-NSQIP morbidity and mortality data, which are limited to the first 30 postoperative days, may be skewed because AEs that occurred after that interval are not captured. Second, coding of pneumonia in ACS-NSQIP does not convey specific information about the disease and its severity—infectious organism(s) responsible; acquisition setting (healthcare or community); treatment given, including antibiotic(s) selection, steroid use, dosing, and duration; and measures of treatment efficacy—limiting interpretation of the difference in delay to surgery. We cannot say whether the longer interval in patients with pneumonia reflects medical optimization, or whether the delay itself or any interventions during that time positively or negatively affected outcomes. In addition, despite using a large national database, we obtained a relatively small sample of patients (82) who had pneumonia before surgical hip fracture repair.

Multivariate analysis controlling for baseline demographics and comorbidities revealed that multiple SAEs were independently associated with preoperative pneumonia (overall SAE, RR = 1.79). Postoperative use of ventilator support for longer than 48 hours (RR = 6.48) and coma longer than 24 hours (RR = 7.31) are expected given the severity of pulmonary compromise in the study cohort.28,29 Acute renal failure (RR = 14.61) can occur in both hip fracture patients and community-acquired pneumonia patients and may be a multifactorial complication of the pulmonary infection, of the anesthesia, or of the surgical intervention in this cohort.30-32Unadjusted mortality in hip fracture takes months to a year to normalize to that of age-matched controls.32-34 In our series, the unadjusted death rate in the pneumonia cohort (Figure) was transiently elevated during the first weeks after surgery but then drew nearer the rate in the nondiseased hip fracture cohort by the end of the first month. Early death in the pneumonia group likely was multifactorial, potentially influenced by the increased burden of comorbidities in the pneumonia group at baseline, and the longer delay to surgery,35-38 as well as by the natural history of treated pneumonia in hospital patients, who, compared with age-matched hospitalized controls, also exhibit higher mortality during only the first 2 to 4 months of hospitalization for pneumonia.39 We regret that quality improvement strategies in the treatment of geriatric hip fracture surgery with pneumonia cannot be extrapolated from these results.

Similarly, the utility of BMI <18.5 kg/m2 as an actionable preoperative finding cannot be assessed from these results. However, we propose that underweight geriatric hip fracture patients with pneumonia may benefit from more aggressive preoperative optimization that does not delay surgery. Higher acuity of postoperative care, including more intensive nursing care and early coordination of care with respiratory therapists and medical comanagement teams, may also be beneficial.

Anesthesia type did not differ between patients with and without preoperative pneumonia and was not associated with AEs in patients with preoperative pneumonia. Consistent with our findings, multiple studies have reported no significant differences in short-term outcomes of hip fracture repair between general and spinal anesthesia, though no other study has compared the benefits of general and spinal anesthesia for patients with preoperative pneumonia.40-44 Although spinal anesthesia (relative to general anesthesia) has been reported to have benefits in hip and knee arthroplasty, these benefits appear not to translate to hip fracture repair.45-50 The results of the present study suggest that general and spinal anesthesia may be equivalent in terms of risk for the geriatric hip fracture patient with preoperative pneumonia.43,44Our attempt to evaluate the CURB-65 pneumonia severity score as a prognosticator of AEs was thwarted by the absence of required variables in the ACS-NSQIP dataset (confusion, uremia, dyspnea, and age were available; hypotension and blood pressure were not). In our analysis, we did include, individually, variables previously found to predict AEs in the medical pneumonia population (confusion, uremia, dyspnea at rest, anemia).9-11,32 However, these clinical findings are nonspecific in hip fracture patients, who may become anemic, confused, dyspneic, or uremic from a multitude of factors related to their injury and unrelated to pneumonia, including but not limited to hemorrhage, muscle damage, renal injury, and pulmonary embolism. It is not surprising that confusion, uremia, dyspnea at rest, and anemia were not individually predictive of AEs or death within 30 days after surgery in the cohort of geriatric hip fracture patients with pneumonia.

There is no literature that argues for or against delaying hip fracture surgery in geriatric hip fracture patients with pneumonia. The surgical delay observed in this population is ostensibly related to medical optimization of the pneumonia and/or underlying comorbidities. However, we did not find a morbidity or mortality detriment or benefit in delaying surgery by 1 to 4 days in this population. Delay of surgery is a poor covariate, given extensive confounding by medical management and preoperative optimizing of comorbid conditions (reflected in our independent variable and covariates) as well as institutional and surgeon variations in policy and behavior and other unaccounted influences. Although some authors have found no difference in mortality or major AEs between hip fracture patients who had a surgical delay and those who did not,31,51-53 other series and meta-analyses have suggested a mortality detriment in a surgical delay of more than 2 days36,54 or 4 days55 from admission. Given our data, we cannot recommend against immediate hip fracture repair in the subpopulation of geriatric hip fracture patients with pneumonia.

Our study findings suggest that preoperative pneumonia is a rare independent risk factor for AEs after hip fracture surgery in geriatric patients. Underweight BMI is predictive of death in geriatric hip fracture surgery patients who present with pneumonia, whereas early surgical repair appears not to be associated with adverse outcomes. Further investigation is warranted to determine if such patients benefit from specific preoperative and postoperative strategies for optimizing medical and surgical care based on these findings.

Am J Orthop. 2017;46(3):E177-E185. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

  • The prevalence of preoperative pneumonia is 1.2% among hip fracture patients aged >65 years.
  • Preoperative pneumonia is an independent risk factor for mortality and adverse events including renal failure, prolonged ventilator dependence, and prolonged altered mental status after geriatric hip fracture surgery.
  • Underweight BMI (<18.5 kg/m2) was associated with higher mortality within 30 days among hip fracture patients admitted with pneumonia.
  • The mortality rate normalized to that of patients without pneumonia within 2 weeks of hip fracture surgery.
  • Time from admission to surgery was not associated with adverse events or mortality among hip fracture patients admitted with pneumonia.

Preoperative pneumonia remains relatively unexplored as a risk factor for adverse outcomes in geriatric hip fracture surgery. Dated studies report a 0.3% to 3.2% prevalence of “recent pneumonia” in patients presenting with hip fracture but provide neither a definition of pneumonia based on clinical criteria nor a subset analysis of outcomes in the pneumonia group.1-3 Although active pneumonia has been identified as a preoperative optimization target in the management guidelines for geriatric hip fracture,4 we are unaware of any studies that have reported on differences in demographics, comorbidities, delay to surgery, or adverse outcomes between hip fracture patients with and without preoperative pneumonia.

This paucity of information on the effect of preoperative pneumonia in the hip fracture population may be related to low prevalence of preoperative pneumonia and a cadre of variable definitions, which limit identification of a cohort of patients with preoperative pneumonia large enough from which to draw meaningful results. Database studies, especially those using surgical registries rather than administrative or reimbursement data, offer particular advantages for investigation of such rare clinical entities.5Medical care of patients with pneumonia alone is known to be facilitated by assessments of mortality risk from clinical and laboratory data. The modified British Thoracic Society rule/CURB-65 (confusion, urea, respiratory rate, blood pressure) score is strongly predictive of mortality in hospitalized adults with pneumonia (odds ratio [OR], 4.59; 95% confidence interval [CI], 1.42-14.85; P = .011) and may guide antibiotic therapy, laboratory investigations, and the decision to intubate in a patient with pneumonia.6-8 This score is predictive of adverse events (AEs), hospital length of stay, and use of intensive care services.6,7,9-13 We hypothesized that preoperative clinical indicators assessed by pneumonia severity scores as well as patient demographics and baseline comorbidities may also have prognostic value for risk of AEs in a cohort of geriatric hip fracture surgery patients with preoperative pneumonia.

In this article, we first describe the prevalence of preoperative pneumonia in geriatric hip fracture surgery patients as well as demographic and operative differences between patients with and without the disease. We then ask 3 questions: Is preoperative pneumonia an independent risk factor for mortality and adverse outcomes in geriatric hip fracture surgery? Is there a postoperative interval during which the unadjusted mortality rate is higher among patients with preoperative pneumonia? In patients with preoperative pneumonia, what are the predictors of morbidity and mortality?

Methods

Yale University’s Human Investigations Committee approved this retrospective cohort study, which used the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database for the period 2005 to 2012. ACS-NSQIP is a prospective, multi-institutional outcomes program that collects data on preoperative comorbidities, intraoperative variables, and 30-day postoperative outcomes for patients undergoing surgical procedures in inpatient and outpatient settings.14

Unlike administrative databases, which are based on reimbursement data, ACS-NSQIP data are collected by trained surgical clinical reviewers for the purposes of quality improvement and clinical research, and data quality is ensured with routine auditing.15 The program has gained a high degree of respect as a powerful and valid data source in both general16 and orthopedic17 surgery literature. The database offers a particular advantage with respect to the study of preoperative pneumonia: Only patients with new or recently diagnosed pneumonia on antibiotic therapy who meet strict criteria for characteristic findings on chest radiography, clinical signs and symptoms of respiratory illness, and positive cultures are coded as having actively treated pneumonia at time of surgery.15

To identify hip fracture patients over the age of 65 years who underwent operative fixation of a hip fracture, we used Current Procedural Terminology (CPT) hip fracture codes, including 27235 (percutaneous screw fixation), 27236 or 27244 (plate-and-screw fixation), and 27245 (intramedullary device), as well as 27125 (hemiarthroplasty) and 27130 (arthroplasty) for patients with a postoperative International Classification of Disease, Ninth Revision (ICD-9) diagnosis code (820.x, 820.2x, or 820.8) consistent with acute hip fracture.18,19 Procedure type, anesthesia type, and delay from admission to surgery were captured for all procedures.

Preoperative demographics included age, sex, transfer origin, functional status, and body mass index (BMI) category. Binary comorbidities were classified as preoperative anemia (hematocrit, <0.41 for men, <0.36 for women), confusion, dyspnea at rest, uremia (blood urea nitrogen, >6.8 mmol/L), history of cardiovascular disease (congestive heart failure, myocardial infarction, percutaneous coronary intervention, angina pectoris, medically treated hypertension, peripheral vascular disease, or resting claudication), chronic obstructive pulmonary disease, diabetes, renal disease (renal failure or dialysis), and cigarette use in preceding 12 months.20,21 Although preoperative hypotension and respiratory rate are often considered in patients with pneumonia, these variables were not available from the ACS-NSQIP data.6,22Pearson χ2 test for categorical variables was used to compare baseline demographics and operative characteristics between patients with and without pneumonia, and Student t test was used to compare intervals from hospital admission to hip fracture surgery, surgery start to surgery stop, and surgery to discharge between patients with and without preoperative pneumonia.

Binary outcome measures were compared between patients with and without preoperative pneumonia. “Any AE” included any serious AE (SAE) or any minor AE. SAEs included death, acute renal failure, ventilator use >48 hours, unplanned intubation, septic shock, sepsis, return to operating room, coma >24 hours, cardiac arrest requiring cardiopulmonary resuscitation, myocardial infarction, thromboembolic event (deep vein thrombosis or pulmonary embolism), and stroke/cerebrovascular accident. Minor AEs included progressive renal insufficiency, urinary tract infection, organ/space infection, superficial surgical-site infection, deep surgical-site infection, and wound dehiscence. Other binary outcome measures included discharge destination and unplanned readmission within 30 days after hip fracture surgery.23Poisson regression with robust error variance as described by Zou24 was used to compare the rates of any, minor, and individual AEs, and any SAEs, between patients with and without pneumonia. Multivariate analysis accounted for the baseline variables in Table 1. AEs that occurred more than once in each group were included in the analyses.



Kaplan-Meier survival analysis was performed for postoperative mortality within 30 days. Within the preoperative pneumonia group, covariates from Table 1 were identified as predictors of any AE, SAE, or death within 30 days after hip fracture surgery by stepwise multivariate Poisson regression with robust error variance. When interval from admission to surgery was longer than 24, 48, 72, or 96 hours, it was also included as a covariate. Variables that did not show an association with AEs at the P < .20 level were not included in the final regression model. All analyses were performed with Stata/SE Version 12.0 statistical software (StataCorp).

 

 

Results

Of the 7128 geriatric hip fracture patients in this study, 82 (1.2%) had active pneumonia at time of surgery (Table 1). Age, BMI, preoperative uremia, history of cardiovascular disease, diabetes, renal disease, and smoking were similar between groups. In addition, there was no difference in anesthesia type or fixation procedure between the pneumonia and no-pneumonia groups. Patients with preoperative pneumonia differed significantly with respect to sex, transfer from facility, preoperative functional dependence, anemia, confusion, dyspnea at rest, and history of chronic obstructive pulmonary disease (Table 1).

Interval from admission to surgery was longer (P < .001) for geriatric hip fracture patients with preoperative pneumonia (mean, 6.8 days; 95% CI, 2.5-11.1 days) than for those without pneumonia (mean, 1.5 days; CI, 1.4-1.5 days). There was no difference (P = .124) in operative time between the pneumonia group (mean, 72.8 min; CI, 64.0-81.5 min) and the no-pneumonia group (mean, 66.1 min; CI, 61.2-67.0 min). Interval from surgery to discharge was longer (P < .001) for patients with preoperative pneumonia (mean, 10.1 days; CI, 6.9-13.4 days) than for those without pneumonia (mean, 6.3 days; CI, 6.1-6.4 days).

Adverse outcomes of geriatric hip fracture surgery are listed in Table 2. In the multivariate analysis, preoperative pneumonia was significantly associated with any AE (relative risk [RR]) = 1.44) and any SAE (RR = 1.79).

Specific AEs were also assessed. In terms of SAEs, patients with pneumonia were more likely to die (RR = 2.08), develop acute renal failure (RR = 14.61), become comatose for more than 24 hours (RR = 7.31), and require mechanical ventilation for more than 48 hours after surgery (RR = 6.48). In terms of minor AEs, there were no significant differences between patients with and without pneumonia.

Survival patterns diverged between patients with and without preoperative pneumonia (Figure). The unadjusted mortality rate was qualitatively higher in patients with preoperative pneumonia than in patients without pneumonia during the first days after hip fracture (slopes of unadjusted mortality curves in Figure). Of note, no patient under age 75 years with pneumonia at time of surgery died within the 30-day study period.

Among geriatric hip fracture patients with preoperative pneumonia, multivariate analyses revealed no significant association of any preoperative comorbidity with any AE or any SAE. Given the gravity of the death complication, however, death within 30 days after surgery was analyzed separately, and was found to be significantly associated (RR = 4.67) with being underweight (BMI, <18.5 kg/m2) (Table 3). Admission-to-surgery interval longer than 24, 48, 72, or 96 hours did not reach significance at the P < 0.2 level in the stepwise regressions and therefore was not associated with a higher or lower risk of any AE, SAE, or death.

Discussion

In the general US population, pneumonia accounts for 1.4% of deaths in people 65 years to 74 years old, 2.1% in people 75 years to 84 years, and 3.1% in people 85 years or older. In total, 3.4% of hospital inpatient deaths are attributed to pneumonia.25 In hospitalized general orthopedic surgical patients as well as hip fracture patients, pneumonia is strongly associated with increased mortality.26,27

We identified a preoperative pneumonia prevalence of 1.2%, which is comparable to the rates reported in the literature (0.3%-3.2%).1-3 To our knowledge, our study represents the largest series of patients with preoperative pneumonia at time of hip fracture repair, and the first to independently associate preoperative pneumonia with increased incidence of AEs, including death.

This study had its limitations. First, the ACS-NSQIP morbidity and mortality data, which are limited to the first 30 postoperative days, may be skewed because AEs that occurred after that interval are not captured. Second, coding of pneumonia in ACS-NSQIP does not convey specific information about the disease and its severity—infectious organism(s) responsible; acquisition setting (healthcare or community); treatment given, including antibiotic(s) selection, steroid use, dosing, and duration; and measures of treatment efficacy—limiting interpretation of the difference in delay to surgery. We cannot say whether the longer interval in patients with pneumonia reflects medical optimization, or whether the delay itself or any interventions during that time positively or negatively affected outcomes. In addition, despite using a large national database, we obtained a relatively small sample of patients (82) who had pneumonia before surgical hip fracture repair.

Multivariate analysis controlling for baseline demographics and comorbidities revealed that multiple SAEs were independently associated with preoperative pneumonia (overall SAE, RR = 1.79). Postoperative use of ventilator support for longer than 48 hours (RR = 6.48) and coma longer than 24 hours (RR = 7.31) are expected given the severity of pulmonary compromise in the study cohort.28,29 Acute renal failure (RR = 14.61) can occur in both hip fracture patients and community-acquired pneumonia patients and may be a multifactorial complication of the pulmonary infection, of the anesthesia, or of the surgical intervention in this cohort.30-32Unadjusted mortality in hip fracture takes months to a year to normalize to that of age-matched controls.32-34 In our series, the unadjusted death rate in the pneumonia cohort (Figure) was transiently elevated during the first weeks after surgery but then drew nearer the rate in the nondiseased hip fracture cohort by the end of the first month. Early death in the pneumonia group likely was multifactorial, potentially influenced by the increased burden of comorbidities in the pneumonia group at baseline, and the longer delay to surgery,35-38 as well as by the natural history of treated pneumonia in hospital patients, who, compared with age-matched hospitalized controls, also exhibit higher mortality during only the first 2 to 4 months of hospitalization for pneumonia.39 We regret that quality improvement strategies in the treatment of geriatric hip fracture surgery with pneumonia cannot be extrapolated from these results.

Similarly, the utility of BMI <18.5 kg/m2 as an actionable preoperative finding cannot be assessed from these results. However, we propose that underweight geriatric hip fracture patients with pneumonia may benefit from more aggressive preoperative optimization that does not delay surgery. Higher acuity of postoperative care, including more intensive nursing care and early coordination of care with respiratory therapists and medical comanagement teams, may also be beneficial.

Anesthesia type did not differ between patients with and without preoperative pneumonia and was not associated with AEs in patients with preoperative pneumonia. Consistent with our findings, multiple studies have reported no significant differences in short-term outcomes of hip fracture repair between general and spinal anesthesia, though no other study has compared the benefits of general and spinal anesthesia for patients with preoperative pneumonia.40-44 Although spinal anesthesia (relative to general anesthesia) has been reported to have benefits in hip and knee arthroplasty, these benefits appear not to translate to hip fracture repair.45-50 The results of the present study suggest that general and spinal anesthesia may be equivalent in terms of risk for the geriatric hip fracture patient with preoperative pneumonia.43,44Our attempt to evaluate the CURB-65 pneumonia severity score as a prognosticator of AEs was thwarted by the absence of required variables in the ACS-NSQIP dataset (confusion, uremia, dyspnea, and age were available; hypotension and blood pressure were not). In our analysis, we did include, individually, variables previously found to predict AEs in the medical pneumonia population (confusion, uremia, dyspnea at rest, anemia).9-11,32 However, these clinical findings are nonspecific in hip fracture patients, who may become anemic, confused, dyspneic, or uremic from a multitude of factors related to their injury and unrelated to pneumonia, including but not limited to hemorrhage, muscle damage, renal injury, and pulmonary embolism. It is not surprising that confusion, uremia, dyspnea at rest, and anemia were not individually predictive of AEs or death within 30 days after surgery in the cohort of geriatric hip fracture patients with pneumonia.

There is no literature that argues for or against delaying hip fracture surgery in geriatric hip fracture patients with pneumonia. The surgical delay observed in this population is ostensibly related to medical optimization of the pneumonia and/or underlying comorbidities. However, we did not find a morbidity or mortality detriment or benefit in delaying surgery by 1 to 4 days in this population. Delay of surgery is a poor covariate, given extensive confounding by medical management and preoperative optimizing of comorbid conditions (reflected in our independent variable and covariates) as well as institutional and surgeon variations in policy and behavior and other unaccounted influences. Although some authors have found no difference in mortality or major AEs between hip fracture patients who had a surgical delay and those who did not,31,51-53 other series and meta-analyses have suggested a mortality detriment in a surgical delay of more than 2 days36,54 or 4 days55 from admission. Given our data, we cannot recommend against immediate hip fracture repair in the subpopulation of geriatric hip fracture patients with pneumonia.

Our study findings suggest that preoperative pneumonia is a rare independent risk factor for AEs after hip fracture surgery in geriatric patients. Underweight BMI is predictive of death in geriatric hip fracture surgery patients who present with pneumonia, whereas early surgical repair appears not to be associated with adverse outcomes. Further investigation is warranted to determine if such patients benefit from specific preoperative and postoperative strategies for optimizing medical and surgical care based on these findings.

Am J Orthop. 2017;46(3):E177-E185. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

References

1. Sexson SB, Lehner JT. Factors affecting hip fracture mortality. J Orthop Trauma. 1987;1(4):298-305.

2. Mullen JO, Mullen NL. Hip fracture mortality: a prospective, multifactorial study to predict and minimize death risk. Clin Orthop Relat Res. 1992;(280):214-222.

3. Kenzora JE, McCarthy RE, Lowell JD, Sledge CB. Hip fracture mortality. Relation to age, treatment, preoperative illness, time of surgery, and complications. Clin Orthop Relat Res. 1984;(186):45-56.

4. Auron-Gomez M, Michota F. Medical management of hip fracture. Clin Geriatr Med. 2008;24(4):701-719.

5. Bohl DD, Basques BA, Golinvaux NS, Baumgaertner MR, Grauer JN. Nationwide Inpatient Sample and National Surgical Quality Improvement Program give different results in hip fracture studies. Clin Orthop Relat Res. 2014;472(6):1672-1680.

6. Lim WS, van der Eerden MM, Laing R, et al. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax. 2003;58(5):377-382.

7. Myint PK, Kamath AV, Vowler SL, Maisey DN, Harrison BDW. The CURB (confusion, urea, respiratory rate and blood pressure) criteria in community-acquired pneumonia (CAP) in hospitalised elderly patients aged 65 years and over: a prospective observational cohort study. Age Ageing. 2005;34(1):75-77.

8. Wilkinson M, Woodhead MA. Guidelines for community-acquired pneumonia in the ICU. Curr Opin Crit Care. 2004;10(1):59-64.

9. Buising K, Thursky K, Black J, et al. A prospective comparison of severity scores for identifying patients with severe community acquired pneumonia: reconsidering what is meant by severe pneumonia. Thorax. 2006;61(5):419-424.

10. Ewig S, De Roux A, Bauer T, et al. Validation of predictive rules and indices of severity for community acquired pneumonia. Thorax. 2004;59(5):421-427.

11. Yandiola PP, Capelastegui A, Quintana J, et al. Prospective comparison of severity scores for predicting clinically relevant outcomes for patients hospitalized with community-acquired pneumonia. Chest. 2009;135(6):1572-1579.

12. Lim WS, Lewis S, Macfarlane JT. Severity prediction rules in community acquired pneumonia: a validation study. Thorax. 2000;55(3):219-223.

13. Bauer TT, Ewig S, Marre R, Suttorp N, Welte T; CAPNETZ Study Group. CRB‐65 predicts death from community‐acquired pneumonia. J Intern Med. 2006;260(1):93-101.

14. Khuri SF. The NSQIP: a new frontier in surgery. Surgery. 2005;138(5):837-843.

15. American College of Surgeons. User Guide for the 2012 ACS NSQIP Participant Use Data File: American College of Surgeons National Surgical Quality Improvement Program. https://www.facs.org/~/media/files/quality%20programs/nsqip/ug12.ashx. Published October 2013. Accessed October 8, 2014.

16. Ingraham AM, Richards KE, Hall BL, Ko CY. Quality improvement in surgery: the American College of Surgeons National Surgical Quality Improvement Program approach. Adv Surg. 2010;44(1):251-267.

17. Schilling PL, Hallstrom BR, Birkmeyer JD, Carpenter JE. Prioritizing perioperative quality improvement in orthopaedic surgery. J Bone Joint Surg Am. 2010;92(9):1884-1889.

18. Radcliff TA, Henderson WG, Stoner TJ, Khuri SF, Dohm M, Hutt E. Patient risk factors, operative care, and outcomes among older community-dwelling male veterans with hip fracture. J Bone Joint Surg Am. 2008;90(1):34-42.

19. Katzan I, Cebul R, Husak S, Dawson N, Baker D. The effect of pneumonia on mortality among patients hospitalized for acute stroke. Neurology. 2003;60(4):620-625.

20. Fisher MA, Matthei JD, Obirieze A, et al. Open reduction internal fixation versus hemiarthroplasty versus total hip arthroplasty in the elderly: a review of the National Surgical Quality Improvement Program database. J Surg Res. 2013;181(2):193-198.

21. Pugely AJ, Martin CT, Gao Y, Klocke NF, Callaghan JJ, Marsh JL. A risk calculator for short-term morbidity and mortality after hip fracture surgery. J Orthop Trauma. 2014;28(2):63-69.

22. Fine MJ, Smith MA, Carson CA, et al. Prognosis and outcomes of patients with community-acquired pneumonia: a meta-analysis. JAMA. 1996;275(2):134-141.

23. Donegan DJ, Gay AN, Baldwin K, Morales EE, Esterhai JL Jr, Mehta S. Use of medical comorbidities to predict complications after hip fracture surgery in the elderly. J Bone Joint Surg Am. 2010;92(4):807-813.

24. Zou G. A modified poisson regression approach to prospective studies with binary data. Am J Epidemiol. 2004:159(7):702-706.

25. Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2010. Natl Vital Stat Rep. 20138;61(4):1-117.

26. Bhattacharyya T, Iorio R, Healy WL. Rate of and risk factors for acute inpatient mortality after orthopaedic surgery. J Bone Joint Surg Am. 2002;84(4):562-572.

27. Myers AH, Robinson EG, Van Natta ML, Michelson JD, Collins K, Baker SP. Hip fractures among the elderly: factors associated with in-hospital mortality. Am J Epidemiol. 1991;134(10):1128-1137.

28. Mandell LA, Wunderink RG, Anzueto A, et al; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(suppl 2):S27-S72.

29. Leroy O, Santre C, Beuscart C, et al. A five-year study of severe community-acquired pneumonia with emphasis on prognosis in patients admitted to an intensive care unit. Intensive Care Med. 1995;21(1):24-31.

30. Urwin S, Parker M, Griffiths R. General versus regional anaesthesia for hip fracture surgery: a meta-analysis of randomized trials. Br J Anaesth. 2000;84(4):450-455.

31. Orosz GM, Magaziner J, Hannan EL, et al. Association of timing of surgery for hip fracture and patient outcomes. JAMA. 2004;291(14):1738-1743.

32. Niederman MS, Mandell LA, Anzueto A, et al; American Thoracic Society. Guidelines for the management of adults with community-acquired pneumonia: diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med. 2001;163(7):1730-1754.

33. Koval KJ, Skovron ML, Aharonoff GB, Zuckerman JD. Predictors of functional recovery after hip fracture in the elderly. Clin Orthop Relat Res. 1998;(348):22-28.

34. Doruk H, Mas MR, Yildiz C, Sonmez A, Kýrdemir V. The effect of the timing of hip fracture surgery on the activity of daily living and mortality in elderly. Arch Gerontol Geriatr. 2004;39(2):179-185.

35. George GH, Patel S. Secondary prevention of hip fracture. Rheumatology. 2000;39(4):346-349.

36. Bottle A, Aylin P. Mortality associated with delay in operation after hip fracture: observational study. BMJ. 2006;332(7547):947-951.

37. Grimes JP, Gregory PM, Noveck H, Butler MS, Carson JL. The effects of time-to-surgery on mortality and morbidity in patients following hip fracture. Am J Med. 2002;112(9):702-709.

38. Simunovic N, Devereaux P, Sprague S, et al. Effect of early surgery after hip fracture on mortality and complications: systematic review and meta-analysis. CMAJ. 2010;182(15):1609-1616.

 

 

39. Kaplan V, Clermont G, Griffin MF, et al. Pneumonia: still the old man’s friend? Arch Intern Med. 2003;163(3):317-323.

40. Parker MJ, Handoll HH, Griffiths R. Anaesthesia for hip fracture surgery in adults. Cochrane Database Syst Rev. 2004;(4):CD000521.

41. Chakladar A, White SM. Cost estimates of spinal versus general anaesthesia for fractured neck of femur surgery. Anaesthesia. 2010;65(8):810-814.

42. White SM, Moppett IK, Griffiths R. Outcome by mode of anaesthesia for hip fracture surgery. An observational audit of 65 535 patients in a national dataset. Anaesthesia. 2014;69(3):224-230.

43. Gilbert TB, Hawkes WG, Hebel JR, et al. Spinal anesthesia versus general anesthesia for hip fracture repair: a longitudinal observation of 741 elderly patients during 2-year follow-up. Am J Orthop. 2000;29(1):25-35.

44. O’Hara DA, Duff A, Berlin JA, et al. The effect of anesthetic technique on postoperative outcomes in hip fracture repair. Anesthesiology. 2000;92(4):947-957.

45. Hole A, Terjesen T, Breivik H. Epidural versus general anaesthesia for total hip arthroplasty in elderly patients. Acta Anaesthesiol Scand. 1980;24(4):279-287.

46. Rashiq S, Finegan BA. The effect of spinal anesthesia on blood transfusion rate in total joint arthroplasty. Can J Surg. 2006;49(6):391-396.

47. Chang CC, Lin HC, Lin HW, Lin HC. Anesthetic management and surgical site infections in total hip or knee replacement: a population-based study. Anesthesiology. 2010;113(2):279-284.

48. Mauermann WJ, Shilling AM, Zuo Z. A comparison of neuraxial block versus general anesthesia for elective total hip replacement: a meta-analysis. Anesth Analg. 2006;103(4):1018-1025.

49. Hu S, Zhang ZY, Hua YQ, Li J, Cai ZD. A comparison of regional and general anaesthesia for total replacement of the hip or knee: a meta-analysis. J Bone Joint Surg Br. 2009;91(7):935-942.

50. Pugely AJ, Martin CT, Gao Y, Mendoza-Lattes S, Callaghan JJ. Differences in short-term complications between spinal and general anesthesia for primary total knee arthroplasty. J Bone Joint Surg Am. 2013;95(3):193-199.

51. Khan SK, Kalra S, Khanna A, Thiruvengada MM, Parker MJ. Timing of surgery for hip fractures: a systematic review of 52 published studies involving 291,413 patients. Injury. 2009;40(7):692-697.

52. Majumdar SR, Beaupre LA, Johnston DW, Dick DA, Cinats JG, Jiang HX. Lack of association between mortality and timing of surgical fixation in elderly patients with hip fracture: results of a retrospective population-based cohort study. Med Care. 2006;44(6):552-559.

53. Moran CG, Wenn RT, Sikand M, Taylor AM. Early mortality after hip fracture: is delay before surgery important? J Bone Joint Surg Am. 2005;87(3):483-489.

54. Shiga T, Wajima Zi, Ohe Y. Is operative delay associated with increased mortality of hip fracture patients? Systematic review, meta-analysis, and meta-regression. Can J Anesth. 2008;55(3):146-154.

55. Streubel P, Ricci W, Wong A, Gardner M. Mortality after distal femur fractures in elderly patients. Clin Orthop Relat Res. 2011;469(4):1188-1196.

References

1. Sexson SB, Lehner JT. Factors affecting hip fracture mortality. J Orthop Trauma. 1987;1(4):298-305.

2. Mullen JO, Mullen NL. Hip fracture mortality: a prospective, multifactorial study to predict and minimize death risk. Clin Orthop Relat Res. 1992;(280):214-222.

3. Kenzora JE, McCarthy RE, Lowell JD, Sledge CB. Hip fracture mortality. Relation to age, treatment, preoperative illness, time of surgery, and complications. Clin Orthop Relat Res. 1984;(186):45-56.

4. Auron-Gomez M, Michota F. Medical management of hip fracture. Clin Geriatr Med. 2008;24(4):701-719.

5. Bohl DD, Basques BA, Golinvaux NS, Baumgaertner MR, Grauer JN. Nationwide Inpatient Sample and National Surgical Quality Improvement Program give different results in hip fracture studies. Clin Orthop Relat Res. 2014;472(6):1672-1680.

6. Lim WS, van der Eerden MM, Laing R, et al. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax. 2003;58(5):377-382.

7. Myint PK, Kamath AV, Vowler SL, Maisey DN, Harrison BDW. The CURB (confusion, urea, respiratory rate and blood pressure) criteria in community-acquired pneumonia (CAP) in hospitalised elderly patients aged 65 years and over: a prospective observational cohort study. Age Ageing. 2005;34(1):75-77.

8. Wilkinson M, Woodhead MA. Guidelines for community-acquired pneumonia in the ICU. Curr Opin Crit Care. 2004;10(1):59-64.

9. Buising K, Thursky K, Black J, et al. A prospective comparison of severity scores for identifying patients with severe community acquired pneumonia: reconsidering what is meant by severe pneumonia. Thorax. 2006;61(5):419-424.

10. Ewig S, De Roux A, Bauer T, et al. Validation of predictive rules and indices of severity for community acquired pneumonia. Thorax. 2004;59(5):421-427.

11. Yandiola PP, Capelastegui A, Quintana J, et al. Prospective comparison of severity scores for predicting clinically relevant outcomes for patients hospitalized with community-acquired pneumonia. Chest. 2009;135(6):1572-1579.

12. Lim WS, Lewis S, Macfarlane JT. Severity prediction rules in community acquired pneumonia: a validation study. Thorax. 2000;55(3):219-223.

13. Bauer TT, Ewig S, Marre R, Suttorp N, Welte T; CAPNETZ Study Group. CRB‐65 predicts death from community‐acquired pneumonia. J Intern Med. 2006;260(1):93-101.

14. Khuri SF. The NSQIP: a new frontier in surgery. Surgery. 2005;138(5):837-843.

15. American College of Surgeons. User Guide for the 2012 ACS NSQIP Participant Use Data File: American College of Surgeons National Surgical Quality Improvement Program. https://www.facs.org/~/media/files/quality%20programs/nsqip/ug12.ashx. Published October 2013. Accessed October 8, 2014.

16. Ingraham AM, Richards KE, Hall BL, Ko CY. Quality improvement in surgery: the American College of Surgeons National Surgical Quality Improvement Program approach. Adv Surg. 2010;44(1):251-267.

17. Schilling PL, Hallstrom BR, Birkmeyer JD, Carpenter JE. Prioritizing perioperative quality improvement in orthopaedic surgery. J Bone Joint Surg Am. 2010;92(9):1884-1889.

18. Radcliff TA, Henderson WG, Stoner TJ, Khuri SF, Dohm M, Hutt E. Patient risk factors, operative care, and outcomes among older community-dwelling male veterans with hip fracture. J Bone Joint Surg Am. 2008;90(1):34-42.

19. Katzan I, Cebul R, Husak S, Dawson N, Baker D. The effect of pneumonia on mortality among patients hospitalized for acute stroke. Neurology. 2003;60(4):620-625.

20. Fisher MA, Matthei JD, Obirieze A, et al. Open reduction internal fixation versus hemiarthroplasty versus total hip arthroplasty in the elderly: a review of the National Surgical Quality Improvement Program database. J Surg Res. 2013;181(2):193-198.

21. Pugely AJ, Martin CT, Gao Y, Klocke NF, Callaghan JJ, Marsh JL. A risk calculator for short-term morbidity and mortality after hip fracture surgery. J Orthop Trauma. 2014;28(2):63-69.

22. Fine MJ, Smith MA, Carson CA, et al. Prognosis and outcomes of patients with community-acquired pneumonia: a meta-analysis. JAMA. 1996;275(2):134-141.

23. Donegan DJ, Gay AN, Baldwin K, Morales EE, Esterhai JL Jr, Mehta S. Use of medical comorbidities to predict complications after hip fracture surgery in the elderly. J Bone Joint Surg Am. 2010;92(4):807-813.

24. Zou G. A modified poisson regression approach to prospective studies with binary data. Am J Epidemiol. 2004:159(7):702-706.

25. Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2010. Natl Vital Stat Rep. 20138;61(4):1-117.

26. Bhattacharyya T, Iorio R, Healy WL. Rate of and risk factors for acute inpatient mortality after orthopaedic surgery. J Bone Joint Surg Am. 2002;84(4):562-572.

27. Myers AH, Robinson EG, Van Natta ML, Michelson JD, Collins K, Baker SP. Hip fractures among the elderly: factors associated with in-hospital mortality. Am J Epidemiol. 1991;134(10):1128-1137.

28. Mandell LA, Wunderink RG, Anzueto A, et al; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(suppl 2):S27-S72.

29. Leroy O, Santre C, Beuscart C, et al. A five-year study of severe community-acquired pneumonia with emphasis on prognosis in patients admitted to an intensive care unit. Intensive Care Med. 1995;21(1):24-31.

30. Urwin S, Parker M, Griffiths R. General versus regional anaesthesia for hip fracture surgery: a meta-analysis of randomized trials. Br J Anaesth. 2000;84(4):450-455.

31. Orosz GM, Magaziner J, Hannan EL, et al. Association of timing of surgery for hip fracture and patient outcomes. JAMA. 2004;291(14):1738-1743.

32. Niederman MS, Mandell LA, Anzueto A, et al; American Thoracic Society. Guidelines for the management of adults with community-acquired pneumonia: diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med. 2001;163(7):1730-1754.

33. Koval KJ, Skovron ML, Aharonoff GB, Zuckerman JD. Predictors of functional recovery after hip fracture in the elderly. Clin Orthop Relat Res. 1998;(348):22-28.

34. Doruk H, Mas MR, Yildiz C, Sonmez A, Kýrdemir V. The effect of the timing of hip fracture surgery on the activity of daily living and mortality in elderly. Arch Gerontol Geriatr. 2004;39(2):179-185.

35. George GH, Patel S. Secondary prevention of hip fracture. Rheumatology. 2000;39(4):346-349.

36. Bottle A, Aylin P. Mortality associated with delay in operation after hip fracture: observational study. BMJ. 2006;332(7547):947-951.

37. Grimes JP, Gregory PM, Noveck H, Butler MS, Carson JL. The effects of time-to-surgery on mortality and morbidity in patients following hip fracture. Am J Med. 2002;112(9):702-709.

38. Simunovic N, Devereaux P, Sprague S, et al. Effect of early surgery after hip fracture on mortality and complications: systematic review and meta-analysis. CMAJ. 2010;182(15):1609-1616.

 

 

39. Kaplan V, Clermont G, Griffin MF, et al. Pneumonia: still the old man’s friend? Arch Intern Med. 2003;163(3):317-323.

40. Parker MJ, Handoll HH, Griffiths R. Anaesthesia for hip fracture surgery in adults. Cochrane Database Syst Rev. 2004;(4):CD000521.

41. Chakladar A, White SM. Cost estimates of spinal versus general anaesthesia for fractured neck of femur surgery. Anaesthesia. 2010;65(8):810-814.

42. White SM, Moppett IK, Griffiths R. Outcome by mode of anaesthesia for hip fracture surgery. An observational audit of 65 535 patients in a national dataset. Anaesthesia. 2014;69(3):224-230.

43. Gilbert TB, Hawkes WG, Hebel JR, et al. Spinal anesthesia versus general anesthesia for hip fracture repair: a longitudinal observation of 741 elderly patients during 2-year follow-up. Am J Orthop. 2000;29(1):25-35.

44. O’Hara DA, Duff A, Berlin JA, et al. The effect of anesthetic technique on postoperative outcomes in hip fracture repair. Anesthesiology. 2000;92(4):947-957.

45. Hole A, Terjesen T, Breivik H. Epidural versus general anaesthesia for total hip arthroplasty in elderly patients. Acta Anaesthesiol Scand. 1980;24(4):279-287.

46. Rashiq S, Finegan BA. The effect of spinal anesthesia on blood transfusion rate in total joint arthroplasty. Can J Surg. 2006;49(6):391-396.

47. Chang CC, Lin HC, Lin HW, Lin HC. Anesthetic management and surgical site infections in total hip or knee replacement: a population-based study. Anesthesiology. 2010;113(2):279-284.

48. Mauermann WJ, Shilling AM, Zuo Z. A comparison of neuraxial block versus general anesthesia for elective total hip replacement: a meta-analysis. Anesth Analg. 2006;103(4):1018-1025.

49. Hu S, Zhang ZY, Hua YQ, Li J, Cai ZD. A comparison of regional and general anaesthesia for total replacement of the hip or knee: a meta-analysis. J Bone Joint Surg Br. 2009;91(7):935-942.

50. Pugely AJ, Martin CT, Gao Y, Mendoza-Lattes S, Callaghan JJ. Differences in short-term complications between spinal and general anesthesia for primary total knee arthroplasty. J Bone Joint Surg Am. 2013;95(3):193-199.

51. Khan SK, Kalra S, Khanna A, Thiruvengada MM, Parker MJ. Timing of surgery for hip fractures: a systematic review of 52 published studies involving 291,413 patients. Injury. 2009;40(7):692-697.

52. Majumdar SR, Beaupre LA, Johnston DW, Dick DA, Cinats JG, Jiang HX. Lack of association between mortality and timing of surgical fixation in elderly patients with hip fracture: results of a retrospective population-based cohort study. Med Care. 2006;44(6):552-559.

53. Moran CG, Wenn RT, Sikand M, Taylor AM. Early mortality after hip fracture: is delay before surgery important? J Bone Joint Surg Am. 2005;87(3):483-489.

54. Shiga T, Wajima Zi, Ohe Y. Is operative delay associated with increased mortality of hip fracture patients? Systematic review, meta-analysis, and meta-regression. Can J Anesth. 2008;55(3):146-154.

55. Streubel P, Ricci W, Wong A, Gardner M. Mortality after distal femur fractures in elderly patients. Clin Orthop Relat Res. 2011;469(4):1188-1196.

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VIDEO: Alectinib doubles PFS and then some over crizotinib in ALK+ NSCLC

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– The standard of care for patients with non–small cell lung cancer positive for the anaplastic lymphoma kinase (ALK) is the ALK inhibitor crizotinib (Xalkori). However, many patients on crizotinib will have disease progression within the first year of therapy, and many will go on to have central nervous system (CNS) metastases.

The multicenter international ALEX trial compared crizotinib with the second-generation ALK inhibitor alectinib (Alecensa). The investigators found that alectinib reduced the risk of progression by 53% and the time to CNS progression by 84%.

In this video interview at the annual meeting of the American Society of Clinical Oncology, Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston, outlines the ALEX trial results, which are being hailed as “practice changing.”

The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
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– The standard of care for patients with non–small cell lung cancer positive for the anaplastic lymphoma kinase (ALK) is the ALK inhibitor crizotinib (Xalkori). However, many patients on crizotinib will have disease progression within the first year of therapy, and many will go on to have central nervous system (CNS) metastases.

The multicenter international ALEX trial compared crizotinib with the second-generation ALK inhibitor alectinib (Alecensa). The investigators found that alectinib reduced the risk of progression by 53% and the time to CNS progression by 84%.

In this video interview at the annual meeting of the American Society of Clinical Oncology, Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston, outlines the ALEX trial results, which are being hailed as “practice changing.”

The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel

 

– The standard of care for patients with non–small cell lung cancer positive for the anaplastic lymphoma kinase (ALK) is the ALK inhibitor crizotinib (Xalkori). However, many patients on crizotinib will have disease progression within the first year of therapy, and many will go on to have central nervous system (CNS) metastases.

The multicenter international ALEX trial compared crizotinib with the second-generation ALK inhibitor alectinib (Alecensa). The investigators found that alectinib reduced the risk of progression by 53% and the time to CNS progression by 84%.

In this video interview at the annual meeting of the American Society of Clinical Oncology, Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston, outlines the ALEX trial results, which are being hailed as “practice changing.”

The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
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VIDEO: Combined immunotherapy strategy shows promise in advanced solid tumors

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– Adding an experimental immune-enhancing agent to a checkpoint inhibitor was safe and showed early promise of activity against advanced solid tumors in a phase I/IIa clinical trial.

BMS-986156 is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucorticoid-induced tumor necrosis factor receptor-related gene. The drug acts synergistically with the programmed-death 1 inhibitor (PD-1) nivolumab (Opdivo) by increasing survival of T effector cells, promoting regulatory T-cell depletion and reduction, and reducing regulatory T cell suppression of T effector cells to produce a more robust antitumor immune response.

In this video interview at the annual meeting of the American Society of Clinical Oncology, Lillian Siu, MD, from the Princess Margaret Hospital, Toronto, describes how the combination has induced durable partial responses in patients with tumors thought to be insensitive to immunotherapy, as well as patients who had disease progression while on a PD-1 inhibitor.

The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
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– Adding an experimental immune-enhancing agent to a checkpoint inhibitor was safe and showed early promise of activity against advanced solid tumors in a phase I/IIa clinical trial.

BMS-986156 is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucorticoid-induced tumor necrosis factor receptor-related gene. The drug acts synergistically with the programmed-death 1 inhibitor (PD-1) nivolumab (Opdivo) by increasing survival of T effector cells, promoting regulatory T-cell depletion and reduction, and reducing regulatory T cell suppression of T effector cells to produce a more robust antitumor immune response.

In this video interview at the annual meeting of the American Society of Clinical Oncology, Lillian Siu, MD, from the Princess Margaret Hospital, Toronto, describes how the combination has induced durable partial responses in patients with tumors thought to be insensitive to immunotherapy, as well as patients who had disease progression while on a PD-1 inhibitor.

The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel

 

– Adding an experimental immune-enhancing agent to a checkpoint inhibitor was safe and showed early promise of activity against advanced solid tumors in a phase I/IIa clinical trial.

BMS-986156 is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucorticoid-induced tumor necrosis factor receptor-related gene. The drug acts synergistically with the programmed-death 1 inhibitor (PD-1) nivolumab (Opdivo) by increasing survival of T effector cells, promoting regulatory T-cell depletion and reduction, and reducing regulatory T cell suppression of T effector cells to produce a more robust antitumor immune response.

In this video interview at the annual meeting of the American Society of Clinical Oncology, Lillian Siu, MD, from the Princess Margaret Hospital, Toronto, describes how the combination has induced durable partial responses in patients with tumors thought to be insensitive to immunotherapy, as well as patients who had disease progression while on a PD-1 inhibitor.

The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
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Scheduling patterns: Time for a change?

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Bob Wachter, MD, created buzz in March 2016 when, at the SHM annual meeting in San Diego, he displayed a slide titled “What did we get wrong?” The slide contained the copy, “Hospitalist shifts run 7 a.m.-7 p.m.; 10 a.m.-10 p.m. 7on/7off” circled in bold red.

Over the last several years, thought leaders in the hospital medicine field have expressed concern that this one-size-fits-all schedule model is a threat to the well-being of many physicians and, by extension, the sustainability of their hospital medicine groups. Despite this, the 2016 State of Hospital Medicine Report reveals relatively little change in the way hospital medicine groups schedule their physicians.

Dr. Kimberly Eisenstock
Most groups (69.2%), report the duration of scheduled day shifts to be between 12 and 13.9 hours, similar to the 65.4% reported in the 2014 survey for this same metric. Likely, most of these shifts are the traditional 12-hour shift displayed on Dr. Wachter’s slide. Groups reporting shorter shifts tended to be either very large, with the number of bodies needed to develop flexible scheduling, or in academic settings where they could utilize house-staff coverage.

Night shifts echo this trend. There is an even greater number of groups utilizing the 12- to 13.9-hour shift length (79%), which has also varied less at just approximately 5% in either direction over the last two surveys. It is likely very hard to be creative with the shift length for your night physicians when the group is structured predominately around a 12-hour day position.

The 12-hour shift scheduled in long blocks is straightforward to employ for the scheduler, limits hand offs of care, and maximizes number of days off. So, why are Wachter et al. calling for change? Seven day stretches off may seem attractive when you are just starting out, but, as physicians mature, the very long day competes with family time that cannot be made up on weekday mornings when others are at school and work. Furthermore, the very long hours for 7 days straight lead to burn out and eventually retention issues as well. Some argue that this design promotes disengagement. It sets the expectation that, during “off” weeks, physicians might be unavailable for email responses, committee meetings, or participation in quality improvement initiatives, which disrupts integration into the larger hospital community and perhaps even our own career advancement.

Some groups are trying to address these concerns with innovative approaches to block scheduling. While the hallmark hospital medicine schedule of 7on/7off blocks remains the predominant model – 38.1% of all groups – this represents a drop of approximately 15%, compared with the prior survey. A new large contingent of groups entering the survey this year utilize a Monday-Friday model with rotating moonlighter/weekend coverage. This lifestyle and family-friendly model predominates in the Midwest. It is also found more in smaller groups, which may employ this model to keep the most system-knowledgeable worker around during high volume times, as well as to preserve the well-being and retention of their limited physician work force.

Of note, reconfiguring the 7on/7off model does not necessarily translate into more time off. The median number of shifts per year is also relatively stable at 182 which is the exact number of shifts per year in a strict 7on/7off schedule. This number does not vary by region of the country, group size, or teaching status. Some might argue that working 182 annual shifts is ideal, giving hospitalists a “vacation” every other week. However, this line of thought does not take into account the very long workdays, nor the 52 weekend days spent in the hospital – far more than most specialty peers who serve fewer weekend calls often with more limited in-house hours. In addition, one might argue that defining ourselves as available only during our 182 clinical “on” days is not in our own best interest, as it is the important nonclinical quality and committee service activities that are likely to lead to professional recognition and advancement.

Our hospital medicine group has deviated from this scheduling mainstay and requires only 160 shifts per year. We have set this number based on removal of the number of shifts equivalent to the vacation hours received by our medical group peers. The model poses a challenge in terms of matching our productivity up to benchmarks when talking to system leaders. This challenge pales in comparison to the increased buy-in from our physicians, as they feel equitable vacation time signifies respect from the medical group leadership.

In addition, our group has had success in being flexible around the number of days worked in a continuity stretch. We utilize everything from a 3-day block over holidays to a 7-day block. In general, we allow physicians to select their desired block length. The scheduler then works to accommodate that stretch as much as is feasible. The upfront work in this system is significant, but the downstream effect is decreased turnover costs. Even our own entrenched standard of 7on/7off schedules for house staff services (designed to protect continuity for the learner) have been the target of change. A pilot of alternating 4 and 5 day runs in a 4-week stretch has been implemented over the last few months. The number of days the residents are exposed to a given attending is the same in this model, but there is one additional switch day. The additional switch day puts the residents at risk of managing a change in care plan related to change in attending, but this was mitigated by paring attendings with very similar teaching and patient management styles. For our group, the extra administrative effort needed to work around the 7on/7off model has always paid off in terms of provider satisfaction and retention.

On the other hand, although I lead a large academic group, we have not yet developed flexibility around the shift length. Only one of the 29 roles our providers fill each 24-hour period is not a 12-hour shift. Over the years, I have tried to offer alternate models with shorter shifts to improve flow, reduce burn out, and increase family time. No matter how eloquent the reasoning, the response from the group was always the same: a resounding “no.” Most providers felt that they would wind up with a very similar work load and not actually leave the hospital earlier. Other reasons included not wanting to come in more days per month and concerns about increased handoffs/cross coverage.

There is some reason to think change may actually come. For one, burnout is high and may lead physicians to try a new model even with fear of the unknown. Our practice may be reconsidering this one-size-fits-all shift length in the very near future as an increasing percentage of candidates seeking to join our group express a strong interest in finding more accommodating hours.

Overall, I am hopeful that, in the coming years, my hospital medicine group, as well as many others, will heed the thoughts expressed by Dr. Wachter. Finding the flexibility to break out of these rigid scheduling models will be a first step in promoting both physician and system well being.
 

 

Dr. Eisenstock, MD, FHM, is clinical chief, division of hospital medicine, at the University of Massachusetts Memorial Health Care, Worcester.

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Bob Wachter, MD, created buzz in March 2016 when, at the SHM annual meeting in San Diego, he displayed a slide titled “What did we get wrong?” The slide contained the copy, “Hospitalist shifts run 7 a.m.-7 p.m.; 10 a.m.-10 p.m. 7on/7off” circled in bold red.

Over the last several years, thought leaders in the hospital medicine field have expressed concern that this one-size-fits-all schedule model is a threat to the well-being of many physicians and, by extension, the sustainability of their hospital medicine groups. Despite this, the 2016 State of Hospital Medicine Report reveals relatively little change in the way hospital medicine groups schedule their physicians.

Dr. Kimberly Eisenstock
Most groups (69.2%), report the duration of scheduled day shifts to be between 12 and 13.9 hours, similar to the 65.4% reported in the 2014 survey for this same metric. Likely, most of these shifts are the traditional 12-hour shift displayed on Dr. Wachter’s slide. Groups reporting shorter shifts tended to be either very large, with the number of bodies needed to develop flexible scheduling, or in academic settings where they could utilize house-staff coverage.

Night shifts echo this trend. There is an even greater number of groups utilizing the 12- to 13.9-hour shift length (79%), which has also varied less at just approximately 5% in either direction over the last two surveys. It is likely very hard to be creative with the shift length for your night physicians when the group is structured predominately around a 12-hour day position.

The 12-hour shift scheduled in long blocks is straightforward to employ for the scheduler, limits hand offs of care, and maximizes number of days off. So, why are Wachter et al. calling for change? Seven day stretches off may seem attractive when you are just starting out, but, as physicians mature, the very long day competes with family time that cannot be made up on weekday mornings when others are at school and work. Furthermore, the very long hours for 7 days straight lead to burn out and eventually retention issues as well. Some argue that this design promotes disengagement. It sets the expectation that, during “off” weeks, physicians might be unavailable for email responses, committee meetings, or participation in quality improvement initiatives, which disrupts integration into the larger hospital community and perhaps even our own career advancement.

Some groups are trying to address these concerns with innovative approaches to block scheduling. While the hallmark hospital medicine schedule of 7on/7off blocks remains the predominant model – 38.1% of all groups – this represents a drop of approximately 15%, compared with the prior survey. A new large contingent of groups entering the survey this year utilize a Monday-Friday model with rotating moonlighter/weekend coverage. This lifestyle and family-friendly model predominates in the Midwest. It is also found more in smaller groups, which may employ this model to keep the most system-knowledgeable worker around during high volume times, as well as to preserve the well-being and retention of their limited physician work force.

Of note, reconfiguring the 7on/7off model does not necessarily translate into more time off. The median number of shifts per year is also relatively stable at 182 which is the exact number of shifts per year in a strict 7on/7off schedule. This number does not vary by region of the country, group size, or teaching status. Some might argue that working 182 annual shifts is ideal, giving hospitalists a “vacation” every other week. However, this line of thought does not take into account the very long workdays, nor the 52 weekend days spent in the hospital – far more than most specialty peers who serve fewer weekend calls often with more limited in-house hours. In addition, one might argue that defining ourselves as available only during our 182 clinical “on” days is not in our own best interest, as it is the important nonclinical quality and committee service activities that are likely to lead to professional recognition and advancement.

Our hospital medicine group has deviated from this scheduling mainstay and requires only 160 shifts per year. We have set this number based on removal of the number of shifts equivalent to the vacation hours received by our medical group peers. The model poses a challenge in terms of matching our productivity up to benchmarks when talking to system leaders. This challenge pales in comparison to the increased buy-in from our physicians, as they feel equitable vacation time signifies respect from the medical group leadership.

In addition, our group has had success in being flexible around the number of days worked in a continuity stretch. We utilize everything from a 3-day block over holidays to a 7-day block. In general, we allow physicians to select their desired block length. The scheduler then works to accommodate that stretch as much as is feasible. The upfront work in this system is significant, but the downstream effect is decreased turnover costs. Even our own entrenched standard of 7on/7off schedules for house staff services (designed to protect continuity for the learner) have been the target of change. A pilot of alternating 4 and 5 day runs in a 4-week stretch has been implemented over the last few months. The number of days the residents are exposed to a given attending is the same in this model, but there is one additional switch day. The additional switch day puts the residents at risk of managing a change in care plan related to change in attending, but this was mitigated by paring attendings with very similar teaching and patient management styles. For our group, the extra administrative effort needed to work around the 7on/7off model has always paid off in terms of provider satisfaction and retention.

On the other hand, although I lead a large academic group, we have not yet developed flexibility around the shift length. Only one of the 29 roles our providers fill each 24-hour period is not a 12-hour shift. Over the years, I have tried to offer alternate models with shorter shifts to improve flow, reduce burn out, and increase family time. No matter how eloquent the reasoning, the response from the group was always the same: a resounding “no.” Most providers felt that they would wind up with a very similar work load and not actually leave the hospital earlier. Other reasons included not wanting to come in more days per month and concerns about increased handoffs/cross coverage.

There is some reason to think change may actually come. For one, burnout is high and may lead physicians to try a new model even with fear of the unknown. Our practice may be reconsidering this one-size-fits-all shift length in the very near future as an increasing percentage of candidates seeking to join our group express a strong interest in finding more accommodating hours.

Overall, I am hopeful that, in the coming years, my hospital medicine group, as well as many others, will heed the thoughts expressed by Dr. Wachter. Finding the flexibility to break out of these rigid scheduling models will be a first step in promoting both physician and system well being.
 

 

Dr. Eisenstock, MD, FHM, is clinical chief, division of hospital medicine, at the University of Massachusetts Memorial Health Care, Worcester.

 

Bob Wachter, MD, created buzz in March 2016 when, at the SHM annual meeting in San Diego, he displayed a slide titled “What did we get wrong?” The slide contained the copy, “Hospitalist shifts run 7 a.m.-7 p.m.; 10 a.m.-10 p.m. 7on/7off” circled in bold red.

Over the last several years, thought leaders in the hospital medicine field have expressed concern that this one-size-fits-all schedule model is a threat to the well-being of many physicians and, by extension, the sustainability of their hospital medicine groups. Despite this, the 2016 State of Hospital Medicine Report reveals relatively little change in the way hospital medicine groups schedule their physicians.

Dr. Kimberly Eisenstock
Most groups (69.2%), report the duration of scheduled day shifts to be between 12 and 13.9 hours, similar to the 65.4% reported in the 2014 survey for this same metric. Likely, most of these shifts are the traditional 12-hour shift displayed on Dr. Wachter’s slide. Groups reporting shorter shifts tended to be either very large, with the number of bodies needed to develop flexible scheduling, or in academic settings where they could utilize house-staff coverage.

Night shifts echo this trend. There is an even greater number of groups utilizing the 12- to 13.9-hour shift length (79%), which has also varied less at just approximately 5% in either direction over the last two surveys. It is likely very hard to be creative with the shift length for your night physicians when the group is structured predominately around a 12-hour day position.

The 12-hour shift scheduled in long blocks is straightforward to employ for the scheduler, limits hand offs of care, and maximizes number of days off. So, why are Wachter et al. calling for change? Seven day stretches off may seem attractive when you are just starting out, but, as physicians mature, the very long day competes with family time that cannot be made up on weekday mornings when others are at school and work. Furthermore, the very long hours for 7 days straight lead to burn out and eventually retention issues as well. Some argue that this design promotes disengagement. It sets the expectation that, during “off” weeks, physicians might be unavailable for email responses, committee meetings, or participation in quality improvement initiatives, which disrupts integration into the larger hospital community and perhaps even our own career advancement.

Some groups are trying to address these concerns with innovative approaches to block scheduling. While the hallmark hospital medicine schedule of 7on/7off blocks remains the predominant model – 38.1% of all groups – this represents a drop of approximately 15%, compared with the prior survey. A new large contingent of groups entering the survey this year utilize a Monday-Friday model with rotating moonlighter/weekend coverage. This lifestyle and family-friendly model predominates in the Midwest. It is also found more in smaller groups, which may employ this model to keep the most system-knowledgeable worker around during high volume times, as well as to preserve the well-being and retention of their limited physician work force.

Of note, reconfiguring the 7on/7off model does not necessarily translate into more time off. The median number of shifts per year is also relatively stable at 182 which is the exact number of shifts per year in a strict 7on/7off schedule. This number does not vary by region of the country, group size, or teaching status. Some might argue that working 182 annual shifts is ideal, giving hospitalists a “vacation” every other week. However, this line of thought does not take into account the very long workdays, nor the 52 weekend days spent in the hospital – far more than most specialty peers who serve fewer weekend calls often with more limited in-house hours. In addition, one might argue that defining ourselves as available only during our 182 clinical “on” days is not in our own best interest, as it is the important nonclinical quality and committee service activities that are likely to lead to professional recognition and advancement.

Our hospital medicine group has deviated from this scheduling mainstay and requires only 160 shifts per year. We have set this number based on removal of the number of shifts equivalent to the vacation hours received by our medical group peers. The model poses a challenge in terms of matching our productivity up to benchmarks when talking to system leaders. This challenge pales in comparison to the increased buy-in from our physicians, as they feel equitable vacation time signifies respect from the medical group leadership.

In addition, our group has had success in being flexible around the number of days worked in a continuity stretch. We utilize everything from a 3-day block over holidays to a 7-day block. In general, we allow physicians to select their desired block length. The scheduler then works to accommodate that stretch as much as is feasible. The upfront work in this system is significant, but the downstream effect is decreased turnover costs. Even our own entrenched standard of 7on/7off schedules for house staff services (designed to protect continuity for the learner) have been the target of change. A pilot of alternating 4 and 5 day runs in a 4-week stretch has been implemented over the last few months. The number of days the residents are exposed to a given attending is the same in this model, but there is one additional switch day. The additional switch day puts the residents at risk of managing a change in care plan related to change in attending, but this was mitigated by paring attendings with very similar teaching and patient management styles. For our group, the extra administrative effort needed to work around the 7on/7off model has always paid off in terms of provider satisfaction and retention.

On the other hand, although I lead a large academic group, we have not yet developed flexibility around the shift length. Only one of the 29 roles our providers fill each 24-hour period is not a 12-hour shift. Over the years, I have tried to offer alternate models with shorter shifts to improve flow, reduce burn out, and increase family time. No matter how eloquent the reasoning, the response from the group was always the same: a resounding “no.” Most providers felt that they would wind up with a very similar work load and not actually leave the hospital earlier. Other reasons included not wanting to come in more days per month and concerns about increased handoffs/cross coverage.

There is some reason to think change may actually come. For one, burnout is high and may lead physicians to try a new model even with fear of the unknown. Our practice may be reconsidering this one-size-fits-all shift length in the very near future as an increasing percentage of candidates seeking to join our group express a strong interest in finding more accommodating hours.

Overall, I am hopeful that, in the coming years, my hospital medicine group, as well as many others, will heed the thoughts expressed by Dr. Wachter. Finding the flexibility to break out of these rigid scheduling models will be a first step in promoting both physician and system well being.
 

 

Dr. Eisenstock, MD, FHM, is clinical chief, division of hospital medicine, at the University of Massachusetts Memorial Health Care, Worcester.

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BIO-RESORT: A mandate to prescreen PCI patients for silent diabetes

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– Undetected diabetes and prediabetes are pervasive in patients undergoing percutaneous coronary intervention, and they’re associated with a sharply increased risk of major adverse cardiovascular events, according to the results of the potentially practice-changing BIO-RESORT Silent Diabetes Study, Clemens von Birgelen, MD, PhD, reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

“Our data support screening PCI all-comers for silent diabetes, which may help identify patients with an increased event risk and improve their therapy,” said Dr. von Birgelen, professor of cardiology at the Thoraxcentrum of Twente, a high-volume center for cardiac interventions in Enschede, the Netherlands.

Bruce Jancin/Frontline Medical News
Dr. Clemens von Birgelen
He presented the 1-year follow-up results of the prospective, observational BIO-RESORT Silent Diabetes Study, in which 988 Dutch PCI all-comers without known diabetes underwent screening for abnormal glucose metabolism 6 weeks after the procedure.

A substantial one-third of subjects turned out to have abnormal glucose tolerance according to World Health Organization criteria and an International Expert Committee Report (Diabetes Care. 2009 Jul;32[7]:1327-34). In a multivariate analysis, their 1-year rate of the primary study endpoint – target vessel failure, a composite of cardiac death, target vessel-related MI, or target vessel revascularization – was an adjusted 2.2 times greater than in the 788 normoglycemic patients.

Moreover, among the 7% of study participants who met diagnostic criteria for silent diabetes, the risk of target vessel failure was more than 4.4 times greater than in the normoglycemic group.

“To a very great extent, periprocedural MI is the driving force behind this difference that we saw. From a biological point of view, I think that the vulnerability of the vessel in the diabetic or prediabetic patient features more brittle plaque with a higher risk of cholesterol embolization, and with more plaque mass that can be pushed to the side so that side branch vessels can become occluded, leading to periprocedural MI,” he observed.

Glucose metabolism was assessed in all participants by two methods using the conventional cutoffs: a 2-hour oral glucose tolerance test (OGTT), and the combination of fasting plasma glucose and hemoglobin A1c. By OGTT, 7% of patients had silent, previously unrecognized diabetes and another 13% had prediabetes. Using the combination of fasting plasma glucose and HbA1c, a total of 25% of subjects had silent diabetes or prediabetes. Fully 33% of participants had abnormal glucose metabolism by one yardstick or the other.

“What we have seen is there is a group of patients that are missed with either. With the OGTT you don’t see all the diabetics, and with HbA1c and fasting blood glucose you also miss some patients,” said Dr. von Birgelen.

The 1-year cumulative incidence of target vessel failure was 13.2% in patients with silent diabetes as identified by the OGTT and 12.1% in those detected by the alternative method, compared with rates of 2.8% and 3.1%, respectively, in normoglycemic PCI patients. The event rate was 6.1% in patients with prediabetes by OGTT and similar at 5.5% in those found to be prediabetic based on fasting blood glucose and HbA1c, versus rates of 2.8% and 3.1%, respectively, in normoglycemic patients.

“The findings of this study suggest that post-PCI event risk associated with hyperglycemia is a continuum without a clear threshold effect, extending well beyond the threshold that currently defines diabetes,” Dr. von Birgelen said.

Once again, it’s worth emphasizing that the elevated target vessel failure rates seen in patients with abnormal glucose metabolism were due mostly to increased rates of acute MI within the first 24 hours after PCI. The target vessel–related MI rate was 10.3% in patients with silent diabetes, compared with just 1.8% in normoglycemic controls.

Asked what the take-home message for clinicians is from this study, he noted that the Netherlands has a relatively low prevalence of diabetes, and a highly developed primary care medicine system.

“We have a very good one-to-one relationship between the patient and the GP. So if we find 7% silent diabetes and up to one-third of patients with undetected abnormal glucose tolerance in a country with a relatively low prevalence of diabetes, you may expect that in other countries with a higher prevalence and perhaps a less developed primary care system the rate may be much, much higher,” Dr. von Birgelen cautioned.

The implications for the daily clinical practice of interventional cardiology are clear, he continued: “We’ve seen in several trials that the new stents are doing a fantastic job. So if we want to further improve the outcomes in our patients we have to do something else. We should look for subgroups of our PCI patients who have a particularly high risk. And we all realize that diabetics are such a problem, but I think we have shown that the prediabetic patients are also important. So we should identify and pretreat these patients, perhaps with aggressive lipid-lowering therapy during the weeks before a scheduled elective PCI.”

“There are data showing that with aggressive lipid-lowering you might reduce the risk of periprocedural MI,” the cardiologist noted.

As a practical matter, screening via fasting blood glucose and HbA1c is probably the way to go in clinical practice, according to Dr. von Birgelen.

“In this study, we performed the OGTT because it is still considered by many the gold standard. But there is increasing evidence favoring HbA1c data and fasting blood glucose,” he said.

Other possible pre-PCI interventions worthy of consideration in patients found to have previously unsuspected abnormal glucose tolerance might include medical therapy aimed at normalizing glucose metabolism, as well as perhaps resorting to the most potent forms of dual-antiplatelet therapy in patients with stable angina who have impaired glucose tolerance. However, these are possibilities that should be tested in randomized controlled trials before widespread adoption, he added.

The BIO-RESORT Silent Diabetes Study, which will continue for 5 years of post-PCI follow-up, is a prespecified substudy of the previously reported BIO-RESORT trial, which addressed another issue entirely. It was a three-arm, patient-blinded clinical trial comparing 1-year safety and efficacy outcomes in nearly 3,500 PCI patients randomized to PCI with very thin strut biodegradable polymer everolimus- or sirolimus-eluting stents or a durable polymer zotarolimus-eluting stent. Outcomes proved noninferior across the three treatment groups (Lancet. 2016 Nov 26;388[10060]:2607-17).

Dr. von Birgelen observed that the silent diabetes study broke new ground. Prior studies of PCI outcomes in patients with unrecognized diabetes were limited to recipients of plain old balloon angioplasty, bare metal, or first-generation drug-eluting stents. And studies of PCI in patients with unrecognized prediabetes are virtually nonexistent.

As the principal investigator for both the parent BIO-RESORT trial and the silent diabetes substudy, Dr. von Birgelen received research grants from Biotronik, Boston Scientific, and Medtronic, the cosponsors. He applauded the three companies for funding the silent diabetes substudy in the interest of science even though it had no commercial relevance to their stent businesses.
 

 

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– Undetected diabetes and prediabetes are pervasive in patients undergoing percutaneous coronary intervention, and they’re associated with a sharply increased risk of major adverse cardiovascular events, according to the results of the potentially practice-changing BIO-RESORT Silent Diabetes Study, Clemens von Birgelen, MD, PhD, reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

“Our data support screening PCI all-comers for silent diabetes, which may help identify patients with an increased event risk and improve their therapy,” said Dr. von Birgelen, professor of cardiology at the Thoraxcentrum of Twente, a high-volume center for cardiac interventions in Enschede, the Netherlands.

Bruce Jancin/Frontline Medical News
Dr. Clemens von Birgelen
He presented the 1-year follow-up results of the prospective, observational BIO-RESORT Silent Diabetes Study, in which 988 Dutch PCI all-comers without known diabetes underwent screening for abnormal glucose metabolism 6 weeks after the procedure.

A substantial one-third of subjects turned out to have abnormal glucose tolerance according to World Health Organization criteria and an International Expert Committee Report (Diabetes Care. 2009 Jul;32[7]:1327-34). In a multivariate analysis, their 1-year rate of the primary study endpoint – target vessel failure, a composite of cardiac death, target vessel-related MI, or target vessel revascularization – was an adjusted 2.2 times greater than in the 788 normoglycemic patients.

Moreover, among the 7% of study participants who met diagnostic criteria for silent diabetes, the risk of target vessel failure was more than 4.4 times greater than in the normoglycemic group.

“To a very great extent, periprocedural MI is the driving force behind this difference that we saw. From a biological point of view, I think that the vulnerability of the vessel in the diabetic or prediabetic patient features more brittle plaque with a higher risk of cholesterol embolization, and with more plaque mass that can be pushed to the side so that side branch vessels can become occluded, leading to periprocedural MI,” he observed.

Glucose metabolism was assessed in all participants by two methods using the conventional cutoffs: a 2-hour oral glucose tolerance test (OGTT), and the combination of fasting plasma glucose and hemoglobin A1c. By OGTT, 7% of patients had silent, previously unrecognized diabetes and another 13% had prediabetes. Using the combination of fasting plasma glucose and HbA1c, a total of 25% of subjects had silent diabetes or prediabetes. Fully 33% of participants had abnormal glucose metabolism by one yardstick or the other.

“What we have seen is there is a group of patients that are missed with either. With the OGTT you don’t see all the diabetics, and with HbA1c and fasting blood glucose you also miss some patients,” said Dr. von Birgelen.

The 1-year cumulative incidence of target vessel failure was 13.2% in patients with silent diabetes as identified by the OGTT and 12.1% in those detected by the alternative method, compared with rates of 2.8% and 3.1%, respectively, in normoglycemic PCI patients. The event rate was 6.1% in patients with prediabetes by OGTT and similar at 5.5% in those found to be prediabetic based on fasting blood glucose and HbA1c, versus rates of 2.8% and 3.1%, respectively, in normoglycemic patients.

“The findings of this study suggest that post-PCI event risk associated with hyperglycemia is a continuum without a clear threshold effect, extending well beyond the threshold that currently defines diabetes,” Dr. von Birgelen said.

Once again, it’s worth emphasizing that the elevated target vessel failure rates seen in patients with abnormal glucose metabolism were due mostly to increased rates of acute MI within the first 24 hours after PCI. The target vessel–related MI rate was 10.3% in patients with silent diabetes, compared with just 1.8% in normoglycemic controls.

Asked what the take-home message for clinicians is from this study, he noted that the Netherlands has a relatively low prevalence of diabetes, and a highly developed primary care medicine system.

“We have a very good one-to-one relationship between the patient and the GP. So if we find 7% silent diabetes and up to one-third of patients with undetected abnormal glucose tolerance in a country with a relatively low prevalence of diabetes, you may expect that in other countries with a higher prevalence and perhaps a less developed primary care system the rate may be much, much higher,” Dr. von Birgelen cautioned.

The implications for the daily clinical practice of interventional cardiology are clear, he continued: “We’ve seen in several trials that the new stents are doing a fantastic job. So if we want to further improve the outcomes in our patients we have to do something else. We should look for subgroups of our PCI patients who have a particularly high risk. And we all realize that diabetics are such a problem, but I think we have shown that the prediabetic patients are also important. So we should identify and pretreat these patients, perhaps with aggressive lipid-lowering therapy during the weeks before a scheduled elective PCI.”

“There are data showing that with aggressive lipid-lowering you might reduce the risk of periprocedural MI,” the cardiologist noted.

As a practical matter, screening via fasting blood glucose and HbA1c is probably the way to go in clinical practice, according to Dr. von Birgelen.

“In this study, we performed the OGTT because it is still considered by many the gold standard. But there is increasing evidence favoring HbA1c data and fasting blood glucose,” he said.

Other possible pre-PCI interventions worthy of consideration in patients found to have previously unsuspected abnormal glucose tolerance might include medical therapy aimed at normalizing glucose metabolism, as well as perhaps resorting to the most potent forms of dual-antiplatelet therapy in patients with stable angina who have impaired glucose tolerance. However, these are possibilities that should be tested in randomized controlled trials before widespread adoption, he added.

The BIO-RESORT Silent Diabetes Study, which will continue for 5 years of post-PCI follow-up, is a prespecified substudy of the previously reported BIO-RESORT trial, which addressed another issue entirely. It was a three-arm, patient-blinded clinical trial comparing 1-year safety and efficacy outcomes in nearly 3,500 PCI patients randomized to PCI with very thin strut biodegradable polymer everolimus- or sirolimus-eluting stents or a durable polymer zotarolimus-eluting stent. Outcomes proved noninferior across the three treatment groups (Lancet. 2016 Nov 26;388[10060]:2607-17).

Dr. von Birgelen observed that the silent diabetes study broke new ground. Prior studies of PCI outcomes in patients with unrecognized diabetes were limited to recipients of plain old balloon angioplasty, bare metal, or first-generation drug-eluting stents. And studies of PCI in patients with unrecognized prediabetes are virtually nonexistent.

As the principal investigator for both the parent BIO-RESORT trial and the silent diabetes substudy, Dr. von Birgelen received research grants from Biotronik, Boston Scientific, and Medtronic, the cosponsors. He applauded the three companies for funding the silent diabetes substudy in the interest of science even though it had no commercial relevance to their stent businesses.
 

 

 

– Undetected diabetes and prediabetes are pervasive in patients undergoing percutaneous coronary intervention, and they’re associated with a sharply increased risk of major adverse cardiovascular events, according to the results of the potentially practice-changing BIO-RESORT Silent Diabetes Study, Clemens von Birgelen, MD, PhD, reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

“Our data support screening PCI all-comers for silent diabetes, which may help identify patients with an increased event risk and improve their therapy,” said Dr. von Birgelen, professor of cardiology at the Thoraxcentrum of Twente, a high-volume center for cardiac interventions in Enschede, the Netherlands.

Bruce Jancin/Frontline Medical News
Dr. Clemens von Birgelen
He presented the 1-year follow-up results of the prospective, observational BIO-RESORT Silent Diabetes Study, in which 988 Dutch PCI all-comers without known diabetes underwent screening for abnormal glucose metabolism 6 weeks after the procedure.

A substantial one-third of subjects turned out to have abnormal glucose tolerance according to World Health Organization criteria and an International Expert Committee Report (Diabetes Care. 2009 Jul;32[7]:1327-34). In a multivariate analysis, their 1-year rate of the primary study endpoint – target vessel failure, a composite of cardiac death, target vessel-related MI, or target vessel revascularization – was an adjusted 2.2 times greater than in the 788 normoglycemic patients.

Moreover, among the 7% of study participants who met diagnostic criteria for silent diabetes, the risk of target vessel failure was more than 4.4 times greater than in the normoglycemic group.

“To a very great extent, periprocedural MI is the driving force behind this difference that we saw. From a biological point of view, I think that the vulnerability of the vessel in the diabetic or prediabetic patient features more brittle plaque with a higher risk of cholesterol embolization, and with more plaque mass that can be pushed to the side so that side branch vessels can become occluded, leading to periprocedural MI,” he observed.

Glucose metabolism was assessed in all participants by two methods using the conventional cutoffs: a 2-hour oral glucose tolerance test (OGTT), and the combination of fasting plasma glucose and hemoglobin A1c. By OGTT, 7% of patients had silent, previously unrecognized diabetes and another 13% had prediabetes. Using the combination of fasting plasma glucose and HbA1c, a total of 25% of subjects had silent diabetes or prediabetes. Fully 33% of participants had abnormal glucose metabolism by one yardstick or the other.

“What we have seen is there is a group of patients that are missed with either. With the OGTT you don’t see all the diabetics, and with HbA1c and fasting blood glucose you also miss some patients,” said Dr. von Birgelen.

The 1-year cumulative incidence of target vessel failure was 13.2% in patients with silent diabetes as identified by the OGTT and 12.1% in those detected by the alternative method, compared with rates of 2.8% and 3.1%, respectively, in normoglycemic PCI patients. The event rate was 6.1% in patients with prediabetes by OGTT and similar at 5.5% in those found to be prediabetic based on fasting blood glucose and HbA1c, versus rates of 2.8% and 3.1%, respectively, in normoglycemic patients.

“The findings of this study suggest that post-PCI event risk associated with hyperglycemia is a continuum without a clear threshold effect, extending well beyond the threshold that currently defines diabetes,” Dr. von Birgelen said.

Once again, it’s worth emphasizing that the elevated target vessel failure rates seen in patients with abnormal glucose metabolism were due mostly to increased rates of acute MI within the first 24 hours after PCI. The target vessel–related MI rate was 10.3% in patients with silent diabetes, compared with just 1.8% in normoglycemic controls.

Asked what the take-home message for clinicians is from this study, he noted that the Netherlands has a relatively low prevalence of diabetes, and a highly developed primary care medicine system.

“We have a very good one-to-one relationship between the patient and the GP. So if we find 7% silent diabetes and up to one-third of patients with undetected abnormal glucose tolerance in a country with a relatively low prevalence of diabetes, you may expect that in other countries with a higher prevalence and perhaps a less developed primary care system the rate may be much, much higher,” Dr. von Birgelen cautioned.

The implications for the daily clinical practice of interventional cardiology are clear, he continued: “We’ve seen in several trials that the new stents are doing a fantastic job. So if we want to further improve the outcomes in our patients we have to do something else. We should look for subgroups of our PCI patients who have a particularly high risk. And we all realize that diabetics are such a problem, but I think we have shown that the prediabetic patients are also important. So we should identify and pretreat these patients, perhaps with aggressive lipid-lowering therapy during the weeks before a scheduled elective PCI.”

“There are data showing that with aggressive lipid-lowering you might reduce the risk of periprocedural MI,” the cardiologist noted.

As a practical matter, screening via fasting blood glucose and HbA1c is probably the way to go in clinical practice, according to Dr. von Birgelen.

“In this study, we performed the OGTT because it is still considered by many the gold standard. But there is increasing evidence favoring HbA1c data and fasting blood glucose,” he said.

Other possible pre-PCI interventions worthy of consideration in patients found to have previously unsuspected abnormal glucose tolerance might include medical therapy aimed at normalizing glucose metabolism, as well as perhaps resorting to the most potent forms of dual-antiplatelet therapy in patients with stable angina who have impaired glucose tolerance. However, these are possibilities that should be tested in randomized controlled trials before widespread adoption, he added.

The BIO-RESORT Silent Diabetes Study, which will continue for 5 years of post-PCI follow-up, is a prespecified substudy of the previously reported BIO-RESORT trial, which addressed another issue entirely. It was a three-arm, patient-blinded clinical trial comparing 1-year safety and efficacy outcomes in nearly 3,500 PCI patients randomized to PCI with very thin strut biodegradable polymer everolimus- or sirolimus-eluting stents or a durable polymer zotarolimus-eluting stent. Outcomes proved noninferior across the three treatment groups (Lancet. 2016 Nov 26;388[10060]:2607-17).

Dr. von Birgelen observed that the silent diabetes study broke new ground. Prior studies of PCI outcomes in patients with unrecognized diabetes were limited to recipients of plain old balloon angioplasty, bare metal, or first-generation drug-eluting stents. And studies of PCI in patients with unrecognized prediabetes are virtually nonexistent.

As the principal investigator for both the parent BIO-RESORT trial and the silent diabetes substudy, Dr. von Birgelen received research grants from Biotronik, Boston Scientific, and Medtronic, the cosponsors. He applauded the three companies for funding the silent diabetes substudy in the interest of science even though it had no commercial relevance to their stent businesses.
 

 

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Key clinical point: Patients undergoing nonurgent PCI should be screened for abnormal glucose tolerance beforehand.

Major finding: One-third of patients undergoing PCI have unsuspected silent diabetes or prediabetes, placing them at increased risk for major adverse cardiac events.

Data source: This prospective observational study included 988 patients not known to have diabetes who underwent screening for abnormal glucose tolerance 6 weeks after PCI with stenting.

Disclosures: The study was cosponsored by Biotronik, Boston Scientific, and Medtronic.