Acute promyelocytic leukemia

Image courtesy of The Armed

Forces Institute of Pathology

A class of circular RNAs may play a key role in the development and progression of certain leukemias and other cancers, according to research published in Cell.

Investigators found that cancer-associated chromosomal translocations give rise to fusion circular RNAs (f-circRNAs).

And these f-circRNAs aid cellular transformation, promote cell viability, confer treatment resistance, and exhibit tumor-promoting properties in vivo.

“Cancer is essentially a disease of mutated or broken genes, so that motivated us to examine whether circular RNAs, like proteins, can be affected by these chromosomal breaks,” said study author Pier Paolo Pandolfi, MD, PhD, of Beth Israel Deaconess Medical Center in Boston, Massachusetts.

“Our work paves the way to discovering many more of these unusual RNAs and how they contribute to cancer, which could reveal new mechanisms and druggable pathways involved in tumor progression.”

Curious about the possibility of circular RNAs contributing to cancer, Dr Pandolfi and his colleagues set out to see if they could detect relevant changes in tumors known to harbor distinct fusion proteins.

The team examined acute promyelocytic leukemia, which often carries a translocation between the PML and RARα genes, and acute myeloid leukemia, which can harbor a translocation between the MLL and AF9 genes.

The investigators found f-circRNAs corresponding to different exons associated with the PML-RARα gene fusion and the MLL-AF9 gene fusion. Normally, multiple circular RNAs can be generated from a single gene, so the team was not surprised to find different f-circRNAs emerging from the same fusion gene.

Dr Pandolfi and his colleagues also uncovered f-circRNAs in solid tumors—in Ewing sarcoma and lung cancer.

The team identified the f-circRNAs using 2 distinct methods—PCR-based amplification and sequencing-based approaches. They said this suggests f-circRNAs are bona fide biological entities, rather than experimental artifacts.

“Our ability to readily detect these fusion-circular RNAs—and their normal, non-fused counterparts—will be enhanced by advances in sequencing technology and analytic methods,” said study author Jlenia Guarnerio, PhD, also of Beth Israel Deaconess Medical Center.

“Indeed, as we look ahead to cataloguing them comprehensively across all cancers and to deeply understanding their mechanisms of action, we will need to propel these new methodologies even further.”

To determine whether f-circRNAs play a functional role in cancer, the investigators introduced the RNAs into cells. This caused the cells to increase their proliferation and tendency to overgrow—features shared by tumor cells.

On the other hand, when the team blocked f-circRNA activity, the cells’ normal behaviors were restored.

Dr Pandolfi and his colleagues also conducted experiments using a mouse model of leukemia. They focused on a specific f-circRNA associated with the MLL-AF9 fusion gene, called f-circM9.

Although f-circM9 could not trigger leukemia on its own, it appeared to work with other cancer-promoting signals—such as the MLL-AF9 fusion protein—to cause leukemia.

Additional experiments suggested that f-circM9 may also help tumor cells persist despite treatment with anticancer drugs.

“These results are particularly exciting because they suggest that drugs directed at fusion-circular RNAs could be a powerful strategy to pursue for future therapeutic development in cancer,” Dr Pandolfi said.

“[However,] our knowledge of circular RNAs is really in its infancy. We know that, normally, they can bind proteins as well as DNA and microRNAs, but much more needs to be done to understand how fusion-circular RNAs work. We have only scratched the surface of these RNAs and their roles in cancer and other diseases.”

Acute promyelocytic leukemia

Image courtesy of The Armed

Forces Institute of Pathology

A class of circular RNAs may play a key role in the development and progression of certain leukemias and other cancers, according to research published in Cell.

Investigators found that cancer-associated chromosomal translocations give rise to fusion circular RNAs (f-circRNAs).

And these f-circRNAs aid cellular transformation, promote cell viability, confer treatment resistance, and exhibit tumor-promoting properties in vivo.

“Cancer is essentially a disease of mutated or broken genes, so that motivated us to examine whether circular RNAs, like proteins, can be affected by these chromosomal breaks,” said study author Pier Paolo Pandolfi, MD, PhD, of Beth Israel Deaconess Medical Center in Boston, Massachusetts.

“Our work paves the way to discovering many more of these unusual RNAs and how they contribute to cancer, which could reveal new mechanisms and druggable pathways involved in tumor progression.”

Curious about the possibility of circular RNAs contributing to cancer, Dr Pandolfi and his colleagues set out to see if they could detect relevant changes in tumors known to harbor distinct fusion proteins.

The team examined acute promyelocytic leukemia, which often carries a translocation between the PML and RARα genes, and acute myeloid leukemia, which can harbor a translocation between the MLL and AF9 genes.

The investigators found f-circRNAs corresponding to different exons associated with the PML-RARα gene fusion and the MLL-AF9 gene fusion. Normally, multiple circular RNAs can be generated from a single gene, so the team was not surprised to find different f-circRNAs emerging from the same fusion gene.

Dr Pandolfi and his colleagues also uncovered f-circRNAs in solid tumors—in Ewing sarcoma and lung cancer.

The team identified the f-circRNAs using 2 distinct methods—PCR-based amplification and sequencing-based approaches. They said this suggests f-circRNAs are bona fide biological entities, rather than experimental artifacts.

“Our ability to readily detect these fusion-circular RNAs—and their normal, non-fused counterparts—will be enhanced by advances in sequencing technology and analytic methods,” said study author Jlenia Guarnerio, PhD, also of Beth Israel Deaconess Medical Center.

“Indeed, as we look ahead to cataloguing them comprehensively across all cancers and to deeply understanding their mechanisms of action, we will need to propel these new methodologies even further.”

To determine whether f-circRNAs play a functional role in cancer, the investigators introduced the RNAs into cells. This caused the cells to increase their proliferation and tendency to overgrow—features shared by tumor cells.

On the other hand, when the team blocked f-circRNA activity, the cells’ normal behaviors were restored.

Dr Pandolfi and his colleagues also conducted experiments using a mouse model of leukemia. They focused on a specific f-circRNA associated with the MLL-AF9 fusion gene, called f-circM9.

Although f-circM9 could not trigger leukemia on its own, it appeared to work with other cancer-promoting signals—such as the MLL-AF9 fusion protein—to cause leukemia.

Additional experiments suggested that f-circM9 may also help tumor cells persist despite treatment with anticancer drugs.

“These results are particularly exciting because they suggest that drugs directed at fusion-circular RNAs could be a powerful strategy to pursue for future therapeutic development in cancer,” Dr Pandolfi said.

“[However,] our knowledge of circular RNAs is really in its infancy. We know that, normally, they can bind proteins as well as DNA and microRNAs, but much more needs to be done to understand how fusion-circular RNAs work. We have only scratched the surface of these RNAs and their roles in cancer and other diseases.”

Acute promyelocytic leukemia

Image courtesy of The Armed

Forces Institute of Pathology

A class of circular RNAs may play a key role in the development and progression of certain leukemias and other cancers, according to research published in Cell.

Investigators found that cancer-associated chromosomal translocations give rise to fusion circular RNAs (f-circRNAs).

And these f-circRNAs aid cellular transformation, promote cell viability, confer treatment resistance, and exhibit tumor-promoting properties in vivo.

“Cancer is essentially a disease of mutated or broken genes, so that motivated us to examine whether circular RNAs, like proteins, can be affected by these chromosomal breaks,” said study author Pier Paolo Pandolfi, MD, PhD, of Beth Israel Deaconess Medical Center in Boston, Massachusetts.

“Our work paves the way to discovering many more of these unusual RNAs and how they contribute to cancer, which could reveal new mechanisms and druggable pathways involved in tumor progression.”

Curious about the possibility of circular RNAs contributing to cancer, Dr Pandolfi and his colleagues set out to see if they could detect relevant changes in tumors known to harbor distinct fusion proteins.

The team examined acute promyelocytic leukemia, which often carries a translocation between the PML and RARα genes, and acute myeloid leukemia, which can harbor a translocation between the MLL and AF9 genes.

The investigators found f-circRNAs corresponding to different exons associated with the PML-RARα gene fusion and the MLL-AF9 gene fusion. Normally, multiple circular RNAs can be generated from a single gene, so the team was not surprised to find different f-circRNAs emerging from the same fusion gene.

Dr Pandolfi and his colleagues also uncovered f-circRNAs in solid tumors—in Ewing sarcoma and lung cancer.

The team identified the f-circRNAs using 2 distinct methods—PCR-based amplification and sequencing-based approaches. They said this suggests f-circRNAs are bona fide biological entities, rather than experimental artifacts.

“Our ability to readily detect these fusion-circular RNAs—and their normal, non-fused counterparts—will be enhanced by advances in sequencing technology and analytic methods,” said study author Jlenia Guarnerio, PhD, also of Beth Israel Deaconess Medical Center.

“Indeed, as we look ahead to cataloguing them comprehensively across all cancers and to deeply understanding their mechanisms of action, we will need to propel these new methodologies even further.”

To determine whether f-circRNAs play a functional role in cancer, the investigators introduced the RNAs into cells. This caused the cells to increase their proliferation and tendency to overgrow—features shared by tumor cells.

On the other hand, when the team blocked f-circRNA activity, the cells’ normal behaviors were restored.

Dr Pandolfi and his colleagues also conducted experiments using a mouse model of leukemia. They focused on a specific f-circRNA associated with the MLL-AF9 fusion gene, called f-circM9.

Although f-circM9 could not trigger leukemia on its own, it appeared to work with other cancer-promoting signals—such as the MLL-AF9 fusion protein—to cause leukemia.

Additional experiments suggested that f-circM9 may also help tumor cells persist despite treatment with anticancer drugs.

“These results are particularly exciting because they suggest that drugs directed at fusion-circular RNAs could be a powerful strategy to pursue for future therapeutic development in cancer,” Dr Pandolfi said.

“[However,] our knowledge of circular RNAs is really in its infancy. We know that, normally, they can bind proteins as well as DNA and microRNAs, but much more needs to be done to understand how fusion-circular RNAs work. We have only scratched the surface of these RNAs and their roles in cancer and other diseases.”

Acute myeloid leukemia

Image by Lance Liotta

The US Food and Drug Administration (FDA) has granted orphan designation for the radioimmunoconjugate Iomab-B to be used as a conditioning agent for patients with relapsed or refractory acute myeloid leukemia (AML) who are undergoing hematopoietic stem cell transplant (HSCT).

Iomab-B is a radioimmunoconjugate consisting of BC8, a novel murine monoclonal antibody, and the radioisotope iodine-131.

BC8 targets CD45, a pan-leukocytic antigen widely expressed on white blood cells. This makes BC8 potentially useful in targeting white blood cells in preparation for HSCT.

When labeled with radioactive isotopes, BC8 carries radioactivity directly to the site of cancerous growth and bone marrow, while avoiding the effects of radiation on most healthy tissues, according to Actinium Pharmaceuticals, Inc., the company developing Iomab-B.

Actinium said Iomab-B has been tested as a myeloconditioning/myeloablative agent in more than 250 patients with incurable hematologic malignancies.

The company has released data from a phase 1/2 trial of Iomab-B in patients with relapsed/refractory AML who are older than 50.

The data show that patients who received Iomab-B before HSCT (n=27) had higher rates of survival at 1 and 2 years than patients who underwent HSCT with conventional myeloablative conditioning (n=10) or chemotherapy (n=61).

One-year survival rates were 30% in the Iomab-B arm and 10% each in the conventional conditioning and chemotherapy arms. Two-year survival rates were 19%, 0%, and 0%, respectively.

Now, Actinium is planning a phase 3 trial of Iomab-B in relapsed/refractory AML patients over the age of 55.

About orphan designation

The FDA grants orphan designation to drugs intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

Acute myeloid leukemia

Image by Lance Liotta

The US Food and Drug Administration (FDA) has granted orphan designation for the radioimmunoconjugate Iomab-B to be used as a conditioning agent for patients with relapsed or refractory acute myeloid leukemia (AML) who are undergoing hematopoietic stem cell transplant (HSCT).

Iomab-B is a radioimmunoconjugate consisting of BC8, a novel murine monoclonal antibody, and the radioisotope iodine-131.

BC8 targets CD45, a pan-leukocytic antigen widely expressed on white blood cells. This makes BC8 potentially useful in targeting white blood cells in preparation for HSCT.

When labeled with radioactive isotopes, BC8 carries radioactivity directly to the site of cancerous growth and bone marrow, while avoiding the effects of radiation on most healthy tissues, according to Actinium Pharmaceuticals, Inc., the company developing Iomab-B.

Actinium said Iomab-B has been tested as a myeloconditioning/myeloablative agent in more than 250 patients with incurable hematologic malignancies.

The company has released data from a phase 1/2 trial of Iomab-B in patients with relapsed/refractory AML who are older than 50.

The data show that patients who received Iomab-B before HSCT (n=27) had higher rates of survival at 1 and 2 years than patients who underwent HSCT with conventional myeloablative conditioning (n=10) or chemotherapy (n=61).

One-year survival rates were 30% in the Iomab-B arm and 10% each in the conventional conditioning and chemotherapy arms. Two-year survival rates were 19%, 0%, and 0%, respectively.

Now, Actinium is planning a phase 3 trial of Iomab-B in relapsed/refractory AML patients over the age of 55.

About orphan designation

The FDA grants orphan designation to drugs intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

Acute myeloid leukemia

Image by Lance Liotta

The US Food and Drug Administration (FDA) has granted orphan designation for the radioimmunoconjugate Iomab-B to be used as a conditioning agent for patients with relapsed or refractory acute myeloid leukemia (AML) who are undergoing hematopoietic stem cell transplant (HSCT).

Iomab-B is a radioimmunoconjugate consisting of BC8, a novel murine monoclonal antibody, and the radioisotope iodine-131.

BC8 targets CD45, a pan-leukocytic antigen widely expressed on white blood cells. This makes BC8 potentially useful in targeting white blood cells in preparation for HSCT.

When labeled with radioactive isotopes, BC8 carries radioactivity directly to the site of cancerous growth and bone marrow, while avoiding the effects of radiation on most healthy tissues, according to Actinium Pharmaceuticals, Inc., the company developing Iomab-B.

Actinium said Iomab-B has been tested as a myeloconditioning/myeloablative agent in more than 250 patients with incurable hematologic malignancies.

The company has released data from a phase 1/2 trial of Iomab-B in patients with relapsed/refractory AML who are older than 50.

The data show that patients who received Iomab-B before HSCT (n=27) had higher rates of survival at 1 and 2 years than patients who underwent HSCT with conventional myeloablative conditioning (n=10) or chemotherapy (n=61).

One-year survival rates were 30% in the Iomab-B arm and 10% each in the conventional conditioning and chemotherapy arms. Two-year survival rates were 19%, 0%, and 0%, respectively.

Now, Actinium is planning a phase 3 trial of Iomab-B in relapsed/refractory AML patients over the age of 55.

About orphan designation

The FDA grants orphan designation to drugs intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

Red blood cells

Top-line results from a phase 3 trial suggest the oral, iron-based drug ferric citrate is more effective than placebo for treating iron deficiency anemia in adults with stage 3-5, non-dialysis-dependent chronic kidney disease.

Fifty-two percent of patients who received ferric citrate achieved at least a 1 g/dL increase in hemoglobin over a 16-week period, compared to 19% of patients who received placebo.

Researchers said the safety profile of ferric citrate in this trial was consistent with that in previous studies.

Keryx Biopharmaceuticals, Inc., the company developing ferric citrate, recently announced these results.

Patients and treatment

In this phase 3 study, researchers compared treatment with ferric citrate to placebo in 234 patients who previously had not adequately responded to or tolerated current oral iron therapies. The patients were not allowed to receive any iron (intravenous or oral) or erythropoiesis-stimulating agents during this study.

The patients were randomized 1:1 to receive ferric citrate (n=117) or placebo (n=115). Two patients in the placebo arm discontinued the study and were not included in the efficacy analysis. One discontinued after randomization prior to receiving placebo, and the other discontinued after taking a dose of placebo but before having laboratory values drawn.

The study had a 16-week, randomized, double-blind, placebo-controlled efficacy period, followed by an 8-week, open-label safety extension period. During the extension period, all patients remaining in the study, including the placebo arm, received ferric citrate.

During the efficacy period, ferric citrate was administered at a starting dose of 3 tablets per day, with food, and could be titrated every 4 weeks by an additional 3 tablets, for up to 12 tablets per day. The mean dose of ferric citrate was 5 tablets per day.

Baseline laboratory values were similar between the treatment arms. The mean hemoglobin was 10.4 g/dL in both arms.

The mean transferrin saturation was 20.2% in the ferric citrate arm and 19.6% in the placebo arm. The mean ferritin was 85.9 ng/mL and 81.7 ng/mL, respectively. And the mean serum phosphate was 4.2 mg/dL and 4.1 mg/dL, respectively.

Efficacy results

The study achieved its primary endpoint, with 52.1% (61/117) of patients who received ferric citrate achieving a 1g/dL or greater rise in hemoglobin at any time point during the 16-week efficacy period, compared to 19.1% (22/115) of patients in the placebo arm (P<0.001).

The researchers also observed significant differences in all pre-specified secondary efficacy endpoints.

The mean change in hemoglobin was 0.75 g/dL in the ferric citrate arm and -0.08 g/dL in the placebo arm (P<0.001). The mean change in transferrin saturation was 17.8% and -0.6%, respectively (P<0.001).

The mean change in ferritin was 162.5 ng/mL and -7.7 ng/mL, respectively (P<0.001). And the mean change in serum phosphate was -0.43 mg/dL and -0.22 mg/dL, respectively (P=0.02).

The proportion of patients with a durable response during the efficacy period was 48.7% in the ferric citrate arm and 14.8% in the placebo arm (P<0.001).

A durable response was defined as a mean change in hemoglobin from baseline of at least 0.75 g/dL over any 4-week time period during the efficacy period, provided that an increase of at least 1.0 g/dL had occurred during that 4-week period.

Safety results

During the efficacy period, the majority of adverse events (AEs) were mild to moderate. The most common AEs—in the ferric citrate and placebo arms, respectively—were diarrhea (20.5% vs 16.4%), constipation (18.8% vs 12.9%), discolored feces (14.5% vs 0%), and nausea (11.1% vs 2.6%).

Hypophosphatemia was reported in 4 patients—1 in the ferric citrate arm and 3 in the placebo arm.

Twenty-six percent (31/117) of ferric citrate-treated patients and 30% (35/116) of patients receiving placebo discontinued treatment during the efficacy period. Twelve patients treated with ferric citrate discontinued due to an AE, as did 10 patients who received placebo.

During the efficacy period, the rate of serious AEs was balanced between the ferric citrate and placebo arms, at 12% and 10%, respectively. None of the serious AEs were deemed drug-related.

Over the course of the study, there were 2 deaths reported. Both occurred in patients receiving ferric citrate, but neither were considered drug-related.

Red blood cells

Top-line results from a phase 3 trial suggest the oral, iron-based drug ferric citrate is more effective than placebo for treating iron deficiency anemia in adults with stage 3-5, non-dialysis-dependent chronic kidney disease.

Fifty-two percent of patients who received ferric citrate achieved at least a 1 g/dL increase in hemoglobin over a 16-week period, compared to 19% of patients who received placebo.

Researchers said the safety profile of ferric citrate in this trial was consistent with that in previous studies.

Keryx Biopharmaceuticals, Inc., the company developing ferric citrate, recently announced these results.

Patients and treatment

In this phase 3 study, researchers compared treatment with ferric citrate to placebo in 234 patients who previously had not adequately responded to or tolerated current oral iron therapies. The patients were not allowed to receive any iron (intravenous or oral) or erythropoiesis-stimulating agents during this study.

The patients were randomized 1:1 to receive ferric citrate (n=117) or placebo (n=115). Two patients in the placebo arm discontinued the study and were not included in the efficacy analysis. One discontinued after randomization prior to receiving placebo, and the other discontinued after taking a dose of placebo but before having laboratory values drawn.

The study had a 16-week, randomized, double-blind, placebo-controlled efficacy period, followed by an 8-week, open-label safety extension period. During the extension period, all patients remaining in the study, including the placebo arm, received ferric citrate.

During the efficacy period, ferric citrate was administered at a starting dose of 3 tablets per day, with food, and could be titrated every 4 weeks by an additional 3 tablets, for up to 12 tablets per day. The mean dose of ferric citrate was 5 tablets per day.

Baseline laboratory values were similar between the treatment arms. The mean hemoglobin was 10.4 g/dL in both arms.

The mean transferrin saturation was 20.2% in the ferric citrate arm and 19.6% in the placebo arm. The mean ferritin was 85.9 ng/mL and 81.7 ng/mL, respectively. And the mean serum phosphate was 4.2 mg/dL and 4.1 mg/dL, respectively.

Efficacy results

The study achieved its primary endpoint, with 52.1% (61/117) of patients who received ferric citrate achieving a 1g/dL or greater rise in hemoglobin at any time point during the 16-week efficacy period, compared to 19.1% (22/115) of patients in the placebo arm (P<0.001).

The researchers also observed significant differences in all pre-specified secondary efficacy endpoints.

The mean change in hemoglobin was 0.75 g/dL in the ferric citrate arm and -0.08 g/dL in the placebo arm (P<0.001). The mean change in transferrin saturation was 17.8% and -0.6%, respectively (P<0.001).

The mean change in ferritin was 162.5 ng/mL and -7.7 ng/mL, respectively (P<0.001). And the mean change in serum phosphate was -0.43 mg/dL and -0.22 mg/dL, respectively (P=0.02).

The proportion of patients with a durable response during the efficacy period was 48.7% in the ferric citrate arm and 14.8% in the placebo arm (P<0.001).

A durable response was defined as a mean change in hemoglobin from baseline of at least 0.75 g/dL over any 4-week time period during the efficacy period, provided that an increase of at least 1.0 g/dL had occurred during that 4-week period.

Safety results

During the efficacy period, the majority of adverse events (AEs) were mild to moderate. The most common AEs—in the ferric citrate and placebo arms, respectively—were diarrhea (20.5% vs 16.4%), constipation (18.8% vs 12.9%), discolored feces (14.5% vs 0%), and nausea (11.1% vs 2.6%).

Hypophosphatemia was reported in 4 patients—1 in the ferric citrate arm and 3 in the placebo arm.

Twenty-six percent (31/117) of ferric citrate-treated patients and 30% (35/116) of patients receiving placebo discontinued treatment during the efficacy period. Twelve patients treated with ferric citrate discontinued due to an AE, as did 10 patients who received placebo.

During the efficacy period, the rate of serious AEs was balanced between the ferric citrate and placebo arms, at 12% and 10%, respectively. None of the serious AEs were deemed drug-related.

Over the course of the study, there were 2 deaths reported. Both occurred in patients receiving ferric citrate, but neither were considered drug-related.

Red blood cells

Top-line results from a phase 3 trial suggest the oral, iron-based drug ferric citrate is more effective than placebo for treating iron deficiency anemia in adults with stage 3-5, non-dialysis-dependent chronic kidney disease.

Fifty-two percent of patients who received ferric citrate achieved at least a 1 g/dL increase in hemoglobin over a 16-week period, compared to 19% of patients who received placebo.

Researchers said the safety profile of ferric citrate in this trial was consistent with that in previous studies.

Keryx Biopharmaceuticals, Inc., the company developing ferric citrate, recently announced these results.

Patients and treatment

In this phase 3 study, researchers compared treatment with ferric citrate to placebo in 234 patients who previously had not adequately responded to or tolerated current oral iron therapies. The patients were not allowed to receive any iron (intravenous or oral) or erythropoiesis-stimulating agents during this study.

The patients were randomized 1:1 to receive ferric citrate (n=117) or placebo (n=115). Two patients in the placebo arm discontinued the study and were not included in the efficacy analysis. One discontinued after randomization prior to receiving placebo, and the other discontinued after taking a dose of placebo but before having laboratory values drawn.

The study had a 16-week, randomized, double-blind, placebo-controlled efficacy period, followed by an 8-week, open-label safety extension period. During the extension period, all patients remaining in the study, including the placebo arm, received ferric citrate.

During the efficacy period, ferric citrate was administered at a starting dose of 3 tablets per day, with food, and could be titrated every 4 weeks by an additional 3 tablets, for up to 12 tablets per day. The mean dose of ferric citrate was 5 tablets per day.

Baseline laboratory values were similar between the treatment arms. The mean hemoglobin was 10.4 g/dL in both arms.

The mean transferrin saturation was 20.2% in the ferric citrate arm and 19.6% in the placebo arm. The mean ferritin was 85.9 ng/mL and 81.7 ng/mL, respectively. And the mean serum phosphate was 4.2 mg/dL and 4.1 mg/dL, respectively.

Efficacy results

The study achieved its primary endpoint, with 52.1% (61/117) of patients who received ferric citrate achieving a 1g/dL or greater rise in hemoglobin at any time point during the 16-week efficacy period, compared to 19.1% (22/115) of patients in the placebo arm (P<0.001).

The researchers also observed significant differences in all pre-specified secondary efficacy endpoints.

The mean change in hemoglobin was 0.75 g/dL in the ferric citrate arm and -0.08 g/dL in the placebo arm (P<0.001). The mean change in transferrin saturation was 17.8% and -0.6%, respectively (P<0.001).

The mean change in ferritin was 162.5 ng/mL and -7.7 ng/mL, respectively (P<0.001). And the mean change in serum phosphate was -0.43 mg/dL and -0.22 mg/dL, respectively (P=0.02).

The proportion of patients with a durable response during the efficacy period was 48.7% in the ferric citrate arm and 14.8% in the placebo arm (P<0.001).

A durable response was defined as a mean change in hemoglobin from baseline of at least 0.75 g/dL over any 4-week time period during the efficacy period, provided that an increase of at least 1.0 g/dL had occurred during that 4-week period.

Safety results

During the efficacy period, the majority of adverse events (AEs) were mild to moderate. The most common AEs—in the ferric citrate and placebo arms, respectively—were diarrhea (20.5% vs 16.4%), constipation (18.8% vs 12.9%), discolored feces (14.5% vs 0%), and nausea (11.1% vs 2.6%).

Hypophosphatemia was reported in 4 patients—1 in the ferric citrate arm and 3 in the placebo arm.

Twenty-six percent (31/117) of ferric citrate-treated patients and 30% (35/116) of patients receiving placebo discontinued treatment during the efficacy period. Twelve patients treated with ferric citrate discontinued due to an AE, as did 10 patients who received placebo.

During the efficacy period, the rate of serious AEs was balanced between the ferric citrate and placebo arms, at 12% and 10%, respectively. None of the serious AEs were deemed drug-related.

Over the course of the study, there were 2 deaths reported. Both occurred in patients receiving ferric citrate, but neither were considered drug-related.

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Table of Contents

• Lessons From History: The Ethical Foundation of VA Health Care
• Calcium-Containing Crystal-Associated Arthropathies in the Elderly
• Recurrent Abdominal Pain and Bowel Edema in a Middle-Aged Woman
• Implementing the EQUiPPED Medication Management Program
• Academic Reasonable Accommodations for Post-9/11 Veterans With Psychiatric Diagnoses, Part 1
• An ECHO-Based Program to Provide Geriatric Specialty Care Consultation and Education
• Possible Simeprevir/Sofosbuvir-Induced Hepatic Decompensation With Acute Kidney Failure

Table of Contents

• Lessons From History: The Ethical Foundation of VA Health Care
• Calcium-Containing Crystal-Associated Arthropathies in the Elderly
• Recurrent Abdominal Pain and Bowel Edema in a Middle-Aged Woman
• Implementing the EQUiPPED Medication Management Program
• Academic Reasonable Accommodations for Post-9/11 Veterans With Psychiatric Diagnoses, Part 1
• An ECHO-Based Program to Provide Geriatric Specialty Care Consultation and Education
• Possible Simeprevir/Sofosbuvir-Induced Hepatic Decompensation With Acute Kidney Failure

Table of Contents

• Lessons From History: The Ethical Foundation of VA Health Care
• Calcium-Containing Crystal-Associated Arthropathies in the Elderly
• Recurrent Abdominal Pain and Bowel Edema in a Middle-Aged Woman
• Implementing the EQUiPPED Medication Management Program
• Academic Reasonable Accommodations for Post-9/11 Veterans With Psychiatric Diagnoses, Part 1
• An ECHO-Based Program to Provide Geriatric Specialty Care Consultation and Education
• Possible Simeprevir/Sofosbuvir-Induced Hepatic Decompensation With Acute Kidney Failure

Health care providers performing esophageal manometry should keep in mind eight new quality measures listed and validated in a recent study published in the April issue of Clinical Gastroenterology and Hepatology (Clin Gastroenterol Hepatol. 2015 Oct 20. doi: 10.1016/j.cgh.2015.10.006), which researchers believe will significantly improve the performance of esophageal manometry and interpretation of data culled from such procedures.

“Despite its critical importance in the diagnosis and management of esophageal motility disorders, features of a high-quality esophageal manometry [study] have not been formally defined,” said the study authors, led by Dr. Rena Yadlapati of Northwestern University in Chicago. “Standardizing key aspects of esophageal manometry is imperative to ensure the delivery of high-quality care.”

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

Dr. Yadlapati and her coinvestigators carried out the study in accordance with guidelines set out by the RAND/UCLA Appropriateness Method (RAM), They began by recruiting a panel of 15 esophageal manometry experts with leadership, geographical diversity, and a wide range of practice settings being the key criteria in their selection.

Investigators then conducted a literature review, selecting the 30 most relevant randomized, controlled trials, retrospective studies, and systematic reviews from the past 10 years. From this review, investigators created a list of 30 possible quality measures, all of which were then sent to each member of the expert panel via email for them to rank on a 9-point interval scale, and modify if necessary.

Those rankings were then used to determine the appropriateness of each proposed quality measure at a face-to-face meeting among the investigators and the 15-member expert panel, at which 17 quality measures were determined to be appropriate. In all, 2 measures dealt with competency, 2 pertained to assessment before procedure, 3 were regarding performance of the procedure itself, and 10 were about interpretation of data obtained from esophageal manometry; the 10 measures concerning interpretation of data were compiled into 1 measure, leaving a total of 8 that were ultimately approved.

The quality measures for competency are as follows:

• “If esophageal manometry is performed, then the technician must be competent to perform esophageal manometry.”

• “If a physician is considered competent to interpret esophageal manometry, then the physician must interpret a minimum number of esophageal manometry studies annually.”

For assessment before procedure, the measures state the following:

• “If a patient is referred for esophageal manometry, then the patient should have undergone an evaluation for structural abnormalities before manometry.”

• “If an esophageal manometry is performed, then informed consent must be obtained and documented.”

Quality measures regarding the procedure itself state the following:

• “If an esophageal manometry study is performed, then a time interval of at least 30 seconds should occur between swallows.”

• “If an esophageal manometry study is performed, then at least 10 wet swallows should be attempted.”

• “If an esophageal manometry study is performed, then at least seven evaluable wet swallows should be included.”

Finally, regarding interpretation of data, the single quality measures states that “If an esophageal manometry study is interpreted, then a complete procedure report should document the following:

• “Reason for referral.”

• “Clinical diagnosis.”

• “Diagnosis according to formally validated classification scheme.”

• “Documentation of formally validated classification scheme used.”

• “Summary of results”

• “Tabulated results including upper esophageal sphincter activity, interpretation of esophagogastric junction relaxation, documentation of pressure inversion point if technically feasible, pressurization pattern and contractile pattern.”

• “Technical limitation (if applicable).”

• “Communication to referring provider.”

“These eight appropriate quality measures are considered absolutely necessary in the performance and interpretation of esophageal manometry,” the authors concluded. “In particular, measures 3-8 are clinically feasible and measurable, and should serve as an initial framework to benchmark quality and reduce variability in esophageal manometry practices.”

This study was funded by the Alumnae of Northwestern University, and a grant to Dr. Yadlapati (T32 DK101363-02). Five coinvestigators disclosed consultancy and speaking relationships with Boston Scientific, Cook Endoscopy, EndoStim, Given Imaging, Covidien, and Sandhill Scientific.

[email protected]

Health care providers performing esophageal manometry should keep in mind eight new quality measures listed and validated in a recent study published in the April issue of Clinical Gastroenterology and Hepatology (Clin Gastroenterol Hepatol. 2015 Oct 20. doi: 10.1016/j.cgh.2015.10.006), which researchers believe will significantly improve the performance of esophageal manometry and interpretation of data culled from such procedures.

“Despite its critical importance in the diagnosis and management of esophageal motility disorders, features of a high-quality esophageal manometry [study] have not been formally defined,” said the study authors, led by Dr. Rena Yadlapati of Northwestern University in Chicago. “Standardizing key aspects of esophageal manometry is imperative to ensure the delivery of high-quality care.”

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

Dr. Yadlapati and her coinvestigators carried out the study in accordance with guidelines set out by the RAND/UCLA Appropriateness Method (RAM), They began by recruiting a panel of 15 esophageal manometry experts with leadership, geographical diversity, and a wide range of practice settings being the key criteria in their selection.

Investigators then conducted a literature review, selecting the 30 most relevant randomized, controlled trials, retrospective studies, and systematic reviews from the past 10 years. From this review, investigators created a list of 30 possible quality measures, all of which were then sent to each member of the expert panel via email for them to rank on a 9-point interval scale, and modify if necessary.

Those rankings were then used to determine the appropriateness of each proposed quality measure at a face-to-face meeting among the investigators and the 15-member expert panel, at which 17 quality measures were determined to be appropriate. In all, 2 measures dealt with competency, 2 pertained to assessment before procedure, 3 were regarding performance of the procedure itself, and 10 were about interpretation of data obtained from esophageal manometry; the 10 measures concerning interpretation of data were compiled into 1 measure, leaving a total of 8 that were ultimately approved.

The quality measures for competency are as follows:

• “If esophageal manometry is performed, then the technician must be competent to perform esophageal manometry.”

• “If a physician is considered competent to interpret esophageal manometry, then the physician must interpret a minimum number of esophageal manometry studies annually.”

For assessment before procedure, the measures state the following:

• “If a patient is referred for esophageal manometry, then the patient should have undergone an evaluation for structural abnormalities before manometry.”

• “If an esophageal manometry is performed, then informed consent must be obtained and documented.”

Quality measures regarding the procedure itself state the following:

• “If an esophageal manometry study is performed, then a time interval of at least 30 seconds should occur between swallows.”

• “If an esophageal manometry study is performed, then at least 10 wet swallows should be attempted.”

• “If an esophageal manometry study is performed, then at least seven evaluable wet swallows should be included.”

Finally, regarding interpretation of data, the single quality measures states that “If an esophageal manometry study is interpreted, then a complete procedure report should document the following:

• “Reason for referral.”

• “Clinical diagnosis.”

• “Diagnosis according to formally validated classification scheme.”

• “Documentation of formally validated classification scheme used.”

• “Summary of results”

• “Tabulated results including upper esophageal sphincter activity, interpretation of esophagogastric junction relaxation, documentation of pressure inversion point if technically feasible, pressurization pattern and contractile pattern.”

• “Technical limitation (if applicable).”

• “Communication to referring provider.”

“These eight appropriate quality measures are considered absolutely necessary in the performance and interpretation of esophageal manometry,” the authors concluded. “In particular, measures 3-8 are clinically feasible and measurable, and should serve as an initial framework to benchmark quality and reduce variability in esophageal manometry practices.”

This study was funded by the Alumnae of Northwestern University, and a grant to Dr. Yadlapati (T32 DK101363-02). Five coinvestigators disclosed consultancy and speaking relationships with Boston Scientific, Cook Endoscopy, EndoStim, Given Imaging, Covidien, and Sandhill Scientific.

[email protected]

Health care providers performing esophageal manometry should keep in mind eight new quality measures listed and validated in a recent study published in the April issue of Clinical Gastroenterology and Hepatology (Clin Gastroenterol Hepatol. 2015 Oct 20. doi: 10.1016/j.cgh.2015.10.006), which researchers believe will significantly improve the performance of esophageal manometry and interpretation of data culled from such procedures.

“Despite its critical importance in the diagnosis and management of esophageal motility disorders, features of a high-quality esophageal manometry [study] have not been formally defined,” said the study authors, led by Dr. Rena Yadlapati of Northwestern University in Chicago. “Standardizing key aspects of esophageal manometry is imperative to ensure the delivery of high-quality care.”

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

Dr. Yadlapati and her coinvestigators carried out the study in accordance with guidelines set out by the RAND/UCLA Appropriateness Method (RAM), They began by recruiting a panel of 15 esophageal manometry experts with leadership, geographical diversity, and a wide range of practice settings being the key criteria in their selection.

Investigators then conducted a literature review, selecting the 30 most relevant randomized, controlled trials, retrospective studies, and systematic reviews from the past 10 years. From this review, investigators created a list of 30 possible quality measures, all of which were then sent to each member of the expert panel via email for them to rank on a 9-point interval scale, and modify if necessary.

Those rankings were then used to determine the appropriateness of each proposed quality measure at a face-to-face meeting among the investigators and the 15-member expert panel, at which 17 quality measures were determined to be appropriate. In all, 2 measures dealt with competency, 2 pertained to assessment before procedure, 3 were regarding performance of the procedure itself, and 10 were about interpretation of data obtained from esophageal manometry; the 10 measures concerning interpretation of data were compiled into 1 measure, leaving a total of 8 that were ultimately approved.

The quality measures for competency are as follows:

• “If esophageal manometry is performed, then the technician must be competent to perform esophageal manometry.”

• “If a physician is considered competent to interpret esophageal manometry, then the physician must interpret a minimum number of esophageal manometry studies annually.”

For assessment before procedure, the measures state the following:

• “If a patient is referred for esophageal manometry, then the patient should have undergone an evaluation for structural abnormalities before manometry.”

• “If an esophageal manometry is performed, then informed consent must be obtained and documented.”

Quality measures regarding the procedure itself state the following:

• “If an esophageal manometry study is performed, then a time interval of at least 30 seconds should occur between swallows.”

• “If an esophageal manometry study is performed, then at least 10 wet swallows should be attempted.”

• “If an esophageal manometry study is performed, then at least seven evaluable wet swallows should be included.”

Finally, regarding interpretation of data, the single quality measures states that “If an esophageal manometry study is interpreted, then a complete procedure report should document the following:

• “Reason for referral.”

• “Clinical diagnosis.”

• “Diagnosis according to formally validated classification scheme.”

• “Documentation of formally validated classification scheme used.”

• “Summary of results”

• “Tabulated results including upper esophageal sphincter activity, interpretation of esophagogastric junction relaxation, documentation of pressure inversion point if technically feasible, pressurization pattern and contractile pattern.”

• “Technical limitation (if applicable).”

• “Communication to referring provider.”

“These eight appropriate quality measures are considered absolutely necessary in the performance and interpretation of esophageal manometry,” the authors concluded. “In particular, measures 3-8 are clinically feasible and measurable, and should serve as an initial framework to benchmark quality and reduce variability in esophageal manometry practices.”

This study was funded by the Alumnae of Northwestern University, and a grant to Dr. Yadlapati (T32 DK101363-02). Five coinvestigators disclosed consultancy and speaking relationships with Boston Scientific, Cook Endoscopy, EndoStim, Given Imaging, Covidien, and Sandhill Scientific.

[email protected]

Patients who receive rectal indomethacin after undergoing endoscopic retrograde cholangiopancreatography (ERCP) are not any less likely to develop pancreatitis than individuals who don’t, according to the findings of a recent study published in Gastroenterology (2016 Jan 9. doi: 10.1053/j.gastro.2015.12.018).

“These results are in contrast to recent studies highlighting the benefit of rectal NSAIDS to prevent PEP [post-ECRP pancreatitis] in high-risk patients [and] counter the guidelines espoused by the European Society for Gastrointestinal Endoscopy, which recently recommended giving rectal indomethacin to prevent PEP in all patients undergoing ERCP,” said the study authors, led by Dr. John M. Levenick of Penn State University in Hershey, Pa.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

Dr. Levenick and his coinvestigators screened 604 consecutive patients undergoing ERCP, with and without endoscopic ultrasound, at the Dartmouth-Hitchcock Medical Center between March 2013 and December 2014, eventually enrolling and randomizing 449 subjects into two cohorts: one in which subjects were given indomethacin after undergoing ERCP (n = 223), and one in which subjects were simply given a placebo (n = 226). Randomization happened after subjects’ major papilla had been reached, and cannulation attempts were started.

Individuals were excluded if they had active acute pancreatitis or had undergone ERCP to treat or diagnose acute pancreatitis, if they had any contraindications or allergies to NSAIDs, or were younger than 18 years of age, among other factors. The mean age of the indomethacin cohort was 64.9 years, with 118 (52.9%) females; in the placebo cohort, mean age was 64.3 years and 118 (52.2%) were female.

Pancreatitis occurred in 27 subjects overall, 16 (7.2%) of whom were in the indomethacin cohort and the other 11 (4.9%) were on placebo followed ERCP (P = .33). No subjects receiving indomethacin had severe or moderately severe PEP, but one subject had severe PEP and one had moderately severe PEP in the placebo cohort (P = 1.0). There was no necrotizing pancreatitis in either cohort, nor were there any significant differences in gastrointestinal bleeding (P = .75), death (P = .25), or 30-day hospital readmission (P = .1) between the two cohorts.

“Prophylactic rectal indomethacin did not reduce the incidence or severity of PEP in consecutive patients undergoing ERCP,” Dr. Levenick and his coauthors concluded, adding that “guidelines that recommend the administration of rectal indomethacin in all patients undergoing ERCP should be reconsidered.”

This study was funded by the National Pancreas Foundation and a grant from the National Institutes of Health. Dr. Levenick and his coauthors did not report any financial disclosures.

[email protected]

Patients who receive rectal indomethacin after undergoing endoscopic retrograde cholangiopancreatography (ERCP) are not any less likely to develop pancreatitis than individuals who don’t, according to the findings of a recent study published in Gastroenterology (2016 Jan 9. doi: 10.1053/j.gastro.2015.12.018).

“These results are in contrast to recent studies highlighting the benefit of rectal NSAIDS to prevent PEP [post-ECRP pancreatitis] in high-risk patients [and] counter the guidelines espoused by the European Society for Gastrointestinal Endoscopy, which recently recommended giving rectal indomethacin to prevent PEP in all patients undergoing ERCP,” said the study authors, led by Dr. John M. Levenick of Penn State University in Hershey, Pa.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

Dr. Levenick and his coinvestigators screened 604 consecutive patients undergoing ERCP, with and without endoscopic ultrasound, at the Dartmouth-Hitchcock Medical Center between March 2013 and December 2014, eventually enrolling and randomizing 449 subjects into two cohorts: one in which subjects were given indomethacin after undergoing ERCP (n = 223), and one in which subjects were simply given a placebo (n = 226). Randomization happened after subjects’ major papilla had been reached, and cannulation attempts were started.

Individuals were excluded if they had active acute pancreatitis or had undergone ERCP to treat or diagnose acute pancreatitis, if they had any contraindications or allergies to NSAIDs, or were younger than 18 years of age, among other factors. The mean age of the indomethacin cohort was 64.9 years, with 118 (52.9%) females; in the placebo cohort, mean age was 64.3 years and 118 (52.2%) were female.

Pancreatitis occurred in 27 subjects overall, 16 (7.2%) of whom were in the indomethacin cohort and the other 11 (4.9%) were on placebo followed ERCP (P = .33). No subjects receiving indomethacin had severe or moderately severe PEP, but one subject had severe PEP and one had moderately severe PEP in the placebo cohort (P = 1.0). There was no necrotizing pancreatitis in either cohort, nor were there any significant differences in gastrointestinal bleeding (P = .75), death (P = .25), or 30-day hospital readmission (P = .1) between the two cohorts.

“Prophylactic rectal indomethacin did not reduce the incidence or severity of PEP in consecutive patients undergoing ERCP,” Dr. Levenick and his coauthors concluded, adding that “guidelines that recommend the administration of rectal indomethacin in all patients undergoing ERCP should be reconsidered.”

This study was funded by the National Pancreas Foundation and a grant from the National Institutes of Health. Dr. Levenick and his coauthors did not report any financial disclosures.

[email protected]

Patients who receive rectal indomethacin after undergoing endoscopic retrograde cholangiopancreatography (ERCP) are not any less likely to develop pancreatitis than individuals who don’t, according to the findings of a recent study published in Gastroenterology (2016 Jan 9. doi: 10.1053/j.gastro.2015.12.018).

“These results are in contrast to recent studies highlighting the benefit of rectal NSAIDS to prevent PEP [post-ECRP pancreatitis] in high-risk patients [and] counter the guidelines espoused by the European Society for Gastrointestinal Endoscopy, which recently recommended giving rectal indomethacin to prevent PEP in all patients undergoing ERCP,” said the study authors, led by Dr. John M. Levenick of Penn State University in Hershey, Pa.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

Dr. Levenick and his coinvestigators screened 604 consecutive patients undergoing ERCP, with and without endoscopic ultrasound, at the Dartmouth-Hitchcock Medical Center between March 2013 and December 2014, eventually enrolling and randomizing 449 subjects into two cohorts: one in which subjects were given indomethacin after undergoing ERCP (n = 223), and one in which subjects were simply given a placebo (n = 226). Randomization happened after subjects’ major papilla had been reached, and cannulation attempts were started.

Individuals were excluded if they had active acute pancreatitis or had undergone ERCP to treat or diagnose acute pancreatitis, if they had any contraindications or allergies to NSAIDs, or were younger than 18 years of age, among other factors. The mean age of the indomethacin cohort was 64.9 years, with 118 (52.9%) females; in the placebo cohort, mean age was 64.3 years and 118 (52.2%) were female.

Pancreatitis occurred in 27 subjects overall, 16 (7.2%) of whom were in the indomethacin cohort and the other 11 (4.9%) were on placebo followed ERCP (P = .33). No subjects receiving indomethacin had severe or moderately severe PEP, but one subject had severe PEP and one had moderately severe PEP in the placebo cohort (P = 1.0). There was no necrotizing pancreatitis in either cohort, nor were there any significant differences in gastrointestinal bleeding (P = .75), death (P = .25), or 30-day hospital readmission (P = .1) between the two cohorts.

“Prophylactic rectal indomethacin did not reduce the incidence or severity of PEP in consecutive patients undergoing ERCP,” Dr. Levenick and his coauthors concluded, adding that “guidelines that recommend the administration of rectal indomethacin in all patients undergoing ERCP should be reconsidered.”

This study was funded by the National Pancreas Foundation and a grant from the National Institutes of Health. Dr. Levenick and his coauthors did not report any financial disclosures.

[email protected]

As magnetic resonance imaging technology continues to advance year after year, so does MRI’s ability to accurately detect pancreatic cysts, according to a new study published in the April issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2015.08.038).

“To our knowledge, this is the first study to analyze the relationship between the technical improvements in imaging techniques (specifically, MRI) and the presence of incidentally found PCLs [pancreatic cystic lesions],” said the study authors, led by Dr. Michael B. Wallace of the Mayo Clinic in Jacksonville, Fla.

Dr. Wallace and his coinvestigators launched this retrospective descriptive study selecting the first 50 consecutive abdominal MRI patients at the Jacksonville Mayo Clinic during January and February of each year from 2005 through 2014, for a total of 500 cases who met inclusion criteria included in the study. Patients were excluded if they had preexisting symptomatic or asymptomatic pancreatitis, either acute or chronic, pancreatic masses, pancreatic cysts, pancreatic surgery, pancreatic symptoms, or any pancreas-related indications found by MRI.

The clinic underwent periodic MRI updates over the course of the 10-year study, along with requisite software updates to “take advantage of the new hardware technology,” the study explains. Major hardware improvements, provided by Siemens Medical Solutions USA, were Symphony/Sonata, Espree/Avanto, and Aera/Skyra, while software updates corresponding to each hardware update were VA, VB, and VD, respectively.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

Furthermore, each software update had other, smaller upgrades, leading to a total of 20 combinations of MRI hardware and software on which MRIs were performed over the 10 years. Every MRI taken included “an axial and a coronal T2-weighted single-shot (HASTE) pulse sequence [with] TR 1400-1500 ms, TE 82-99 ms, and slice thickness 5-7 mm (gap, 0.5-0.7 mm).” Each MRI was analyzed by a pancreatic MRI specialist to find incidental cysts.

The number of patients found with pancreatic cysts increased incrementally from 2005 to 2014, with 2010 being the year with the highest number. A total of 208 subjects (41.6%) were found to have incidental cysts, but only 44 of these cases were discovered in the original MRI. The presence of cysts was associated with older age in patients who had them; only 20% of all subjects under 50 years of age had cysts, compared to 32.4% of those between 50 and 60 years, 54.9% of those between 60 and 70 years, and 61.5% of those over the age of 70 years (P less than .01).

Additionally, 56.4% of all subjects with diabetes (P less than .01), 59.0% of subjects with nonmelanoma skin cancer (P less than .03), and 58.1% of those with hepatocarcinoma (P less than .02) were also found to have cysts. Most striking, however, is that newer hardware and software permutations were able to detect cysts in 56.3% (Skyra) of patients who had them, compared with only 30.3% (Symphony) of patients who underwent MRI on older technology.

“The variable field strength” (1.5 T vs. 3 T) was not significantly related to the presence of PCLs,” Dr. Wallace and his coauthors concluded. “We believe this may be secondary to the lack of power of the analysis, because only 6% of the examinations were 3-T studies. Therefore, we speculate that this relationship may be confirmed if the number of 3-T studies increased.”

Males and females each made up roughly 50% of the study population, with a median age of 60 years and 85% being white. Additionally, 4% of subjects had a family history of pancreatic cancer, 12% had a personal history of solid organ transplant, and 53% had a personal history of smoking.

This study was funded by the Mayo Clinic. Dr. Wallace disclosed that he has received grant funding from Olympus, Boston Scientific, and Cosmo Pharmaceuticals, and travel support from Olympus. No other authors reported any financial disclosures.

[email protected]

As magnetic resonance imaging technology continues to advance year after year, so does MRI’s ability to accurately detect pancreatic cysts, according to a new study published in the April issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2015.08.038).

“To our knowledge, this is the first study to analyze the relationship between the technical improvements in imaging techniques (specifically, MRI) and the presence of incidentally found PCLs [pancreatic cystic lesions],” said the study authors, led by Dr. Michael B. Wallace of the Mayo Clinic in Jacksonville, Fla.

Dr. Wallace and his coinvestigators launched this retrospective descriptive study selecting the first 50 consecutive abdominal MRI patients at the Jacksonville Mayo Clinic during January and February of each year from 2005 through 2014, for a total of 500 cases who met inclusion criteria included in the study. Patients were excluded if they had preexisting symptomatic or asymptomatic pancreatitis, either acute or chronic, pancreatic masses, pancreatic cysts, pancreatic surgery, pancreatic symptoms, or any pancreas-related indications found by MRI.

The clinic underwent periodic MRI updates over the course of the 10-year study, along with requisite software updates to “take advantage of the new hardware technology,” the study explains. Major hardware improvements, provided by Siemens Medical Solutions USA, were Symphony/Sonata, Espree/Avanto, and Aera/Skyra, while software updates corresponding to each hardware update were VA, VB, and VD, respectively.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

Furthermore, each software update had other, smaller upgrades, leading to a total of 20 combinations of MRI hardware and software on which MRIs were performed over the 10 years. Every MRI taken included “an axial and a coronal T2-weighted single-shot (HASTE) pulse sequence [with] TR 1400-1500 ms, TE 82-99 ms, and slice thickness 5-7 mm (gap, 0.5-0.7 mm).” Each MRI was analyzed by a pancreatic MRI specialist to find incidental cysts.

The number of patients found with pancreatic cysts increased incrementally from 2005 to 2014, with 2010 being the year with the highest number. A total of 208 subjects (41.6%) were found to have incidental cysts, but only 44 of these cases were discovered in the original MRI. The presence of cysts was associated with older age in patients who had them; only 20% of all subjects under 50 years of age had cysts, compared to 32.4% of those between 50 and 60 years, 54.9% of those between 60 and 70 years, and 61.5% of those over the age of 70 years (P less than .01).

Additionally, 56.4% of all subjects with diabetes (P less than .01), 59.0% of subjects with nonmelanoma skin cancer (P less than .03), and 58.1% of those with hepatocarcinoma (P less than .02) were also found to have cysts. Most striking, however, is that newer hardware and software permutations were able to detect cysts in 56.3% (Skyra) of patients who had them, compared with only 30.3% (Symphony) of patients who underwent MRI on older technology.

“The variable field strength” (1.5 T vs. 3 T) was not significantly related to the presence of PCLs,” Dr. Wallace and his coauthors concluded. “We believe this may be secondary to the lack of power of the analysis, because only 6% of the examinations were 3-T studies. Therefore, we speculate that this relationship may be confirmed if the number of 3-T studies increased.”

Males and females each made up roughly 50% of the study population, with a median age of 60 years and 85% being white. Additionally, 4% of subjects had a family history of pancreatic cancer, 12% had a personal history of solid organ transplant, and 53% had a personal history of smoking.

This study was funded by the Mayo Clinic. Dr. Wallace disclosed that he has received grant funding from Olympus, Boston Scientific, and Cosmo Pharmaceuticals, and travel support from Olympus. No other authors reported any financial disclosures.

[email protected]

As magnetic resonance imaging technology continues to advance year after year, so does MRI’s ability to accurately detect pancreatic cysts, according to a new study published in the April issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2015.08.038).

“To our knowledge, this is the first study to analyze the relationship between the technical improvements in imaging techniques (specifically, MRI) and the presence of incidentally found PCLs [pancreatic cystic lesions],” said the study authors, led by Dr. Michael B. Wallace of the Mayo Clinic in Jacksonville, Fla.

Dr. Wallace and his coinvestigators launched this retrospective descriptive study selecting the first 50 consecutive abdominal MRI patients at the Jacksonville Mayo Clinic during January and February of each year from 2005 through 2014, for a total of 500 cases who met inclusion criteria included in the study. Patients were excluded if they had preexisting symptomatic or asymptomatic pancreatitis, either acute or chronic, pancreatic masses, pancreatic cysts, pancreatic surgery, pancreatic symptoms, or any pancreas-related indications found by MRI.

The clinic underwent periodic MRI updates over the course of the 10-year study, along with requisite software updates to “take advantage of the new hardware technology,” the study explains. Major hardware improvements, provided by Siemens Medical Solutions USA, were Symphony/Sonata, Espree/Avanto, and Aera/Skyra, while software updates corresponding to each hardware update were VA, VB, and VD, respectively.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

Furthermore, each software update had other, smaller upgrades, leading to a total of 20 combinations of MRI hardware and software on which MRIs were performed over the 10 years. Every MRI taken included “an axial and a coronal T2-weighted single-shot (HASTE) pulse sequence [with] TR 1400-1500 ms, TE 82-99 ms, and slice thickness 5-7 mm (gap, 0.5-0.7 mm).” Each MRI was analyzed by a pancreatic MRI specialist to find incidental cysts.

The number of patients found with pancreatic cysts increased incrementally from 2005 to 2014, with 2010 being the year with the highest number. A total of 208 subjects (41.6%) were found to have incidental cysts, but only 44 of these cases were discovered in the original MRI. The presence of cysts was associated with older age in patients who had them; only 20% of all subjects under 50 years of age had cysts, compared to 32.4% of those between 50 and 60 years, 54.9% of those between 60 and 70 years, and 61.5% of those over the age of 70 years (P less than .01).

Additionally, 56.4% of all subjects with diabetes (P less than .01), 59.0% of subjects with nonmelanoma skin cancer (P less than .03), and 58.1% of those with hepatocarcinoma (P less than .02) were also found to have cysts. Most striking, however, is that newer hardware and software permutations were able to detect cysts in 56.3% (Skyra) of patients who had them, compared with only 30.3% (Symphony) of patients who underwent MRI on older technology.

“The variable field strength” (1.5 T vs. 3 T) was not significantly related to the presence of PCLs,” Dr. Wallace and his coauthors concluded. “We believe this may be secondary to the lack of power of the analysis, because only 6% of the examinations were 3-T studies. Therefore, we speculate that this relationship may be confirmed if the number of 3-T studies increased.”

Males and females each made up roughly 50% of the study population, with a median age of 60 years and 85% being white. Additionally, 4% of subjects had a family history of pancreatic cancer, 12% had a personal history of solid organ transplant, and 53% had a personal history of smoking.

This study was funded by the Mayo Clinic. Dr. Wallace disclosed that he has received grant funding from Olympus, Boston Scientific, and Cosmo Pharmaceuticals, and travel support from Olympus. No other authors reported any financial disclosures.

[email protected]

In contrast to stable chronic obstructive pulmonary disease (COPD),¹ acute exacerbations of COPD pose special management challenges and can significantly increase the risk of morbidity and death and the cost of care.

This review addresses the definition and diagnosis of COPD exacerbations, disease burden and costs, etiology and pathogenesis, and management and prevention strategies.

DEFINITIONS ARE PROBLEMATIC

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines a COPD exacer­bation as “an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication.”² It further categorizes acute exacerbations by severity:

• Mild—treated with increased frequency of doses of existing medications
• Moderate—treated with corticosteroids or antibiotics, or both
• Severe—requires hospital utilization (either emergency room treatment or admission).

Although descriptive and useful for retrospective analyses, this current definition poses ambiguities for clinicians. Day-to-day variation in symptoms is not routinely assessed, so deviations from baseline may be difficult to detect. Although clinical tools are available for assessing symptoms in stable and exacerbated states (eg, the COPD assessment test³ and the Exacerbations of Chronic Pulmonary Disease Tool [EXACT]⁴), they have not been widely adopted in daily practice. Also, according to the current definition, the severity of an exacerbation can be classified only after the course of action is determined, so the severity is not helpful for forming a management strategy at bedside. In addition, physicians may have different thresholds for prescribing antibiotics and corticosteroids.

An earlier definition categorized a COPD exacerbation by the presence of its three cardinal symptoms (ie, increased shortness of breath, sputum volume, and purulence):

• Type I—all three symptoms present
• Type II—two symptoms present
• Type III—one symptom present, accompanied by at least one of the following: upper respiratory tract infection within the past 5 days, unexplained fever, increased wheezing or cough, or 20% increased respiratory rate or heart rate from baseline.

This older definition was successfully used in a prospective clinical trial to identify patients who benefited most from antibiotics for COPD exacerbations.⁵

COPD exacerbation: an acute worsening of respiratory symptoms

Despite these caveats regarding a definition, most clinicians agree on the clinical presentation of a patient with COPD exacerbation: ie, having some combination of shortness of breath, increased sputum volume, and purulence. By the same token, patients with COPD who present with symptoms not typical of an exacerbation should be evaluated for another diagnosis. For instance, Tillie-Leblond et al⁶ reported that 49 (25%) of 197 patients hospitalized with an “unexplained” exacerbation of COPD were eventually diagnosed with pulmonary embolism.

EXACERBATIONS ARE COSTLY

The care of patients with COPD places a great burden on the healthcare system. Using multiple national databases, Ford et al⁷ estimated that medical costs in the United States in 2010 attributable to COPD and its complications were $32.1 billion.

The largest component of direct healthcare costs of COPD is exacerbations and subsequent hospitalizations.⁸ Data from a predominantly Medicare population indicate that the annualized mean COPD-related cost for a patient with no exacerbations was $1,425, compared with $12,765 for a patient with severe exacerbations.⁹ The investigators estimated that reducing exacerbations from two or more to none could save $5,125 per patient per year.

EXACERBATIONS AFFECT HEALTH BEYOND THE EVENT

COPD exacerbations are associated with a faster decline in lung function,¹⁰ reduced quality of life,¹¹ and lost workdays.⁷ A single exacerbation may cause a decline in lung function and health status that may not return to baseline for several months, particularly if another exacerbation occurs within 6 months.^12,13 COPD exacerbations have also been linked to poor clinical outcomes, including death.

In a prospective study in 304 men with COPD followed for 5 years, those who had three or more COPD exacerbations annually were four times as likely to die than patients who did not have an exacerbation.¹⁴ Nevertheless, the relationship with mortality may not be causal: Brusselle pointed out in an editorial¹⁵ that established mortality predictors for COPD do not include exacerbations, and symptomatic patients with COPD without any history of exacerbations are at greater risk of death than those who are asymptomatic but at high risk for exacerbations.

INFECTION + INFLAMMATION = EXACERBATION

An acute COPD exacerbation can be viewed as an acute inflammatory event superimposed on chronic inflammation associated with COPD. Inflammation in the airways increases resistance to air flow with consequent air trapping. Increased resistance and elastic load due to air trapping place respiratory muscles at a mechanical disadvantage and increase the work of breathing.

Infection starts the process

Infections are thought to be the major instigators of COPD exacerbation

Infections, particularly bacterial and viral, are thought to be the major instigators of COPD exacerbation, although environmental factors such as air pollution may also play a role.¹⁶

Airway inflammation is markedly reduced when bacterial infection is eradicated. But if bacterial colonization continues, inflammatory markers remain elevated despite clinical resolution of the exacerbation.¹⁷ Desai et al¹⁸ found that patients with COPD and chronic bronchitis with bacterial colonization had a larger symptom burden than patients without colonization, even without an exacerbation.

Allergic profile increases risk

Although most studies indicate that infection is the main cause of exacerbations, clinicians should consider other mechanisms of inflammation on an individual basis. COPD exacerbations may be phenotyped by measuring inflammatory markers, perhaps as a starting point for tailored therapies.

Bafadhel et al¹⁹ studied 145 patients with COPD over the course of a year and recorded various biomarkers at baseline and during exacerbations. Exacerbations had an inflammatory profile that was predominantly bacterial in 37%, viral in 10%, and eosinophilic in 17%, and had limited changes in the inflammatory profile in 14%. The remaining episodes were combinations of categories. In another study,²⁰ multivariate analysis conducted in two cohorts with COPD found that patients who had an allergic phenotype had more respiratory symptoms and a higher likelihood of COPD exacerbations.

Frequent COPD exacerbations are increasingly recognized as being associated with an asthma-COPD overlap syndrome, consisting of symptoms of increased airflow variability and incompletely reversible airflow obstruction.²¹

Inflammation as a marker of frequent exacerbations

Evidence is accumulating that supports systemic inflammation as a marker of frequent exacerbations. The Copenhagen Heart Study tested for baseline plasma C-reactive protein, fibrinogen, and white blood cell count in 6,574 stable patients with COPD.²² After multivariable adjustment, they found a significantly higher likelihood of having a subsequent exacerbation in patients who had all three biomarkers elevated (odds ratio [OR] 3.7, 95% confidence interval [CI] 1.9–7.4), even in patients with milder COPD and those without previous exacerbations.

Past exacerbations predict risk

A history of exacerbation is the best predictor of future exacerbation

The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study²³ found that a history of acute COPD exacerbation was the single best predictor of future exacerbations. This risk factor remained stable over 3 years and was present across the severity of COPD, ie, patients at lower GOLD stages who had a history of frequent exacerbations were likely to have exacerbations during follow-up.

EXACERBATION INCREASES CARDIOVASCULAR RISK

COPD exacerbations increase the risk of cardiovascular events, particularly myocardial infarction.²⁴ During hospitalization for acute exacerbation of COPD, markers of myocardial injury and heart failure may be elevated and are a predictor of death.²⁵

Patel et al²⁶ measured arterial stiffness (aortic pulse wave velocity, a validated measure of cardiovascular risk) and cardiac biomarkers (troponin and N-terminal B-type natriuretic peptide) at baseline in 98 patients and longitudinally during and after a COPD exacerbation. In addition to increased levels of cardiac biomarkers, they found a significant rise in arterial stiffness during the exacerbation event without return to baseline levels over 35 days of follow-up. The arterial stiffness increase was related to airway inflammation as measured by sputum interleukin 6, particularly in patients with documented lower respiratory tract infection.

Retrospective analysis suggests a reduced all-cause mortality rate in COPD patients who are treated with beta-blockers.²⁷

Recommendation. We recommend that patients already taking a selective beta-blocker continue to do so during a COPD exacerbation.

OUTPATIENT MANAGEMENT

Treatment with a combination of a corticosteroid, antibiotic, and bronchodilator addresses the underlying pathophysiologic processes of an acute exacerbation: inflammation, infection, and airway trapping.

Short course of a corticosteroid improves outcomes

A single exacerbation may worsen health status for several months

A 10-day systemic course of a corticosteroid prescribed for COPD exacerbation before discharge from the emergency department was found to offer a small advantage over placebo for reducing treatment failure (unscheduled physician visits, return to emergency room for recurrent symptoms) and improving dyspnea scores and lung function.²⁸ Even just a 3-day course improved measures of respiration (forced expiratory volume in the first second of expiration [FEV₁] and arterial oxygenation) at days 3 and 10, and reduced treatment failures compared with placebo.²⁹

Corticosteroid prescription should not be taken lightly, because adverse effects are common. In a systematic review, one adverse effect (hyperglycemia, weight gain, or insomnia) occurred for every five people treated.³⁰

Identifying subgroups of patients most likely to benefit from corticosteroid treatment may be helpful. Corticosteroids may delay improvement in patients without eosinophilic inflammation and hasten recovery in those with more than 2% peripheral eosinophils.³¹ Siva et al³² found that limiting corticosteroids to patients with sputum eosinophilia reduced corticosteroid use and reduced severe exacerbations compared with standard care.³²

Recommendation. For an acute exacerbation, we prescribe a short course of corticosteroids (eg, prednisone 40 mg daily for 5 to 7 days). Tapering dosing is probably unnecessary because adrenal insufficiency is uncommon before 2 weeks of corticosteroid exposure. Clinicians should weigh the merits of tapering (reduced corticosteroid exposure) against patient inconvenience and difficulty following complicated instructions.

Antibiotics help, but exact strategy uncertain

Although antibiotic therapy is one of the three pillars of COPD exacerbation management, the optimal antimicrobial agent, duration of therapy, and which patients will benefit remain areas of controversy and research. Thus far, large trials have been unable to definitely show the superiority of one antibiotic over another.^33,34

A 1987 randomized controlled trial⁵ of antibiotic therapy in acute exacerbation of COPD found the greatest benefit to patients who had all three cardinal symptoms (ie, increased shortness of breath, sputum volume, and purulence), with less marked but still significant improvement in patients with two symptoms. In a 2012 multicenter trial³⁵ patients with mild to moderate COPD experiencing an exacerbation were treated with either combined amoxicillin and clavulanate or placebo if they had one of the three cardinal symptoms. The antibiotic group had a significantly higher clinical cure rate at days 9 to 11 (74.1% vs 59.9%) as well as a longer time until the next exacerbation (233 vs 160 days).

Recommendation. Optimal antibiotic management of COPD exacerbations may also depend on risk factors. For patients with at least two cardinal symptoms, we favor a scheme akin to one proposed for treating community-acquired pneumonia (Table 1).^16,36

INPATIENT MANAGEMENT

Corticosteroids improve outcomes

A Department of Veterans Affairs cooperative trial³⁷ randomized 271 patients hospitalized with COPD exacerbation to receive either corticosteroids (intravenous followed by oral) or placebo for either 2 weeks or 8 weeks. Corticosteroid recipients had lower rates of treatment failure at 30 and 90 days, defined as death from any cause, need for mechanical ventilation, readmission, or intensification of pharmacologic therapy. Corticosteroid therapy also reduced hospital length of stay and improved the rate of recovery. The longer corticosteroid course was associated with a higher rate of adverse effects.

Oral corticosteroids not inferior to intravenous

Using the same end point of treatment failure as the Veterans Affairs cooperative trial, deJong et al³⁸ demonstrated that prednisone 60 mg by mouth was not inferior to intravenous prednisone. Neither trial demonstrated a difference in mortality between corticosteroid use and placebo.

Short course of a corticosteroid not inferior to a long course

In 2013, the Reduction in the Use of Corticosteroids in Exacerbated COPD (REDUCE) trial³⁹ randomized 314 patients presenting with an acute COPD exacerbation (92% requiring hospital admission) to oral prednisone 40 mg daily for either 5 days or 14 days. They found that the short course was noninferior in preventing exacerbations over the ensuing 6 months in terms of death and the need for mechanical ventilation.

Recommendation. Our threshold for initiating systemic corticosteroid therapy is lower in hospitalized patients than in outpatients. We recommend the regimen of the REDUCE trial: prednisone 40 mg daily for 5 days.

Corticosteroids for patients on ventilatory support

Severe COPD exacerbations requiring admission to intensive care are a significant source of morbidity and mortality, and the strategy of corticosteroid treatment is still under investigation.

Intravenous corticosteroids are effective. A multicenter trial⁴⁰ in 354 patients requiring either invasive or noninvasive mechanical ventilation randomized them to treatment with either intravenous methylprednisolone (tapered) or placebo. Treatment was associated with fewer mechanical ventilation days and a lower rate of noninvasive ventilation failure.

Low-dose oral corticosteroids ineffective. In contrast, an open-label trial⁴¹ of patients requiring ventilatory support and randomized to either oral prednisone (1 mg/kg for up to 10 days) or usual care found no difference in intensive care length of stay or noninvasive ventilation failure. This study used the oral route and smaller doses, and its open-label design might have introduced bias.

Lower-dose steroids better than high-dose. A 2014 cohort study of 17,239 patients admitted to the ICU with acute exacerbations of COPD evaluated outcomes of treatment with high methylprednisolone dosages (> 240 mg per day) vs lower dosages, using propensity score matching.⁴² No mortality difference was found between the groups. The lower dosage group (median methylprednisolone dose 100 mg per day) had shorter hospital and intensive care unit stays, shorter duration of noninvasive positive pressure ventilation, less need for insulin therapy, and fewer fungal infections.

Antibiotics for hospitalized patients

Only scarce data are available on the use of antibiotics for patients hospitalized with COPD exacerbation. In a study of patients hospitalized with COPD exacerbations, adding doxycycline to corticosteroids led to better clinical success and cure rates at 10 days compared with placebo, but the primary end point of clinical success at 30 days was not different between the two groups.⁴³

BRONCHODILATORS: A MAINSTAY OF COPD TREATMENT

Bronchodilators are an important part of treatment of COPD exacerbations in inpatient and outpatient settings.

Nebulized beta-2 agonists are given every 1 to 4 hours. Albuterol at a 2.5-mg dose in each nebulization was found to be as effective as 5 mg for length of hospital stay and recovery of lung function in patients with an acute exacerbation of COPD.⁴⁴

Adding an anticholinergic may help. Nebulized anticholinergics can be given alone or combined with beta-2 agonists. Whether long-acting bronchodilators should be used to manage COPD patients hospitalized with an exacerbation requires further inquiry. In an observational study with historical controls, Drescher and colleagues⁴⁵ found cost savings and shorter hospital stays if tiotropium (a long-acting anticholinergic) was added to the respiratory care protocol, which also included formoterol (a long-acting beta-2 agonist).

OXYGEN: TITRATED APPROACH SAFER

Caution is needed to avoid hyperoxemic hypercapnia in patients on oxygen

Oxygen should be supplied during a COPD exacerbation to ensure adequate oxyhemoglobin saturation. Caution is needed to avoid hyperoxemic hypercapnia, particularly in patients with severe COPD and propensity to ventilatory failure. The routine administration of oxygen at high concentrations during a COPD exacerbation has been associated with a higher mortality rate than with a titrated oxygen approach.⁴⁶ Long-term oxygen treatment started at discharge or as outpatient therapy is associated with reduced hospital admissions and shorter hospital stays for acute exacerbations of COPD.⁴⁷

VENTILATION SUPPORT

Noninvasive positive-pressure ventilation is a useful adjunct to treatment of COPD exacerbations with evidence of ventilatory failure (ie, acute respiratory acidosis), helping to offset the work of breathing until respiratory system mechanics improve. Keenan et al⁴⁸ reviewed 15 randomized controlled trials, involving 636 patients, of noninvasive positive-pressure ventilation in the setting of COPD exacerbation. They concluded that noninvasive positive-pressure ventilation reduced the in-hospital mortality rate and length of stay compared with standard therapy. Noninvasive positive-pressure ventilation is most useful in patients with severe COPD exacerbations and acute respiratory acidosis (pH < 7.35).⁴⁹

Intubation and mechanical ventilation. Although no standards exist for determining which COPD exacerbations may be too severe for noninvasive positive-pressure ventilation, intubation is clearly indicated for impending respiratory failure or hemodynamic instability. Other factors to consider include the greater likelihood of noninvasive positive-pressure ventilation failure in patients with severe respiratory acidosis (pH < 7.25 is associated with a > 50% failure rate) and in those with no improvement in acidosis or respiratory rate during the first hour after initiation of noninvasive positive-pressure ventilation.⁵⁰

PREVENTING EXACERBATIONS

Recent data indicate that COPD exacerbations can often be prevented (Table 2).

Inhaled pharmacotherapy

Inhaled pharmacotherapeutic agents, singly or in combination, reduce the frequency of COPD exacerbations.

Combined long-acting beta-2 agonist and corticosteroid is better than single-agent therapy. In 2007, the Towards a Revolution in COPD Health (TORCH) trial⁵¹ evaluated outpatient therapy in more than 6,000 patients worldwide with either an inhaled long-acting beta-2 agonist (salmeterol), an inhaled corticosteroid (fluticasone), both drugs in combination, or placebo. Patients had baseline prebronchodilator FEV₁ of less than 60% and were followed for 3 years. No difference was found between the groups in the primary end point of deaths, but the annualized rate of moderate to severe exacerbations was reduced by 25% in the group that received combination therapy vs placebo. Combination therapy showed superior efficacy over individual drug therapy in preventing exacerbations. Treatment with the inhaled corticosteroid, whether alone or in combination with salmeterol, increased the risk of pneumonia.

A long-acting antimuscarinic agent is better than placebo. In 2008, the Understanding Potential Long-Term Impacts on Function With Tiotropium (UPLIFT) trial⁵² randomized nearly 6,000 patients with COPD and a postbronchodilator FEV₁ of less than 70% to placebo or tiotropium, a long-acting antimuscarinic agent. Tiotropium reduced the exacerbation rate by 14% compared with placebo and improved quality of life.

Antimuscarinics may be better than beta-2 agonists. Head-to-head comparisons suggest that long-acting antimuscarinic agents are preferable to long-acting beta-2 agonists for preventing COPD exacerbations.^53,54

Triple therapy: evidence is mixed. For patients with severe symptomatic COPD and frequent exacerbations, triple therapy with a combination of an inhaled long-acting antimuscarinic agent, an inhaled long-acting beta-2 agonist, and an inhaled corticosteroid has been suggested.

Data to support this practice are limited. In the Canadian Optimal Trial,⁵⁵ the rate of exacerbations was not different between tiotropium alone, tiotropium plus salmeterol, and triple therapy. However, the rate of hospitalization for severe exacerbation was lower with triple therapy than tiotropium alone. A large, retrospective cohort study also supported triple therapy by finding reduced mortality, hospitalizations, and need for oral corticosteroid bursts compared to combination therapy with an inhaled long-acting beta-2 agonist and an inhaled corticosteroid.⁵⁶

The drawback of triple therapy is an increased incidence of pneumonia associated with combined beta-2 agonist and corticosteroids, most likely due to the corticosteroid component.⁵¹ The risk appears to be higher for higher potency corticosteroids, eg, fluticasone.⁵⁷

In 2014, the Withdrawal of Inhaled Steroids During Optimised Bronchodilator Management (WISDOM) trial⁵⁸ randomized nearly 2,500 patients with a history of COPD exacerbation receiving triple therapy consisting of tiotropium, salmeterol, and inhaled fluticasone to either continue treatment or withdraw the corticosteroid for 3 months. The investigators defined an annualized exacerbation rate of 1.2 (ie, a 20% increase) as the upper limit of the confidence interval for an acceptable therapeutic margin of noninferiority. The study showed that the risk of moderate to severe exacerbations with combined tiotropium and salmeterol was noninferior to triple therapy.

Nevertheless, caution is advised when removing the corticosteroid component from triple therapy. The trial demonstrated a worsening in overall health status, some reduction in lung function, and a transient increase in severe exacerbations in the withdrawal group. Patients with increased symptom burden at baseline and a history of severe exacerbations may not be optimal candidates for this strategy.

Roflumilast is effective but has side effects

Roflumilast, an oral phosphodiesterase 4 inhibitor, is an anti-inflammatory drug without bronchodilator properties. In randomized controlled trials, the drug was associated with a 17% reduction in acute exacerbations compared with placebo.⁵⁹

Adding roflumilast to either a long-acting beta-2 agonist or a long-acting antimuscarinic agent resulted in a 6% to 8% further reduction in the proportion of patients with exacerbation.^60,61 Martinez et al⁶¹ found that roflumilast added to a regimen of a long-acting beta-2 agonist plus an inhaled corticosteroid reduced moderate to severe exacerbations by 14.2%, even in the presence of tiotropium. Compared with placebo, roflumilast treatment reduced exacerbations necessitating hospitalizations by 23.9%.

The FDA has approved oral roflumilast 500 µg once daily to prevent COPD exacerbations.

Roflumilast is frequently associated with side effects, including gastrointestinal symptoms (chiefly diarrhea), weight loss, and psychiatric effects. A benefit-to-harm study in 2014 concluded that using the drug is only favorable for patients who have a high risk of severe exacerbations, ie, those who have a greater than 22% baseline risk of having at least one exacerbation annually.⁶²

Recommendation. Roflumilast should be reserved for patients who have severe COPD with a chronic bronchitis phenotype (ie, with cough and sputum production) and repeated exacerbations despite an optimal regimen of an inhaled corticosteroid, long-acting beta-2 agonist, and long-acting antimuscarinic agent.

Macrolide antibiotics: Role unclear

Macrolide antibiotics have anti-inflammatory and immunomodulatory activities.

Azithromycin: fewer exacerbations but some side effects. A multicenter trial⁶³ in 1,142 COPD patients randomized to either oral azithromycin 250 mg daily or placebo found a 27% reduction in the risk of COPD exacerbation in the intervention arm. No differences were found between the groups in mortality, hospitalizations, emergency department visits, or respiratory failure. Hearing loss and increased macrolide resistance were noted in the intervention arm. In a secondary subgroup analysis,⁶⁴ no difference in efficacy was found by sex, history of chronic bronchitis, oxygen use, or concomitant COPD treatment.

The COPD: Influence of Macrolides on Exacerbation Frequency in Patients trial⁶⁵ helped refine patient selection for macrolide therapy. In this single-center study, 92 patients with COPD and at least three exacerbations during the year prior to enrollment were randomized to receive either azithromycin 500 mg three times weekly or placebo. Exacerbations in the intervention group were markedly reduced (42%) with no difference in hospitalization rate.

The place of macrolide antibiotics in the treatment strategy of COPD is unclear, and they are not currently part of the GOLD guidelines. Still unknown is the incremental benefit of adding them to existing preventive regimens, cardiovascular safety, side effects, and potential effects on the resident microbial flora. 

Other antibiotics have also been investigated for efficacy in preventing exacerbations.

Moxifloxacin: fewer exacerbations. The Pulsed Moxifloxacin Usage and Its Long-term Impact on the Reduction of Subsequent Exacerbations study⁶⁶ randomized more than 1,000 patients with stable COPD to receive either moxifloxacin 400 mg or placebo daily for 5 days repeated every 8 weeks for six courses. Frequent assessment during the treatment period and for 6 months afterward revealed a reduced exacerbation rate in the intervention group but without benefit in hospitalization rate, mortality, lung function, or health status.

Recommendation. Azithromycin (either 250 mg daily or 500 mg three times weekly) can be considered for patients who have repeated COPD exacerbations despite an optimal regimen of an inhaled corticosteroid, inhaled long-acting beta-2 agonist, and inhaled long-acting antimuscarinic agent. The need to continue azithromycin should be reassessed yearly.

Mucolytics

Greatest benefit to patients not taking inhaled corticosteroids. Mucolytic agents help clear airway secretions by reducing viscosity. N-acetylcysteine and carbocysteine (not available in the United States) also have antioxidant properties that may counteract oxidant stress associated with acute COPD exacerbations.

The Bronchitis Randomized on NAC Cost-Utility Study (BRONCUS)⁶⁷ randomized 523 COPD patients to N-acetylcysteine 600 mg daily or placebo. After 3 years of follow-up, no differences were found in the rate of exacerbations, lung function decline, and quality of life. Subgroup analysis suggested a reduction in exacerbations for patients who were not taking inhaled corticosteroids.

The Effect of Carbocisteine on Acute Exacerbation of Chronic Obstructive Pulmonary Disease (PEACE) study randomized more than 700 patients from multiple centers in China who had COPD and a recent history of exacerbations; they found a 25% lower exacerbation rate over 1 year with carbocysteine vs placebo.⁶⁸ Most of the patients (83%) were not on inhaled corticosteroids, which complemented findings of the BRONCUS trial.

The Effect of High Dose N-acetylcysteine on Air Trapping and Airway Resistance of COPD (HIACE) study randomized 120 patients with stable COPD in a hospital in Hong Kong to either oral N-acetylcysteine (600 mg twice daily) or placebo and found a reduced exacerbation rate of exacerbations. Patients were matched at baseline for inhaled corticosteroid use.⁶⁹

In 2014, the Twice Daily N-acetylcysteine 600 mg for Exacerbations of Chronic Obstructive Pulmonary Disease (PANTHEON) study⁷⁰ randomized 1,006 patients from multiple hospitals in China with a history of moderate to severe COPD and exacerbations to receive either N-acetylcysteine 600 mg twice daily or placebo for 1 year. They found a 22% reduction in exacerbations in the treatment group vs placebo.  

GOLD guidelines² recommend mucolytics for patients with severe COPD and exacerbations when inhaled corticosteroids are not available or affordable.

Recommendation. Mucolytics may be useful for patients with difficulty expectorating and with a history of exacerbations despite appropriate inhaled therapy.

OTHER INTERVENTIONS CAN HELP

Pulmonary rehabilitation provides multiple benefits

Pulmonary rehabilitation increases exercise tolerance and reduces symptoms

Pulmonary rehabilitation increases exercise tolerance and reduces symptom burden in patients with stable COPD. It is also a multidisciplinary effort that may help reinforce adherence to medications, enhance COPD education, and provide closer medical surveillance to patients at high risk for recurrent exacerbations.

A small randomized controlled trial⁷¹ prescribed pulmonary rehabilitation on discharge for a COPD exacerbation and found sustainable improvements in exercise capacity and health status after 3 months.

In a later study,⁷² the same group started pulmonary rehabilitation within a week of hospital discharge and found reduced hospital readmissions over a 3-month period.

Smoking cessation is always worth advocating

A large observational cohort study concluded that current smokers were at a higher risk for COPD exacerbations compared with former smokers.⁷³ Although there are no randomized controlled trials that assess the effects of smoking cessation at the time of COPD exacerbation, we recommend seizing the opportunity to implement this important intervention.

Vaccinations: Influenza and pneumococcal

Influenza vaccination is associated with reduced incidence of hospitalization among patients with cardiopulmonary disease.⁷⁴ A meta-analysis of randomized clinical trials of influenza vaccination for patients with COPD⁷⁵ reported significantly fewer exacerbations from vaccination, mostly owing to fewer episodes occurring after 3 to 4 weeks, coinciding with anticipated vaccine-induced immune protection. Furumoto and colleagues⁷⁶ reported an added benefit of combined vaccination with 23-valent pneumococcal polysaccharide vaccine and influenza vaccine in reducing hospital admissions over influenza vaccination alone. We also recommend providing the 13-valent pneumococcal conjugate vaccine to patients with COPD, particularly for those older than 65, consistent with CDC recommendations.⁷⁷

In contrast to stable chronic obstructive pulmonary disease (COPD),¹ acute exacerbations of COPD pose special management challenges and can significantly increase the risk of morbidity and death and the cost of care.

This review addresses the definition and diagnosis of COPD exacerbations, disease burden and costs, etiology and pathogenesis, and management and prevention strategies.

DEFINITIONS ARE PROBLEMATIC

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines a COPD exacer­bation as “an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication.”² It further categorizes acute exacerbations by severity:

• Mild—treated with increased frequency of doses of existing medications
• Moderate—treated with corticosteroids or antibiotics, or both
• Severe—requires hospital utilization (either emergency room treatment or admission).

Although descriptive and useful for retrospective analyses, this current definition poses ambiguities for clinicians. Day-to-day variation in symptoms is not routinely assessed, so deviations from baseline may be difficult to detect. Although clinical tools are available for assessing symptoms in stable and exacerbated states (eg, the COPD assessment test³ and the Exacerbations of Chronic Pulmonary Disease Tool [EXACT]⁴), they have not been widely adopted in daily practice. Also, according to the current definition, the severity of an exacerbation can be classified only after the course of action is determined, so the severity is not helpful for forming a management strategy at bedside. In addition, physicians may have different thresholds for prescribing antibiotics and corticosteroids.

An earlier definition categorized a COPD exacerbation by the presence of its three cardinal symptoms (ie, increased shortness of breath, sputum volume, and purulence):

• Type I—all three symptoms present
• Type II—two symptoms present
• Type III—one symptom present, accompanied by at least one of the following: upper respiratory tract infection within the past 5 days, unexplained fever, increased wheezing or cough, or 20% increased respiratory rate or heart rate from baseline.

This older definition was successfully used in a prospective clinical trial to identify patients who benefited most from antibiotics for COPD exacerbations.⁵

COPD exacerbation: an acute worsening of respiratory symptoms

Despite these caveats regarding a definition, most clinicians agree on the clinical presentation of a patient with COPD exacerbation: ie, having some combination of shortness of breath, increased sputum volume, and purulence. By the same token, patients with COPD who present with symptoms not typical of an exacerbation should be evaluated for another diagnosis. For instance, Tillie-Leblond et al⁶ reported that 49 (25%) of 197 patients hospitalized with an “unexplained” exacerbation of COPD were eventually diagnosed with pulmonary embolism.

EXACERBATIONS ARE COSTLY

The care of patients with COPD places a great burden on the healthcare system. Using multiple national databases, Ford et al⁷ estimated that medical costs in the United States in 2010 attributable to COPD and its complications were $32.1 billion.

The largest component of direct healthcare costs of COPD is exacerbations and subsequent hospitalizations.⁸ Data from a predominantly Medicare population indicate that the annualized mean COPD-related cost for a patient with no exacerbations was $1,425, compared with $12,765 for a patient with severe exacerbations.⁹ The investigators estimated that reducing exacerbations from two or more to none could save $5,125 per patient per year.

EXACERBATIONS AFFECT HEALTH BEYOND THE EVENT

COPD exacerbations are associated with a faster decline in lung function,¹⁰ reduced quality of life,¹¹ and lost workdays.⁷ A single exacerbation may cause a decline in lung function and health status that may not return to baseline for several months, particularly if another exacerbation occurs within 6 months.^12,13 COPD exacerbations have also been linked to poor clinical outcomes, including death.

In a prospective study in 304 men with COPD followed for 5 years, those who had three or more COPD exacerbations annually were four times as likely to die than patients who did not have an exacerbation.¹⁴ Nevertheless, the relationship with mortality may not be causal: Brusselle pointed out in an editorial¹⁵ that established mortality predictors for COPD do not include exacerbations, and symptomatic patients with COPD without any history of exacerbations are at greater risk of death than those who are asymptomatic but at high risk for exacerbations.

INFECTION + INFLAMMATION = EXACERBATION

An acute COPD exacerbation can be viewed as an acute inflammatory event superimposed on chronic inflammation associated with COPD. Inflammation in the airways increases resistance to air flow with consequent air trapping. Increased resistance and elastic load due to air trapping place respiratory muscles at a mechanical disadvantage and increase the work of breathing.

Infection starts the process

Infections are thought to be the major instigators of COPD exacerbation

Infections, particularly bacterial and viral, are thought to be the major instigators of COPD exacerbation, although environmental factors such as air pollution may also play a role.¹⁶

Airway inflammation is markedly reduced when bacterial infection is eradicated. But if bacterial colonization continues, inflammatory markers remain elevated despite clinical resolution of the exacerbation.¹⁷ Desai et al¹⁸ found that patients with COPD and chronic bronchitis with bacterial colonization had a larger symptom burden than patients without colonization, even without an exacerbation.

Allergic profile increases risk

Although most studies indicate that infection is the main cause of exacerbations, clinicians should consider other mechanisms of inflammation on an individual basis. COPD exacerbations may be phenotyped by measuring inflammatory markers, perhaps as a starting point for tailored therapies.

Bafadhel et al¹⁹ studied 145 patients with COPD over the course of a year and recorded various biomarkers at baseline and during exacerbations. Exacerbations had an inflammatory profile that was predominantly bacterial in 37%, viral in 10%, and eosinophilic in 17%, and had limited changes in the inflammatory profile in 14%. The remaining episodes were combinations of categories. In another study,²⁰ multivariate analysis conducted in two cohorts with COPD found that patients who had an allergic phenotype had more respiratory symptoms and a higher likelihood of COPD exacerbations.

Frequent COPD exacerbations are increasingly recognized as being associated with an asthma-COPD overlap syndrome, consisting of symptoms of increased airflow variability and incompletely reversible airflow obstruction.²¹

Inflammation as a marker of frequent exacerbations

Evidence is accumulating that supports systemic inflammation as a marker of frequent exacerbations. The Copenhagen Heart Study tested for baseline plasma C-reactive protein, fibrinogen, and white blood cell count in 6,574 stable patients with COPD.²² After multivariable adjustment, they found a significantly higher likelihood of having a subsequent exacerbation in patients who had all three biomarkers elevated (odds ratio [OR] 3.7, 95% confidence interval [CI] 1.9–7.4), even in patients with milder COPD and those without previous exacerbations.

Past exacerbations predict risk

A history of exacerbation is the best predictor of future exacerbation

The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study²³ found that a history of acute COPD exacerbation was the single best predictor of future exacerbations. This risk factor remained stable over 3 years and was present across the severity of COPD, ie, patients at lower GOLD stages who had a history of frequent exacerbations were likely to have exacerbations during follow-up.

EXACERBATION INCREASES CARDIOVASCULAR RISK

COPD exacerbations increase the risk of cardiovascular events, particularly myocardial infarction.²⁴ During hospitalization for acute exacerbation of COPD, markers of myocardial injury and heart failure may be elevated and are a predictor of death.²⁵

Patel et al²⁶ measured arterial stiffness (aortic pulse wave velocity, a validated measure of cardiovascular risk) and cardiac biomarkers (troponin and N-terminal B-type natriuretic peptide) at baseline in 98 patients and longitudinally during and after a COPD exacerbation. In addition to increased levels of cardiac biomarkers, they found a significant rise in arterial stiffness during the exacerbation event without return to baseline levels over 35 days of follow-up. The arterial stiffness increase was related to airway inflammation as measured by sputum interleukin 6, particularly in patients with documented lower respiratory tract infection.

Retrospective analysis suggests a reduced all-cause mortality rate in COPD patients who are treated with beta-blockers.²⁷

Recommendation. We recommend that patients already taking a selective beta-blocker continue to do so during a COPD exacerbation.

OUTPATIENT MANAGEMENT

Treatment with a combination of a corticosteroid, antibiotic, and bronchodilator addresses the underlying pathophysiologic processes of an acute exacerbation: inflammation, infection, and airway trapping.

Short course of a corticosteroid improves outcomes

A single exacerbation may worsen health status for several months

A 10-day systemic course of a corticosteroid prescribed for COPD exacerbation before discharge from the emergency department was found to offer a small advantage over placebo for reducing treatment failure (unscheduled physician visits, return to emergency room for recurrent symptoms) and improving dyspnea scores and lung function.²⁸ Even just a 3-day course improved measures of respiration (forced expiratory volume in the first second of expiration [FEV₁] and arterial oxygenation) at days 3 and 10, and reduced treatment failures compared with placebo.²⁹

Corticosteroid prescription should not be taken lightly, because adverse effects are common. In a systematic review, one adverse effect (hyperglycemia, weight gain, or insomnia) occurred for every five people treated.³⁰

Identifying subgroups of patients most likely to benefit from corticosteroid treatment may be helpful. Corticosteroids may delay improvement in patients without eosinophilic inflammation and hasten recovery in those with more than 2% peripheral eosinophils.³¹ Siva et al³² found that limiting corticosteroids to patients with sputum eosinophilia reduced corticosteroid use and reduced severe exacerbations compared with standard care.³²

Recommendation. For an acute exacerbation, we prescribe a short course of corticosteroids (eg, prednisone 40 mg daily for 5 to 7 days). Tapering dosing is probably unnecessary because adrenal insufficiency is uncommon before 2 weeks of corticosteroid exposure. Clinicians should weigh the merits of tapering (reduced corticosteroid exposure) against patient inconvenience and difficulty following complicated instructions.

Antibiotics help, but exact strategy uncertain

Although antibiotic therapy is one of the three pillars of COPD exacerbation management, the optimal antimicrobial agent, duration of therapy, and which patients will benefit remain areas of controversy and research. Thus far, large trials have been unable to definitely show the superiority of one antibiotic over another.^33,34

A 1987 randomized controlled trial⁵ of antibiotic therapy in acute exacerbation of COPD found the greatest benefit to patients who had all three cardinal symptoms (ie, increased shortness of breath, sputum volume, and purulence), with less marked but still significant improvement in patients with two symptoms. In a 2012 multicenter trial³⁵ patients with mild to moderate COPD experiencing an exacerbation were treated with either combined amoxicillin and clavulanate or placebo if they had one of the three cardinal symptoms. The antibiotic group had a significantly higher clinical cure rate at days 9 to 11 (74.1% vs 59.9%) as well as a longer time until the next exacerbation (233 vs 160 days).

Recommendation. Optimal antibiotic management of COPD exacerbations may also depend on risk factors. For patients with at least two cardinal symptoms, we favor a scheme akin to one proposed for treating community-acquired pneumonia (Table 1).^16,36

INPATIENT MANAGEMENT

Corticosteroids improve outcomes

A Department of Veterans Affairs cooperative trial³⁷ randomized 271 patients hospitalized with COPD exacerbation to receive either corticosteroids (intravenous followed by oral) or placebo for either 2 weeks or 8 weeks. Corticosteroid recipients had lower rates of treatment failure at 30 and 90 days, defined as death from any cause, need for mechanical ventilation, readmission, or intensification of pharmacologic therapy. Corticosteroid therapy also reduced hospital length of stay and improved the rate of recovery. The longer corticosteroid course was associated with a higher rate of adverse effects.

Oral corticosteroids not inferior to intravenous

Using the same end point of treatment failure as the Veterans Affairs cooperative trial, deJong et al³⁸ demonstrated that prednisone 60 mg by mouth was not inferior to intravenous prednisone. Neither trial demonstrated a difference in mortality between corticosteroid use and placebo.

Short course of a corticosteroid not inferior to a long course

In 2013, the Reduction in the Use of Corticosteroids in Exacerbated COPD (REDUCE) trial³⁹ randomized 314 patients presenting with an acute COPD exacerbation (92% requiring hospital admission) to oral prednisone 40 mg daily for either 5 days or 14 days. They found that the short course was noninferior in preventing exacerbations over the ensuing 6 months in terms of death and the need for mechanical ventilation.

Recommendation. Our threshold for initiating systemic corticosteroid therapy is lower in hospitalized patients than in outpatients. We recommend the regimen of the REDUCE trial: prednisone 40 mg daily for 5 days.

Corticosteroids for patients on ventilatory support

Severe COPD exacerbations requiring admission to intensive care are a significant source of morbidity and mortality, and the strategy of corticosteroid treatment is still under investigation.

Intravenous corticosteroids are effective. A multicenter trial⁴⁰ in 354 patients requiring either invasive or noninvasive mechanical ventilation randomized them to treatment with either intravenous methylprednisolone (tapered) or placebo. Treatment was associated with fewer mechanical ventilation days and a lower rate of noninvasive ventilation failure.

Low-dose oral corticosteroids ineffective. In contrast, an open-label trial⁴¹ of patients requiring ventilatory support and randomized to either oral prednisone (1 mg/kg for up to 10 days) or usual care found no difference in intensive care length of stay or noninvasive ventilation failure. This study used the oral route and smaller doses, and its open-label design might have introduced bias.

Lower-dose steroids better than high-dose. A 2014 cohort study of 17,239 patients admitted to the ICU with acute exacerbations of COPD evaluated outcomes of treatment with high methylprednisolone dosages (> 240 mg per day) vs lower dosages, using propensity score matching.⁴² No mortality difference was found between the groups. The lower dosage group (median methylprednisolone dose 100 mg per day) had shorter hospital and intensive care unit stays, shorter duration of noninvasive positive pressure ventilation, less need for insulin therapy, and fewer fungal infections.

Antibiotics for hospitalized patients

Only scarce data are available on the use of antibiotics for patients hospitalized with COPD exacerbation. In a study of patients hospitalized with COPD exacerbations, adding doxycycline to corticosteroids led to better clinical success and cure rates at 10 days compared with placebo, but the primary end point of clinical success at 30 days was not different between the two groups.⁴³

BRONCHODILATORS: A MAINSTAY OF COPD TREATMENT

Bronchodilators are an important part of treatment of COPD exacerbations in inpatient and outpatient settings.

Nebulized beta-2 agonists are given every 1 to 4 hours. Albuterol at a 2.5-mg dose in each nebulization was found to be as effective as 5 mg for length of hospital stay and recovery of lung function in patients with an acute exacerbation of COPD.⁴⁴

Adding an anticholinergic may help. Nebulized anticholinergics can be given alone or combined with beta-2 agonists. Whether long-acting bronchodilators should be used to manage COPD patients hospitalized with an exacerbation requires further inquiry. In an observational study with historical controls, Drescher and colleagues⁴⁵ found cost savings and shorter hospital stays if tiotropium (a long-acting anticholinergic) was added to the respiratory care protocol, which also included formoterol (a long-acting beta-2 agonist).

OXYGEN: TITRATED APPROACH SAFER

Caution is needed to avoid hyperoxemic hypercapnia in patients on oxygen

Oxygen should be supplied during a COPD exacerbation to ensure adequate oxyhemoglobin saturation. Caution is needed to avoid hyperoxemic hypercapnia, particularly in patients with severe COPD and propensity to ventilatory failure. The routine administration of oxygen at high concentrations during a COPD exacerbation has been associated with a higher mortality rate than with a titrated oxygen approach.⁴⁶ Long-term oxygen treatment started at discharge or as outpatient therapy is associated with reduced hospital admissions and shorter hospital stays for acute exacerbations of COPD.⁴⁷

VENTILATION SUPPORT

Noninvasive positive-pressure ventilation is a useful adjunct to treatment of COPD exacerbations with evidence of ventilatory failure (ie, acute respiratory acidosis), helping to offset the work of breathing until respiratory system mechanics improve. Keenan et al⁴⁸ reviewed 15 randomized controlled trials, involving 636 patients, of noninvasive positive-pressure ventilation in the setting of COPD exacerbation. They concluded that noninvasive positive-pressure ventilation reduced the in-hospital mortality rate and length of stay compared with standard therapy. Noninvasive positive-pressure ventilation is most useful in patients with severe COPD exacerbations and acute respiratory acidosis (pH < 7.35).⁴⁹

Intubation and mechanical ventilation. Although no standards exist for determining which COPD exacerbations may be too severe for noninvasive positive-pressure ventilation, intubation is clearly indicated for impending respiratory failure or hemodynamic instability. Other factors to consider include the greater likelihood of noninvasive positive-pressure ventilation failure in patients with severe respiratory acidosis (pH < 7.25 is associated with a > 50% failure rate) and in those with no improvement in acidosis or respiratory rate during the first hour after initiation of noninvasive positive-pressure ventilation.⁵⁰

PREVENTING EXACERBATIONS

Recent data indicate that COPD exacerbations can often be prevented (Table 2).

Inhaled pharmacotherapy

Inhaled pharmacotherapeutic agents, singly or in combination, reduce the frequency of COPD exacerbations.

Combined long-acting beta-2 agonist and corticosteroid is better than single-agent therapy. In 2007, the Towards a Revolution in COPD Health (TORCH) trial⁵¹ evaluated outpatient therapy in more than 6,000 patients worldwide with either an inhaled long-acting beta-2 agonist (salmeterol), an inhaled corticosteroid (fluticasone), both drugs in combination, or placebo. Patients had baseline prebronchodilator FEV₁ of less than 60% and were followed for 3 years. No difference was found between the groups in the primary end point of deaths, but the annualized rate of moderate to severe exacerbations was reduced by 25% in the group that received combination therapy vs placebo. Combination therapy showed superior efficacy over individual drug therapy in preventing exacerbations. Treatment with the inhaled corticosteroid, whether alone or in combination with salmeterol, increased the risk of pneumonia.

A long-acting antimuscarinic agent is better than placebo. In 2008, the Understanding Potential Long-Term Impacts on Function With Tiotropium (UPLIFT) trial⁵² randomized nearly 6,000 patients with COPD and a postbronchodilator FEV₁ of less than 70% to placebo or tiotropium, a long-acting antimuscarinic agent. Tiotropium reduced the exacerbation rate by 14% compared with placebo and improved quality of life.

Antimuscarinics may be better than beta-2 agonists. Head-to-head comparisons suggest that long-acting antimuscarinic agents are preferable to long-acting beta-2 agonists for preventing COPD exacerbations.^53,54

Triple therapy: evidence is mixed. For patients with severe symptomatic COPD and frequent exacerbations, triple therapy with a combination of an inhaled long-acting antimuscarinic agent, an inhaled long-acting beta-2 agonist, and an inhaled corticosteroid has been suggested.

Data to support this practice are limited. In the Canadian Optimal Trial,⁵⁵ the rate of exacerbations was not different between tiotropium alone, tiotropium plus salmeterol, and triple therapy. However, the rate of hospitalization for severe exacerbation was lower with triple therapy than tiotropium alone. A large, retrospective cohort study also supported triple therapy by finding reduced mortality, hospitalizations, and need for oral corticosteroid bursts compared to combination therapy with an inhaled long-acting beta-2 agonist and an inhaled corticosteroid.⁵⁶

The drawback of triple therapy is an increased incidence of pneumonia associated with combined beta-2 agonist and corticosteroids, most likely due to the corticosteroid component.⁵¹ The risk appears to be higher for higher potency corticosteroids, eg, fluticasone.⁵⁷

In 2014, the Withdrawal of Inhaled Steroids During Optimised Bronchodilator Management (WISDOM) trial⁵⁸ randomized nearly 2,500 patients with a history of COPD exacerbation receiving triple therapy consisting of tiotropium, salmeterol, and inhaled fluticasone to either continue treatment or withdraw the corticosteroid for 3 months. The investigators defined an annualized exacerbation rate of 1.2 (ie, a 20% increase) as the upper limit of the confidence interval for an acceptable therapeutic margin of noninferiority. The study showed that the risk of moderate to severe exacerbations with combined tiotropium and salmeterol was noninferior to triple therapy.

Nevertheless, caution is advised when removing the corticosteroid component from triple therapy. The trial demonstrated a worsening in overall health status, some reduction in lung function, and a transient increase in severe exacerbations in the withdrawal group. Patients with increased symptom burden at baseline and a history of severe exacerbations may not be optimal candidates for this strategy.

Roflumilast is effective but has side effects

Roflumilast, an oral phosphodiesterase 4 inhibitor, is an anti-inflammatory drug without bronchodilator properties. In randomized controlled trials, the drug was associated with a 17% reduction in acute exacerbations compared with placebo.⁵⁹

Adding roflumilast to either a long-acting beta-2 agonist or a long-acting antimuscarinic agent resulted in a 6% to 8% further reduction in the proportion of patients with exacerbation.^60,61 Martinez et al⁶¹ found that roflumilast added to a regimen of a long-acting beta-2 agonist plus an inhaled corticosteroid reduced moderate to severe exacerbations by 14.2%, even in the presence of tiotropium. Compared with placebo, roflumilast treatment reduced exacerbations necessitating hospitalizations by 23.9%.

The FDA has approved oral roflumilast 500 µg once daily to prevent COPD exacerbations.

Roflumilast is frequently associated with side effects, including gastrointestinal symptoms (chiefly diarrhea), weight loss, and psychiatric effects. A benefit-to-harm study in 2014 concluded that using the drug is only favorable for patients who have a high risk of severe exacerbations, ie, those who have a greater than 22% baseline risk of having at least one exacerbation annually.⁶²

Recommendation. Roflumilast should be reserved for patients who have severe COPD with a chronic bronchitis phenotype (ie, with cough and sputum production) and repeated exacerbations despite an optimal regimen of an inhaled corticosteroid, long-acting beta-2 agonist, and long-acting antimuscarinic agent.

Macrolide antibiotics: Role unclear

Macrolide antibiotics have anti-inflammatory and immunomodulatory activities.

Azithromycin: fewer exacerbations but some side effects. A multicenter trial⁶³ in 1,142 COPD patients randomized to either oral azithromycin 250 mg daily or placebo found a 27% reduction in the risk of COPD exacerbation in the intervention arm. No differences were found between the groups in mortality, hospitalizations, emergency department visits, or respiratory failure. Hearing loss and increased macrolide resistance were noted in the intervention arm. In a secondary subgroup analysis,⁶⁴ no difference in efficacy was found by sex, history of chronic bronchitis, oxygen use, or concomitant COPD treatment.

The COPD: Influence of Macrolides on Exacerbation Frequency in Patients trial⁶⁵ helped refine patient selection for macrolide therapy. In this single-center study, 92 patients with COPD and at least three exacerbations during the year prior to enrollment were randomized to receive either azithromycin 500 mg three times weekly or placebo. Exacerbations in the intervention group were markedly reduced (42%) with no difference in hospitalization rate.

The place of macrolide antibiotics in the treatment strategy of COPD is unclear, and they are not currently part of the GOLD guidelines. Still unknown is the incremental benefit of adding them to existing preventive regimens, cardiovascular safety, side effects, and potential effects on the resident microbial flora. 

Other antibiotics have also been investigated for efficacy in preventing exacerbations.

Moxifloxacin: fewer exacerbations. The Pulsed Moxifloxacin Usage and Its Long-term Impact on the Reduction of Subsequent Exacerbations study⁶⁶ randomized more than 1,000 patients with stable COPD to receive either moxifloxacin 400 mg or placebo daily for 5 days repeated every 8 weeks for six courses. Frequent assessment during the treatment period and for 6 months afterward revealed a reduced exacerbation rate in the intervention group but without benefit in hospitalization rate, mortality, lung function, or health status.

Recommendation. Azithromycin (either 250 mg daily or 500 mg three times weekly) can be considered for patients who have repeated COPD exacerbations despite an optimal regimen of an inhaled corticosteroid, inhaled long-acting beta-2 agonist, and inhaled long-acting antimuscarinic agent. The need to continue azithromycin should be reassessed yearly.

Mucolytics

Greatest benefit to patients not taking inhaled corticosteroids. Mucolytic agents help clear airway secretions by reducing viscosity. N-acetylcysteine and carbocysteine (not available in the United States) also have antioxidant properties that may counteract oxidant stress associated with acute COPD exacerbations.

The Bronchitis Randomized on NAC Cost-Utility Study (BRONCUS)⁶⁷ randomized 523 COPD patients to N-acetylcysteine 600 mg daily or placebo. After 3 years of follow-up, no differences were found in the rate of exacerbations, lung function decline, and quality of life. Subgroup analysis suggested a reduction in exacerbations for patients who were not taking inhaled corticosteroids.

The Effect of Carbocisteine on Acute Exacerbation of Chronic Obstructive Pulmonary Disease (PEACE) study randomized more than 700 patients from multiple centers in China who had COPD and a recent history of exacerbations; they found a 25% lower exacerbation rate over 1 year with carbocysteine vs placebo.⁶⁸ Most of the patients (83%) were not on inhaled corticosteroids, which complemented findings of the BRONCUS trial.

The Effect of High Dose N-acetylcysteine on Air Trapping and Airway Resistance of COPD (HIACE) study randomized 120 patients with stable COPD in a hospital in Hong Kong to either oral N-acetylcysteine (600 mg twice daily) or placebo and found a reduced exacerbation rate of exacerbations. Patients were matched at baseline for inhaled corticosteroid use.⁶⁹

In 2014, the Twice Daily N-acetylcysteine 600 mg for Exacerbations of Chronic Obstructive Pulmonary Disease (PANTHEON) study⁷⁰ randomized 1,006 patients from multiple hospitals in China with a history of moderate to severe COPD and exacerbations to receive either N-acetylcysteine 600 mg twice daily or placebo for 1 year. They found a 22% reduction in exacerbations in the treatment group vs placebo.  

GOLD guidelines² recommend mucolytics for patients with severe COPD and exacerbations when inhaled corticosteroids are not available or affordable.

Recommendation. Mucolytics may be useful for patients with difficulty expectorating and with a history of exacerbations despite appropriate inhaled therapy.

OTHER INTERVENTIONS CAN HELP

Pulmonary rehabilitation provides multiple benefits

Pulmonary rehabilitation increases exercise tolerance and reduces symptoms

Pulmonary rehabilitation increases exercise tolerance and reduces symptom burden in patients with stable COPD. It is also a multidisciplinary effort that may help reinforce adherence to medications, enhance COPD education, and provide closer medical surveillance to patients at high risk for recurrent exacerbations.

A small randomized controlled trial⁷¹ prescribed pulmonary rehabilitation on discharge for a COPD exacerbation and found sustainable improvements in exercise capacity and health status after 3 months.

In a later study,⁷² the same group started pulmonary rehabilitation within a week of hospital discharge and found reduced hospital readmissions over a 3-month period.

Smoking cessation is always worth advocating

A large observational cohort study concluded that current smokers were at a higher risk for COPD exacerbations compared with former smokers.⁷³ Although there are no randomized controlled trials that assess the effects of smoking cessation at the time of COPD exacerbation, we recommend seizing the opportunity to implement this important intervention.

Vaccinations: Influenza and pneumococcal

Influenza vaccination is associated with reduced incidence of hospitalization among patients with cardiopulmonary disease.⁷⁴ A meta-analysis of randomized clinical trials of influenza vaccination for patients with COPD⁷⁵ reported significantly fewer exacerbations from vaccination, mostly owing to fewer episodes occurring after 3 to 4 weeks, coinciding with anticipated vaccine-induced immune protection. Furumoto and colleagues⁷⁶ reported an added benefit of combined vaccination with 23-valent pneumococcal polysaccharide vaccine and influenza vaccine in reducing hospital admissions over influenza vaccination alone. We also recommend providing the 13-valent pneumococcal conjugate vaccine to patients with COPD, particularly for those older than 65, consistent with CDC recommendations.⁷⁷

In contrast to stable chronic obstructive pulmonary disease (COPD),¹ acute exacerbations of COPD pose special management challenges and can significantly increase the risk of morbidity and death and the cost of care.

This review addresses the definition and diagnosis of COPD exacerbations, disease burden and costs, etiology and pathogenesis, and management and prevention strategies.

DEFINITIONS ARE PROBLEMATIC

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines a COPD exacer­bation as “an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication.”² It further categorizes acute exacerbations by severity:

• Mild—treated with increased frequency of doses of existing medications
• Moderate—treated with corticosteroids or antibiotics, or both
• Severe—requires hospital utilization (either emergency room treatment or admission).

Although descriptive and useful for retrospective analyses, this current definition poses ambiguities for clinicians. Day-to-day variation in symptoms is not routinely assessed, so deviations from baseline may be difficult to detect. Although clinical tools are available for assessing symptoms in stable and exacerbated states (eg, the COPD assessment test³ and the Exacerbations of Chronic Pulmonary Disease Tool [EXACT]⁴), they have not been widely adopted in daily practice. Also, according to the current definition, the severity of an exacerbation can be classified only after the course of action is determined, so the severity is not helpful for forming a management strategy at bedside. In addition, physicians may have different thresholds for prescribing antibiotics and corticosteroids.

An earlier definition categorized a COPD exacerbation by the presence of its three cardinal symptoms (ie, increased shortness of breath, sputum volume, and purulence):

• Type I—all three symptoms present
• Type II—two symptoms present
• Type III—one symptom present, accompanied by at least one of the following: upper respiratory tract infection within the past 5 days, unexplained fever, increased wheezing or cough, or 20% increased respiratory rate or heart rate from baseline.

This older definition was successfully used in a prospective clinical trial to identify patients who benefited most from antibiotics for COPD exacerbations.⁵

COPD exacerbation: an acute worsening of respiratory symptoms

Despite these caveats regarding a definition, most clinicians agree on the clinical presentation of a patient with COPD exacerbation: ie, having some combination of shortness of breath, increased sputum volume, and purulence. By the same token, patients with COPD who present with symptoms not typical of an exacerbation should be evaluated for another diagnosis. For instance, Tillie-Leblond et al⁶ reported that 49 (25%) of 197 patients hospitalized with an “unexplained” exacerbation of COPD were eventually diagnosed with pulmonary embolism.

EXACERBATIONS ARE COSTLY

The care of patients with COPD places a great burden on the healthcare system. Using multiple national databases, Ford et al⁷ estimated that medical costs in the United States in 2010 attributable to COPD and its complications were $32.1 billion.

The largest component of direct healthcare costs of COPD is exacerbations and subsequent hospitalizations.⁸ Data from a predominantly Medicare population indicate that the annualized mean COPD-related cost for a patient with no exacerbations was $1,425, compared with $12,765 for a patient with severe exacerbations.⁹ The investigators estimated that reducing exacerbations from two or more to none could save $5,125 per patient per year.

EXACERBATIONS AFFECT HEALTH BEYOND THE EVENT

COPD exacerbations are associated with a faster decline in lung function,¹⁰ reduced quality of life,¹¹ and lost workdays.⁷ A single exacerbation may cause a decline in lung function and health status that may not return to baseline for several months, particularly if another exacerbation occurs within 6 months.^12,13 COPD exacerbations have also been linked to poor clinical outcomes, including death.

In a prospective study in 304 men with COPD followed for 5 years, those who had three or more COPD exacerbations annually were four times as likely to die than patients who did not have an exacerbation.¹⁴ Nevertheless, the relationship with mortality may not be causal: Brusselle pointed out in an editorial¹⁵ that established mortality predictors for COPD do not include exacerbations, and symptomatic patients with COPD without any history of exacerbations are at greater risk of death than those who are asymptomatic but at high risk for exacerbations.

INFECTION + INFLAMMATION = EXACERBATION

An acute COPD exacerbation can be viewed as an acute inflammatory event superimposed on chronic inflammation associated with COPD. Inflammation in the airways increases resistance to air flow with consequent air trapping. Increased resistance and elastic load due to air trapping place respiratory muscles at a mechanical disadvantage and increase the work of breathing.

Infection starts the process

Infections are thought to be the major instigators of COPD exacerbation

Infections, particularly bacterial and viral, are thought to be the major instigators of COPD exacerbation, although environmental factors such as air pollution may also play a role.¹⁶

Airway inflammation is markedly reduced when bacterial infection is eradicated. But if bacterial colonization continues, inflammatory markers remain elevated despite clinical resolution of the exacerbation.¹⁷ Desai et al¹⁸ found that patients with COPD and chronic bronchitis with bacterial colonization had a larger symptom burden than patients without colonization, even without an exacerbation.

Allergic profile increases risk

Although most studies indicate that infection is the main cause of exacerbations, clinicians should consider other mechanisms of inflammation on an individual basis. COPD exacerbations may be phenotyped by measuring inflammatory markers, perhaps as a starting point for tailored therapies.

Bafadhel et al¹⁹ studied 145 patients with COPD over the course of a year and recorded various biomarkers at baseline and during exacerbations. Exacerbations had an inflammatory profile that was predominantly bacterial in 37%, viral in 10%, and eosinophilic in 17%, and had limited changes in the inflammatory profile in 14%. The remaining episodes were combinations of categories. In another study,²⁰ multivariate analysis conducted in two cohorts with COPD found that patients who had an allergic phenotype had more respiratory symptoms and a higher likelihood of COPD exacerbations.

Frequent COPD exacerbations are increasingly recognized as being associated with an asthma-COPD overlap syndrome, consisting of symptoms of increased airflow variability and incompletely reversible airflow obstruction.²¹

Inflammation as a marker of frequent exacerbations

Evidence is accumulating that supports systemic inflammation as a marker of frequent exacerbations. The Copenhagen Heart Study tested for baseline plasma C-reactive protein, fibrinogen, and white blood cell count in 6,574 stable patients with COPD.²² After multivariable adjustment, they found a significantly higher likelihood of having a subsequent exacerbation in patients who had all three biomarkers elevated (odds ratio [OR] 3.7, 95% confidence interval [CI] 1.9–7.4), even in patients with milder COPD and those without previous exacerbations.

Past exacerbations predict risk

A history of exacerbation is the best predictor of future exacerbation

The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study²³ found that a history of acute COPD exacerbation was the single best predictor of future exacerbations. This risk factor remained stable over 3 years and was present across the severity of COPD, ie, patients at lower GOLD stages who had a history of frequent exacerbations were likely to have exacerbations during follow-up.

EXACERBATION INCREASES CARDIOVASCULAR RISK

COPD exacerbations increase the risk of cardiovascular events, particularly myocardial infarction.²⁴ During hospitalization for acute exacerbation of COPD, markers of myocardial injury and heart failure may be elevated and are a predictor of death.²⁵

Patel et al²⁶ measured arterial stiffness (aortic pulse wave velocity, a validated measure of cardiovascular risk) and cardiac biomarkers (troponin and N-terminal B-type natriuretic peptide) at baseline in 98 patients and longitudinally during and after a COPD exacerbation. In addition to increased levels of cardiac biomarkers, they found a significant rise in arterial stiffness during the exacerbation event without return to baseline levels over 35 days of follow-up. The arterial stiffness increase was related to airway inflammation as measured by sputum interleukin 6, particularly in patients with documented lower respiratory tract infection.

Retrospective analysis suggests a reduced all-cause mortality rate in COPD patients who are treated with beta-blockers.²⁷

Recommendation. We recommend that patients already taking a selective beta-blocker continue to do so during a COPD exacerbation.

OUTPATIENT MANAGEMENT

Treatment with a combination of a corticosteroid, antibiotic, and bronchodilator addresses the underlying pathophysiologic processes of an acute exacerbation: inflammation, infection, and airway trapping.

Short course of a corticosteroid improves outcomes

A single exacerbation may worsen health status for several months

A 10-day systemic course of a corticosteroid prescribed for COPD exacerbation before discharge from the emergency department was found to offer a small advantage over placebo for reducing treatment failure (unscheduled physician visits, return to emergency room for recurrent symptoms) and improving dyspnea scores and lung function.²⁸ Even just a 3-day course improved measures of respiration (forced expiratory volume in the first second of expiration [FEV₁] and arterial oxygenation) at days 3 and 10, and reduced treatment failures compared with placebo.²⁹

Corticosteroid prescription should not be taken lightly, because adverse effects are common. In a systematic review, one adverse effect (hyperglycemia, weight gain, or insomnia) occurred for every five people treated.³⁰

Identifying subgroups of patients most likely to benefit from corticosteroid treatment may be helpful. Corticosteroids may delay improvement in patients without eosinophilic inflammation and hasten recovery in those with more than 2% peripheral eosinophils.³¹ Siva et al³² found that limiting corticosteroids to patients with sputum eosinophilia reduced corticosteroid use and reduced severe exacerbations compared with standard care.³²

Recommendation. For an acute exacerbation, we prescribe a short course of corticosteroids (eg, prednisone 40 mg daily for 5 to 7 days). Tapering dosing is probably unnecessary because adrenal insufficiency is uncommon before 2 weeks of corticosteroid exposure. Clinicians should weigh the merits of tapering (reduced corticosteroid exposure) against patient inconvenience and difficulty following complicated instructions.

Antibiotics help, but exact strategy uncertain

Although antibiotic therapy is one of the three pillars of COPD exacerbation management, the optimal antimicrobial agent, duration of therapy, and which patients will benefit remain areas of controversy and research. Thus far, large trials have been unable to definitely show the superiority of one antibiotic over another.^33,34

A 1987 randomized controlled trial⁵ of antibiotic therapy in acute exacerbation of COPD found the greatest benefit to patients who had all three cardinal symptoms (ie, increased shortness of breath, sputum volume, and purulence), with less marked but still significant improvement in patients with two symptoms. In a 2012 multicenter trial³⁵ patients with mild to moderate COPD experiencing an exacerbation were treated with either combined amoxicillin and clavulanate or placebo if they had one of the three cardinal symptoms. The antibiotic group had a significantly higher clinical cure rate at days 9 to 11 (74.1% vs 59.9%) as well as a longer time until the next exacerbation (233 vs 160 days).

Recommendation. Optimal antibiotic management of COPD exacerbations may also depend on risk factors. For patients with at least two cardinal symptoms, we favor a scheme akin to one proposed for treating community-acquired pneumonia (Table 1).^16,36

INPATIENT MANAGEMENT

Corticosteroids improve outcomes

A Department of Veterans Affairs cooperative trial³⁷ randomized 271 patients hospitalized with COPD exacerbation to receive either corticosteroids (intravenous followed by oral) or placebo for either 2 weeks or 8 weeks. Corticosteroid recipients had lower rates of treatment failure at 30 and 90 days, defined as death from any cause, need for mechanical ventilation, readmission, or intensification of pharmacologic therapy. Corticosteroid therapy also reduced hospital length of stay and improved the rate of recovery. The longer corticosteroid course was associated with a higher rate of adverse effects.

Oral corticosteroids not inferior to intravenous

Using the same end point of treatment failure as the Veterans Affairs cooperative trial, deJong et al³⁸ demonstrated that prednisone 60 mg by mouth was not inferior to intravenous prednisone. Neither trial demonstrated a difference in mortality between corticosteroid use and placebo.

Short course of a corticosteroid not inferior to a long course

In 2013, the Reduction in the Use of Corticosteroids in Exacerbated COPD (REDUCE) trial³⁹ randomized 314 patients presenting with an acute COPD exacerbation (92% requiring hospital admission) to oral prednisone 40 mg daily for either 5 days or 14 days. They found that the short course was noninferior in preventing exacerbations over the ensuing 6 months in terms of death and the need for mechanical ventilation.

Recommendation. Our threshold for initiating systemic corticosteroid therapy is lower in hospitalized patients than in outpatients. We recommend the regimen of the REDUCE trial: prednisone 40 mg daily for 5 days.

Corticosteroids for patients on ventilatory support

Severe COPD exacerbations requiring admission to intensive care are a significant source of morbidity and mortality, and the strategy of corticosteroid treatment is still under investigation.

Intravenous corticosteroids are effective. A multicenter trial⁴⁰ in 354 patients requiring either invasive or noninvasive mechanical ventilation randomized them to treatment with either intravenous methylprednisolone (tapered) or placebo. Treatment was associated with fewer mechanical ventilation days and a lower rate of noninvasive ventilation failure.

Low-dose oral corticosteroids ineffective. In contrast, an open-label trial⁴¹ of patients requiring ventilatory support and randomized to either oral prednisone (1 mg/kg for up to 10 days) or usual care found no difference in intensive care length of stay or noninvasive ventilation failure. This study used the oral route and smaller doses, and its open-label design might have introduced bias.

Lower-dose steroids better than high-dose. A 2014 cohort study of 17,239 patients admitted to the ICU with acute exacerbations of COPD evaluated outcomes of treatment with high methylprednisolone dosages (> 240 mg per day) vs lower dosages, using propensity score matching.⁴² No mortality difference was found between the groups. The lower dosage group (median methylprednisolone dose 100 mg per day) had shorter hospital and intensive care unit stays, shorter duration of noninvasive positive pressure ventilation, less need for insulin therapy, and fewer fungal infections.

Antibiotics for hospitalized patients

Only scarce data are available on the use of antibiotics for patients hospitalized with COPD exacerbation. In a study of patients hospitalized with COPD exacerbations, adding doxycycline to corticosteroids led to better clinical success and cure rates at 10 days compared with placebo, but the primary end point of clinical success at 30 days was not different between the two groups.⁴³

BRONCHODILATORS: A MAINSTAY OF COPD TREATMENT

Bronchodilators are an important part of treatment of COPD exacerbations in inpatient and outpatient settings.

Nebulized beta-2 agonists are given every 1 to 4 hours. Albuterol at a 2.5-mg dose in each nebulization was found to be as effective as 5 mg for length of hospital stay and recovery of lung function in patients with an acute exacerbation of COPD.⁴⁴

Adding an anticholinergic may help. Nebulized anticholinergics can be given alone or combined with beta-2 agonists. Whether long-acting bronchodilators should be used to manage COPD patients hospitalized with an exacerbation requires further inquiry. In an observational study with historical controls, Drescher and colleagues⁴⁵ found cost savings and shorter hospital stays if tiotropium (a long-acting anticholinergic) was added to the respiratory care protocol, which also included formoterol (a long-acting beta-2 agonist).

OXYGEN: TITRATED APPROACH SAFER

Caution is needed to avoid hyperoxemic hypercapnia in patients on oxygen

Oxygen should be supplied during a COPD exacerbation to ensure adequate oxyhemoglobin saturation. Caution is needed to avoid hyperoxemic hypercapnia, particularly in patients with severe COPD and propensity to ventilatory failure. The routine administration of oxygen at high concentrations during a COPD exacerbation has been associated with a higher mortality rate than with a titrated oxygen approach.⁴⁶ Long-term oxygen treatment started at discharge or as outpatient therapy is associated with reduced hospital admissions and shorter hospital stays for acute exacerbations of COPD.⁴⁷

VENTILATION SUPPORT

Noninvasive positive-pressure ventilation is a useful adjunct to treatment of COPD exacerbations with evidence of ventilatory failure (ie, acute respiratory acidosis), helping to offset the work of breathing until respiratory system mechanics improve. Keenan et al⁴⁸ reviewed 15 randomized controlled trials, involving 636 patients, of noninvasive positive-pressure ventilation in the setting of COPD exacerbation. They concluded that noninvasive positive-pressure ventilation reduced the in-hospital mortality rate and length of stay compared with standard therapy. Noninvasive positive-pressure ventilation is most useful in patients with severe COPD exacerbations and acute respiratory acidosis (pH < 7.35).⁴⁹

Intubation and mechanical ventilation. Although no standards exist for determining which COPD exacerbations may be too severe for noninvasive positive-pressure ventilation, intubation is clearly indicated for impending respiratory failure or hemodynamic instability. Other factors to consider include the greater likelihood of noninvasive positive-pressure ventilation failure in patients with severe respiratory acidosis (pH < 7.25 is associated with a > 50% failure rate) and in those with no improvement in acidosis or respiratory rate during the first hour after initiation of noninvasive positive-pressure ventilation.⁵⁰

PREVENTING EXACERBATIONS

Recent data indicate that COPD exacerbations can often be prevented (Table 2).

Inhaled pharmacotherapy

Inhaled pharmacotherapeutic agents, singly or in combination, reduce the frequency of COPD exacerbations.

Combined long-acting beta-2 agonist and corticosteroid is better than single-agent therapy. In 2007, the Towards a Revolution in COPD Health (TORCH) trial⁵¹ evaluated outpatient therapy in more than 6,000 patients worldwide with either an inhaled long-acting beta-2 agonist (salmeterol), an inhaled corticosteroid (fluticasone), both drugs in combination, or placebo. Patients had baseline prebronchodilator FEV₁ of less than 60% and were followed for 3 years. No difference was found between the groups in the primary end point of deaths, but the annualized rate of moderate to severe exacerbations was reduced by 25% in the group that received combination therapy vs placebo. Combination therapy showed superior efficacy over individual drug therapy in preventing exacerbations. Treatment with the inhaled corticosteroid, whether alone or in combination with salmeterol, increased the risk of pneumonia.

A long-acting antimuscarinic agent is better than placebo. In 2008, the Understanding Potential Long-Term Impacts on Function With Tiotropium (UPLIFT) trial⁵² randomized nearly 6,000 patients with COPD and a postbronchodilator FEV₁ of less than 70% to placebo or tiotropium, a long-acting antimuscarinic agent. Tiotropium reduced the exacerbation rate by 14% compared with placebo and improved quality of life.

Antimuscarinics may be better than beta-2 agonists. Head-to-head comparisons suggest that long-acting antimuscarinic agents are preferable to long-acting beta-2 agonists for preventing COPD exacerbations.^53,54

Triple therapy: evidence is mixed. For patients with severe symptomatic COPD and frequent exacerbations, triple therapy with a combination of an inhaled long-acting antimuscarinic agent, an inhaled long-acting beta-2 agonist, and an inhaled corticosteroid has been suggested.

Data to support this practice are limited. In the Canadian Optimal Trial,⁵⁵ the rate of exacerbations was not different between tiotropium alone, tiotropium plus salmeterol, and triple therapy. However, the rate of hospitalization for severe exacerbation was lower with triple therapy than tiotropium alone. A large, retrospective cohort study also supported triple therapy by finding reduced mortality, hospitalizations, and need for oral corticosteroid bursts compared to combination therapy with an inhaled long-acting beta-2 agonist and an inhaled corticosteroid.⁵⁶

The drawback of triple therapy is an increased incidence of pneumonia associated with combined beta-2 agonist and corticosteroids, most likely due to the corticosteroid component.⁵¹ The risk appears to be higher for higher potency corticosteroids, eg, fluticasone.⁵⁷

In 2014, the Withdrawal of Inhaled Steroids During Optimised Bronchodilator Management (WISDOM) trial⁵⁸ randomized nearly 2,500 patients with a history of COPD exacerbation receiving triple therapy consisting of tiotropium, salmeterol, and inhaled fluticasone to either continue treatment or withdraw the corticosteroid for 3 months. The investigators defined an annualized exacerbation rate of 1.2 (ie, a 20% increase) as the upper limit of the confidence interval for an acceptable therapeutic margin of noninferiority. The study showed that the risk of moderate to severe exacerbations with combined tiotropium and salmeterol was noninferior to triple therapy.

Nevertheless, caution is advised when removing the corticosteroid component from triple therapy. The trial demonstrated a worsening in overall health status, some reduction in lung function, and a transient increase in severe exacerbations in the withdrawal group. Patients with increased symptom burden at baseline and a history of severe exacerbations may not be optimal candidates for this strategy.

Roflumilast is effective but has side effects

Roflumilast, an oral phosphodiesterase 4 inhibitor, is an anti-inflammatory drug without bronchodilator properties. In randomized controlled trials, the drug was associated with a 17% reduction in acute exacerbations compared with placebo.⁵⁹

Adding roflumilast to either a long-acting beta-2 agonist or a long-acting antimuscarinic agent resulted in a 6% to 8% further reduction in the proportion of patients with exacerbation.^60,61 Martinez et al⁶¹ found that roflumilast added to a regimen of a long-acting beta-2 agonist plus an inhaled corticosteroid reduced moderate to severe exacerbations by 14.2%, even in the presence of tiotropium. Compared with placebo, roflumilast treatment reduced exacerbations necessitating hospitalizations by 23.9%.

The FDA has approved oral roflumilast 500 µg once daily to prevent COPD exacerbations.

Roflumilast is frequently associated with side effects, including gastrointestinal symptoms (chiefly diarrhea), weight loss, and psychiatric effects. A benefit-to-harm study in 2014 concluded that using the drug is only favorable for patients who have a high risk of severe exacerbations, ie, those who have a greater than 22% baseline risk of having at least one exacerbation annually.⁶²

Recommendation. Roflumilast should be reserved for patients who have severe COPD with a chronic bronchitis phenotype (ie, with cough and sputum production) and repeated exacerbations despite an optimal regimen of an inhaled corticosteroid, long-acting beta-2 agonist, and long-acting antimuscarinic agent.

Macrolide antibiotics: Role unclear

Macrolide antibiotics have anti-inflammatory and immunomodulatory activities.

Azithromycin: fewer exacerbations but some side effects. A multicenter trial⁶³ in 1,142 COPD patients randomized to either oral azithromycin 250 mg daily or placebo found a 27% reduction in the risk of COPD exacerbation in the intervention arm. No differences were found between the groups in mortality, hospitalizations, emergency department visits, or respiratory failure. Hearing loss and increased macrolide resistance were noted in the intervention arm. In a secondary subgroup analysis,⁶⁴ no difference in efficacy was found by sex, history of chronic bronchitis, oxygen use, or concomitant COPD treatment.

The COPD: Influence of Macrolides on Exacerbation Frequency in Patients trial⁶⁵ helped refine patient selection for macrolide therapy. In this single-center study, 92 patients with COPD and at least three exacerbations during the year prior to enrollment were randomized to receive either azithromycin 500 mg three times weekly or placebo. Exacerbations in the intervention group were markedly reduced (42%) with no difference in hospitalization rate.

The place of macrolide antibiotics in the treatment strategy of COPD is unclear, and they are not currently part of the GOLD guidelines. Still unknown is the incremental benefit of adding them to existing preventive regimens, cardiovascular safety, side effects, and potential effects on the resident microbial flora. 

Other antibiotics have also been investigated for efficacy in preventing exacerbations.

Moxifloxacin: fewer exacerbations. The Pulsed Moxifloxacin Usage and Its Long-term Impact on the Reduction of Subsequent Exacerbations study⁶⁶ randomized more than 1,000 patients with stable COPD to receive either moxifloxacin 400 mg or placebo daily for 5 days repeated every 8 weeks for six courses. Frequent assessment during the treatment period and for 6 months afterward revealed a reduced exacerbation rate in the intervention group but without benefit in hospitalization rate, mortality, lung function, or health status.

Recommendation. Azithromycin (either 250 mg daily or 500 mg three times weekly) can be considered for patients who have repeated COPD exacerbations despite an optimal regimen of an inhaled corticosteroid, inhaled long-acting beta-2 agonist, and inhaled long-acting antimuscarinic agent. The need to continue azithromycin should be reassessed yearly.

Mucolytics

Greatest benefit to patients not taking inhaled corticosteroids. Mucolytic agents help clear airway secretions by reducing viscosity. N-acetylcysteine and carbocysteine (not available in the United States) also have antioxidant properties that may counteract oxidant stress associated with acute COPD exacerbations.

The Bronchitis Randomized on NAC Cost-Utility Study (BRONCUS)⁶⁷ randomized 523 COPD patients to N-acetylcysteine 600 mg daily or placebo. After 3 years of follow-up, no differences were found in the rate of exacerbations, lung function decline, and quality of life. Subgroup analysis suggested a reduction in exacerbations for patients who were not taking inhaled corticosteroids.

The Effect of Carbocisteine on Acute Exacerbation of Chronic Obstructive Pulmonary Disease (PEACE) study randomized more than 700 patients from multiple centers in China who had COPD and a recent history of exacerbations; they found a 25% lower exacerbation rate over 1 year with carbocysteine vs placebo.⁶⁸ Most of the patients (83%) were not on inhaled corticosteroids, which complemented findings of the BRONCUS trial.

The Effect of High Dose N-acetylcysteine on Air Trapping and Airway Resistance of COPD (HIACE) study randomized 120 patients with stable COPD in a hospital in Hong Kong to either oral N-acetylcysteine (600 mg twice daily) or placebo and found a reduced exacerbation rate of exacerbations. Patients were matched at baseline for inhaled corticosteroid use.⁶⁹

In 2014, the Twice Daily N-acetylcysteine 600 mg for Exacerbations of Chronic Obstructive Pulmonary Disease (PANTHEON) study⁷⁰ randomized 1,006 patients from multiple hospitals in China with a history of moderate to severe COPD and exacerbations to receive either N-acetylcysteine 600 mg twice daily or placebo for 1 year. They found a 22% reduction in exacerbations in the treatment group vs placebo.  

GOLD guidelines² recommend mucolytics for patients with severe COPD and exacerbations when inhaled corticosteroids are not available or affordable.

Recommendation. Mucolytics may be useful for patients with difficulty expectorating and with a history of exacerbations despite appropriate inhaled therapy.

OTHER INTERVENTIONS CAN HELP

Pulmonary rehabilitation provides multiple benefits

Pulmonary rehabilitation increases exercise tolerance and reduces symptoms

Pulmonary rehabilitation increases exercise tolerance and reduces symptom burden in patients with stable COPD. It is also a multidisciplinary effort that may help reinforce adherence to medications, enhance COPD education, and provide closer medical surveillance to patients at high risk for recurrent exacerbations.

A small randomized controlled trial⁷¹ prescribed pulmonary rehabilitation on discharge for a COPD exacerbation and found sustainable improvements in exercise capacity and health status after 3 months.

In a later study,⁷² the same group started pulmonary rehabilitation within a week of hospital discharge and found reduced hospital readmissions over a 3-month period.

Smoking cessation is always worth advocating

A large observational cohort study concluded that current smokers were at a higher risk for COPD exacerbations compared with former smokers.⁷³ Although there are no randomized controlled trials that assess the effects of smoking cessation at the time of COPD exacerbation, we recommend seizing the opportunity to implement this important intervention.

Vaccinations: Influenza and pneumococcal

Influenza vaccination is associated with reduced incidence of hospitalization among patients with cardiopulmonary disease.⁷⁴ A meta-analysis of randomized clinical trials of influenza vaccination for patients with COPD⁷⁵ reported significantly fewer exacerbations from vaccination, mostly owing to fewer episodes occurring after 3 to 4 weeks, coinciding with anticipated vaccine-induced immune protection. Furumoto and colleagues⁷⁶ reported an added benefit of combined vaccination with 23-valent pneumococcal polysaccharide vaccine and influenza vaccine in reducing hospital admissions over influenza vaccination alone. We also recommend providing the 13-valent pneumococcal conjugate vaccine to patients with COPD, particularly for those older than 65, consistent with CDC recommendations.⁷⁷

Managing glycemic control in hospitalized patients with chronic kidney disease (CKD) and diabetes mellitus is a challenge, with no published guidelines. In this setting, avoiding hypoglycemia takes precedence over meeting strict blood glucose targets. Optimal management is essential to reduce hypoglycemia and the risk of death from cardiovascular disease.¹

This article reviews the evidence to guide diabetes management in hospitalized patients with CKD, focusing on blood glucose monitoring, insulin dosing, and concerns about other diabetic agents.

FOCUS ON AVOIDING HYPOGLYCEMIA

CKD is common, estimated to affect more than 50 million people worldwide.² Diabetes mellitus is the primary cause of kidney failure in 45% of dialysis patients with CKD.

Tight control comes with a cost

Hyperglycemia in hospitalized patients is associated with a higher risk of death, a higher risk of infections, and a longer hospital stay.^3,4 In 2001, Van den Berghe et al⁵ found that intensive insulin therapy reduced the mortality rate in critically ill patients in the surgical intensive care unit. But subsequent studies^6,7 found that intensive insulin therapy to achieve tight glycemic control increased rates of morbidity and mortality without adding clinical benefit.

Randomized clinical trials in outpatients have shown that tight control of blood glucose levels reduces microvascular and macrovascular complications in patients with type 1 diabetes.^8–10 In the Diabetes Control and Complications Trial,⁹ compared with conventional therapy, intensive insulin therapy reduced the incidence of retinopathy progression (4.7 vs 1.2 cases per 100 patient-years, number needed to treat [NNT] = 3 for 10 years) and clinical neuropathy (9.8 vs 3.1 per 100 patient-years, NNT = 1.5 for 10 years). The long-term likelihood of a cardiovascular event was also significantly lower in the intensive treatment group (0.38 vs 0.80 events per 100 patient-years).⁹

Similarly, in the Epidemiology of Diabetes Interventions and Complications follow-up study, the intensive therapy group had fewer cardiovascular deaths.¹¹ On the other hand, the risk of severe hypoglycemia and subsequent coma or seizure was significantly higher in the intensive therapy group than in the conventional therapy group (16.3 vs 5.4 per 100 patient-years).⁸

CKD increases hypoglycemia risk

Moen et al¹² found that the incidence of hypoglycemia was significantly higher in patients with CKD (estimated glomerular filtration rate [GFR] < 60 mL/min) with or without diabetes, and that patients with both conditions were at greatest risk (Figure 1). Multiple factors contribute to the increased risk of hypoglycemia: patients with advanced CKD tend to have poor nutrition, resulting in reduced glycogen stores, and a smaller renal mass reduces renal gluconeogenesis and decreases the elimination of insulin and oral antidiabetic agents.

After the onset of diabetic nephropathy, progression of renal complications and overall life expectancy are influenced by earlier glycemic control.⁸ Development of diabetic nephropathy is commonly accompanied by changes in metabolic control, particularly an increased risk of hypoglycemia.¹³ In addition, episodes of severe hypoglycemia constitute an independent cardiovascular risk factor.¹⁴

Aggressive glycemic control in hospitalized patients, particularly those with advanced CKD, is associated with a risk of hypoglycemia without overall improvement in outcomes.¹⁵ Elderly patients with type 2 diabetes are similar to patients with CKD in that they have a reduced GFR and are thus more sensitive to insulin. In both groups, intensifying glycemic control, especially in the hospital, is associated with more frequent episodes of severe hypoglycemia.¹⁶ The focus should be not only on maintaining optimal blood glucose concentration, but also on preventing hypoglycemia.

‘Burnt-out’ diabetes

Paradoxically, patients with end-stage renal disease and type 2 diabetes often experience altered glucose homeostasis with markedly improved glycemic control. They may attain normoglycemia and normalization of hemoglobin A_1c, a condition known as “burnt-out” diabetes. Its precise mechanism is not understood and its significance remains unclear (Table 1).¹⁷

HEMOGLOBIN A_1c CAN BE FALSELY HIGH OR FALSELY LOW

Hemoglobin A_1c measurement is used to diagnose diabetes and to assess long-term glycemic control. It is a measure of the fraction of hemoglobin that has been glycated by exposure to glucose. Because the average lifespan of a red cell is 120 days, the hemoglobin A_1c value reflects the mean blood glucose concentration over the preceding 3 months.

But hemoglobin A_1c measurement has limitations: any condition that alters the lifespan of erythrocytes leads to higher or lower hemoglobin A_1c levels. Hemoglobin A_1c levels are also affected by kidney dysfunction, hemolysis, and acidosis.¹⁸

Falsely high hemoglobin A_1c levels are associated with conditions that prolong the lifespan of erythrocytes, such as asplenia. Iron deficiency also increases the average age of circulating red cells because of reduced red cell production. For patients in whom blood glucose measurements do not correlate with hemoglobin A_1c measurements, iron deficiency anemia should be considered before altering a treatment regimen.

Falsely low hemoglobin A_1c levels are associated with conditions of more rapid erythrocyte turnover, such as autoimmune hemolytic anemia, hereditary spherocytosis, and acute blood loss anemia. In patients with CKD, recombinant erythropoietin treatment lowers hemoglobin A_1c levels by increasing the number of immature red cells, which are less likely to glycosylate.¹⁹

Morgan et al²⁰ compared the association between hemoglobin A_1c and blood glucose levels in diabetic patients with moderate to severe CKD not requiring dialysis and in diabetic patients with normal renal function and found no difference between these two groups, suggesting that hemoglobin A_1c is reliable in this setting. But study results conflict for patients on dialysis, making the usefulness of hemoglobin A_1c testing for those patients less clear. In one study, hemoglobin A_1c testing underestimated glycemic control,²⁰ but other studies found that glycemic control was overestimated.^21,22

Alternatives to hemoglobin A_1c

Other measures of long-term glycemic control such as fructosamine and glycated albumin levels are sometimes used in conditions in which hemoglobin A_1c may not be reliable.

Albumin also undergoes glycation when exposed to glucose. Glycated albumin appears to be a better measure of glycemic control in patients with CKD and diabetes than serum fructosamine,²³ which has failed to show a significant correlation with blood glucose levels in patients with CKD.²⁴ However, because serum albumin has a short half-life, glycated albumin reflects glycemic control in only the approximately 1 to 2 weeks before sampling,²⁵ so monthly monitoring is required.

Glycated albumin levels may be reduced due to increased albumin turnover in patients with nephrotic-range proteinuria and in diabetic patients on peritoneal dialysis. Several issues remain unclear, such as the appropriate target level of glycated albumin and at what stage of CKD it should replace hemoglobin A_1c testing. If an improved assay that is unaffected by changes in serum albumin becomes available, it may be appropriate to use glycated albumin measurements to assess long-term glycemic control for patients with CKD.

In general, therapeutic decisions to achieve optimum glycemic control in patients with diabetes and CKD should be based on hemoglobin A_1c testing, multiple glucose measurements, and patient symptoms of hypoglycemia or hyperglycemia. The best measure for assessing glycemic control in hospitalized patients with CKD remains multiple blood glucose testing daily.

INSULIN THERAPY PREFERRED

Although several studies have evaluated inpatient glycemic control,^26–29 no guidelines have been published for hospitalized patients with diabetes and CKD. Insulin therapy is preferred for achieving glycemic control in acutely ill or hospitalized patients with diabetes. Oral hypoglycemic agents should be discontinued.

Regardless of the form of insulin chosen to treat diabetes, caution is needed for patients with kidney disease. During hospitalization, clinical changes are expected owing to illness and differences in caloric intake and physical activity, resulting in altered insulin sensitivity. Insulin-treated hospitalized patients require individualized care, including multiple daily blood glucose tests and insulin therapy modifications for ideal glycemic control.

For surgical or medical intensive care patients on insulin therapy, the target blood glucose level before meals should be 140 mg/dL, and the target random level should be less than 180 mg/dL.^15,26–29

Basal-bolus insulin

Sliding-scale therapy should be avoided as the only method for glycemic control. Instead, scheduled subcutaneous basal insulin once or twice daily combined with rapid- or short-acting insulin with meals is recommended.

Basal-bolus insulin therapy, one of the most advanced and flexible insulin replacement therapies, mimics endogenous insulin release and offers great advantages in diabetes care. Using mealtime bolus insulin permits variation in the amount of food eaten; more insulin can be taken with a larger meal and less with smaller meals. A bolus approach offers the flexibility of administering rapid-acting insulin immediately after meals when oral intake is variable.

Individualize insulin therapy

Optimizing glycemic control requires an understanding of the altered pharmacokinetics and pharmacodynamics of insulin in patients with diabetic nephropathy. Table 2 shows the pharmacokinetic profiles of insulin preparations in healthy people. Analogue insulins, which are manufactured by recombinant DNA technology, have conformational changes in the insulin molecule that alter their pharmacokinetics and pharmacodynamics. The rapid-acting analogue insulins are absorbed quickly, making them suitable for postprandial glucose control.

Changes in GFR are associated with altered pharmacokinetics and pharmacodynamics of insulin,^30,31 but unlike for oral antidiabetic agents, these properties are not well characterized for insulin preparations in patients with renal insufficiency.^13,32–36

CKD may reduce insulin clearance. Rave et al³² reported that the clearance of regular human insulin was reduced by 30% to 40% in patients with type 1 diabetes and a mean estimated GFR of 54 mL/min. They found that the metabolic activity of insulin lispro was more robust than that of short-acting regular human insulin in patients with diabetic nephropathy. In another study, patients with diabetes treated with insulin aspart did not show any significant change in the required insulin dosage in relation to the renal filtration rate.³⁴ Biesenbach et al³³ found a 38% reduction in insulin requirements in patients with type 1 diabetes as estimated GFR decreased from 80 mL/min to 10 mL/min. Further studies are required to better understand the safety of insulin in treating hospitalized patients with diabetes and renal insufficiency.

Few studies have compared the pharmacodynamics of long-acting insulins in relation to declining renal function. The long-acting analogue insulins have less of a peak than human insulin and thus better mimic endogenous insulin secretion. For insulin detemir, Lindholm and Jacobsen found no significant differences in the pharmacokinetics related to the stages of CKD.³⁵ When using the long-acting insulins glargine or detemir, one should consider giving much lower doses (half the initial starting dosage) and titrating the dosage until target fasting glucose concentrations are reached to prevent hypoglycemia.

Table 3 summarizes recommended insulin dosage adjustments in CKD based on the literature and our clinical experience.

Considerations for dialysis patients

Subcutaneously administered insulin is eliminated renally, unlike endogenous insulin, which undergoes first-pass metabolism in the liver.^13,37 As renal function declines, insulin clearance decreases and the insulin dosage must be reduced to prevent hypoglycemia.

Patients on hemodialysis or peritoneal dialysis pose a challenge for insulin dosing. Hemodialysis improves insulin sensitivity but also increases insulin clearance, making it difficult to determine insulin requirements. Sobngwi et al³⁸ conducted a study in diabetic patients with end-stage renal disease on hemodialysis, using a 24-hour euglycemic clamp. They found that exogenous basal insulin requirements were 25% lower on the day after hemodialysis compared with the day before, but premeal insulin requirements stayed the same.

Peritoneal dialysis exposes patients to a high glucose load via the peritoneum, which can worsen insulin resistance. Intraperitoneal administration of insulin during peritoneal dialysis provides a more physiologic effect than subcutaneous administration: it prevents fluctuations of blood glucose and the formation of insulin antibodies. But insulin requirements are higher owing to a dilutional effect and to insulin binding to the plastic surface of the dialysis fluid reservoir.³⁹

GLYCEMIC CONTROL FOR PROCEDURES

No guidelines have been established regarding the optimal blood glucose range for diabetic patients with CKD undergoing diagnostic or surgical procedures. Given the risk of hypoglycemia in such settings, less-stringent targets are reasonable, ie, premeal blood glucose levels of 140 mg/dL and random blood glucose levels of less than 180 mg/dL.

Before surgery, consideration should be given to the type of diabetes, surgical procedure, and metabolic control. Patients on insulin detemir or glargine as part of a basal-bolus regimen with rapid-acting insulin may safely be given the full dose of their basal insulin the night before or the morning of their procedure. However, patients on neutral protamine Hagedorn (NPH) insulin as a part of their basal-bolus regimen should receive half of their usual dose due to a difference in pharmacokinetic profile compared with insulin glargine or detemir.

In insulin-treated patients undergoing prolonged procedures (eg, coronary artery bypass grafting, transplant):

• Discontinue subcutaneous insulin and start an intravenous insulin infusion, titrated to maintain a blood glucose range of 140 to 180 mg/dL
• Subcutaneous insulin management may be acceptable for patients undergoing shorter outpatient procedures
• Supplemental subcutaneous doses of short- or rapid-acting insulin preparations can be given for blood glucose elevation greater than 180 mg/dL.

AVOID ORAL AGENTS AND NONINSULIN INJECTABLES

Oral antidiabetic agents and noninsulin injectables (Table 4) should generally be avoided in hospitalized patients, especially for those with decompensated heart failure, renal insufficiency, hypoperfusion, or chronic pulmonary disease, or for those given intravenous contrast. Most oral medications used to treat diabetes are affected by reduced kidney function, resulting in prolonged drug exposure and increased risk of hypoglycemia in patients with moderate to severe CKD (stages 3–5).

Metformin, a biguanide, is contraindicated in patients with high serum creatinine levels (> 1.5 mg/dL in men, > 1.4 mg/dL in women) because of the theoretical risk of lactic acidosis.⁴⁰

Sulfonylurea clearance depends on kidney function.⁴¹ Severe prolonged episodes of hypoglycemia have been reported in dialysis patients taking these drugs, except with glipizide, which carries a lower risk.^41,42

Repaglinide, a nonsulfonylurea insulin secretagogue, can be used in CKD stages 3 to 4 without any dosage adjustment.⁴³

Thiazolidinediones have been reported to slow the progression of diabetic kidney disease independent of glycemic control.⁴⁴ Adverse effects include fluid retention, edema, and congestive heart failure. Thiazolidinediones should not be used in patients with New York Heart Association class 3 or 4 heart failure,⁴⁵ and so should not be prescribed in the hospital except for patients who are clinically stable or ready for discharge.

Quick-release bromocriptine, a dopamine receptor agonist, has been shown to be effective in lowering fasting plasma glucose levels and hemoglobin A_1c, and improving glucose tolerance in obese patients with type 2 diabetes, although its usefulness in hospitalized patients with diabetes is not known.^46,47

Dipeptidyl peptidase inhibitors. Sitagliptin and saxagliptin have been shown to be safe and effective in hospitalized patients with type 2 diabetes.⁴⁸ However, except for linagliptin, dose reduction is recommended in patients with CKD stage 3 and higher.^49–52

GLP-1 receptor agonists. Drugs of this class are potent agents for the reduction of glucose in the outpatient setting but are relatively contraindicated if the GFR is less than 30 mL/min, and they are currently not used in the hospital.

BLOOD GLUCOSE MONITORING IN HOSPITALIZED PATIENTS

Bedside blood glucose monitoring is recommended for all hospitalized patients with known diabetes with or without CKD, those with newly recognized hyperglycemia, and those who receive therapy associated with high risk for hyperglycemia, such as glucocorticoid therapy and enteral and parenteral nutrition. For patients on scheduled diets, fingerstick blood glucose monitoring is recommended before meals and at bedtime. In patients with no oral intake or on continuous enteral or parenteral nutrition, blood glucose monitoring every 4 to 6 hours is recommended. More frequent monitoring (eg, adding a 3:00 am check) may be prudent in patients with CKD.

Continuous glucose monitoring systems use a sensor inserted under the skin and transmit information via radio to a wireless monitor. Such systems are more expensive than conventional glucose monitoring but may enable better glucose control by providing real-time glucose measurements, with levels displayed at 5-minute or 1-minute intervals. Marshall et al⁵³ confirmed this technology’s accuracy and precision in uremic patients on dialysis.

Considerations for peritoneal dialysis

For patients on peritoneal dialysis, glucose in the dialysate exacerbates hyperglycemia. Dialysis solutions with the glucose polymer icodextrin as the osmotic agent instead of glucose have been suggested to reduce glucose exposure.

Glucose monitoring systems measure interstitial fluid glucose by the glucose oxidase reaction and therefore are not affected by icodextrin. However, icodextrin is converted to maltose, a disaccharide composed of two glucose molecules, which can cause spuriously high readings in devices that use test strips containing the enzymes glucose dehydrogenase pyrroloquinoline quinone or glucose dye oxidoreductase. Spurious hyperglycemia may lead to giving too much insulin, in turn leading to symptomatic hypoglycemia.

Clinicians caring for patients receiving icodextrin should ensure that the glucose monitoring system uses only test strips that contain glucose oxidase, glucose dehydrogenase-nicotinamide adenine dinucleotide, or glucose dehydrogenase-flavin adenine dinucleotide, which are not affected by icodextrin.⁵⁴

IMPROVING QUALITY

Hospitalized patients face many barriers to optimal glycemic control. Less experienced practitioners tend to have insufficient knowledge of insulin preparations and appropriate insulin dosing. Also, diabetes is often listed as a secondary diagnosis and so may be overlooked by the inpatient care team.

Educational programs should be instituted to overcome these barriers and improve knowledge related to inpatient diabetes care. When necessary, the appropriate use of consultants is important in hospitalized settings to improve quality and make hospital care more efficient and cost-effective.

No national benchmarks currently exist for inpatient diabetes care, and they need to be developed to ensure best practices. Physicians should take the initiative to remedy this by collaborating with other healthcare providers, such as dedicated diabetes educators, nursing staff, pharmacists, registered dietitians, and physicians with expertise in diabetes management, with the aim of achieving optimum glycemic control and minimizing hypoglycemia. 

Managing glycemic control in hospitalized patients with chronic kidney disease (CKD) and diabetes mellitus is a challenge, with no published guidelines. In this setting, avoiding hypoglycemia takes precedence over meeting strict blood glucose targets. Optimal management is essential to reduce hypoglycemia and the risk of death from cardiovascular disease.¹

This article reviews the evidence to guide diabetes management in hospitalized patients with CKD, focusing on blood glucose monitoring, insulin dosing, and concerns about other diabetic agents.

FOCUS ON AVOIDING HYPOGLYCEMIA

CKD is common, estimated to affect more than 50 million people worldwide.² Diabetes mellitus is the primary cause of kidney failure in 45% of dialysis patients with CKD.

Tight control comes with a cost

Hyperglycemia in hospitalized patients is associated with a higher risk of death, a higher risk of infections, and a longer hospital stay.^3,4 In 2001, Van den Berghe et al⁵ found that intensive insulin therapy reduced the mortality rate in critically ill patients in the surgical intensive care unit. But subsequent studies^6,7 found that intensive insulin therapy to achieve tight glycemic control increased rates of morbidity and mortality without adding clinical benefit.

Randomized clinical trials in outpatients have shown that tight control of blood glucose levels reduces microvascular and macrovascular complications in patients with type 1 diabetes.^8–10 In the Diabetes Control and Complications Trial,⁹ compared with conventional therapy, intensive insulin therapy reduced the incidence of retinopathy progression (4.7 vs 1.2 cases per 100 patient-years, number needed to treat [NNT] = 3 for 10 years) and clinical neuropathy (9.8 vs 3.1 per 100 patient-years, NNT = 1.5 for 10 years). The long-term likelihood of a cardiovascular event was also significantly lower in the intensive treatment group (0.38 vs 0.80 events per 100 patient-years).⁹

Similarly, in the Epidemiology of Diabetes Interventions and Complications follow-up study, the intensive therapy group had fewer cardiovascular deaths.¹¹ On the other hand, the risk of severe hypoglycemia and subsequent coma or seizure was significantly higher in the intensive therapy group than in the conventional therapy group (16.3 vs 5.4 per 100 patient-years).⁸

CKD increases hypoglycemia risk

Moen et al¹² found that the incidence of hypoglycemia was significantly higher in patients with CKD (estimated glomerular filtration rate [GFR] < 60 mL/min) with or without diabetes, and that patients with both conditions were at greatest risk (Figure 1). Multiple factors contribute to the increased risk of hypoglycemia: patients with advanced CKD tend to have poor nutrition, resulting in reduced glycogen stores, and a smaller renal mass reduces renal gluconeogenesis and decreases the elimination of insulin and oral antidiabetic agents.

After the onset of diabetic nephropathy, progression of renal complications and overall life expectancy are influenced by earlier glycemic control.⁸ Development of diabetic nephropathy is commonly accompanied by changes in metabolic control, particularly an increased risk of hypoglycemia.¹³ In addition, episodes of severe hypoglycemia constitute an independent cardiovascular risk factor.¹⁴

Aggressive glycemic control in hospitalized patients, particularly those with advanced CKD, is associated with a risk of hypoglycemia without overall improvement in outcomes.¹⁵ Elderly patients with type 2 diabetes are similar to patients with CKD in that they have a reduced GFR and are thus more sensitive to insulin. In both groups, intensifying glycemic control, especially in the hospital, is associated with more frequent episodes of severe hypoglycemia.¹⁶ The focus should be not only on maintaining optimal blood glucose concentration, but also on preventing hypoglycemia.

‘Burnt-out’ diabetes

Paradoxically, patients with end-stage renal disease and type 2 diabetes often experience altered glucose homeostasis with markedly improved glycemic control. They may attain normoglycemia and normalization of hemoglobin A_1c, a condition known as “burnt-out” diabetes. Its precise mechanism is not understood and its significance remains unclear (Table 1).¹⁷

HEMOGLOBIN A_1c CAN BE FALSELY HIGH OR FALSELY LOW

Hemoglobin A_1c measurement is used to diagnose diabetes and to assess long-term glycemic control. It is a measure of the fraction of hemoglobin that has been glycated by exposure to glucose. Because the average lifespan of a red cell is 120 days, the hemoglobin A_1c value reflects the mean blood glucose concentration over the preceding 3 months.

But hemoglobin A_1c measurement has limitations: any condition that alters the lifespan of erythrocytes leads to higher or lower hemoglobin A_1c levels. Hemoglobin A_1c levels are also affected by kidney dysfunction, hemolysis, and acidosis.¹⁸

Falsely high hemoglobin A_1c levels are associated with conditions that prolong the lifespan of erythrocytes, such as asplenia. Iron deficiency also increases the average age of circulating red cells because of reduced red cell production. For patients in whom blood glucose measurements do not correlate with hemoglobin A_1c measurements, iron deficiency anemia should be considered before altering a treatment regimen.

Falsely low hemoglobin A_1c levels are associated with conditions of more rapid erythrocyte turnover, such as autoimmune hemolytic anemia, hereditary spherocytosis, and acute blood loss anemia. In patients with CKD, recombinant erythropoietin treatment lowers hemoglobin A_1c levels by increasing the number of immature red cells, which are less likely to glycosylate.¹⁹

Morgan et al²⁰ compared the association between hemoglobin A_1c and blood glucose levels in diabetic patients with moderate to severe CKD not requiring dialysis and in diabetic patients with normal renal function and found no difference between these two groups, suggesting that hemoglobin A_1c is reliable in this setting. But study results conflict for patients on dialysis, making the usefulness of hemoglobin A_1c testing for those patients less clear. In one study, hemoglobin A_1c testing underestimated glycemic control,²⁰ but other studies found that glycemic control was overestimated.^21,22

Alternatives to hemoglobin A_1c

Other measures of long-term glycemic control such as fructosamine and glycated albumin levels are sometimes used in conditions in which hemoglobin A_1c may not be reliable.

Albumin also undergoes glycation when exposed to glucose. Glycated albumin appears to be a better measure of glycemic control in patients with CKD and diabetes than serum fructosamine,²³ which has failed to show a significant correlation with blood glucose levels in patients with CKD.²⁴ However, because serum albumin has a short half-life, glycated albumin reflects glycemic control in only the approximately 1 to 2 weeks before sampling,²⁵ so monthly monitoring is required.

Glycated albumin levels may be reduced due to increased albumin turnover in patients with nephrotic-range proteinuria and in diabetic patients on peritoneal dialysis. Several issues remain unclear, such as the appropriate target level of glycated albumin and at what stage of CKD it should replace hemoglobin A_1c testing. If an improved assay that is unaffected by changes in serum albumin becomes available, it may be appropriate to use glycated albumin measurements to assess long-term glycemic control for patients with CKD.

In general, therapeutic decisions to achieve optimum glycemic control in patients with diabetes and CKD should be based on hemoglobin A_1c testing, multiple glucose measurements, and patient symptoms of hypoglycemia or hyperglycemia. The best measure for assessing glycemic control in hospitalized patients with CKD remains multiple blood glucose testing daily.

INSULIN THERAPY PREFERRED

Although several studies have evaluated inpatient glycemic control,^26–29 no guidelines have been published for hospitalized patients with diabetes and CKD. Insulin therapy is preferred for achieving glycemic control in acutely ill or hospitalized patients with diabetes. Oral hypoglycemic agents should be discontinued.

Regardless of the form of insulin chosen to treat diabetes, caution is needed for patients with kidney disease. During hospitalization, clinical changes are expected owing to illness and differences in caloric intake and physical activity, resulting in altered insulin sensitivity. Insulin-treated hospitalized patients require individualized care, including multiple daily blood glucose tests and insulin therapy modifications for ideal glycemic control.

For surgical or medical intensive care patients on insulin therapy, the target blood glucose level before meals should be 140 mg/dL, and the target random level should be less than 180 mg/dL.^15,26–29

Basal-bolus insulin

Sliding-scale therapy should be avoided as the only method for glycemic control. Instead, scheduled subcutaneous basal insulin once or twice daily combined with rapid- or short-acting insulin with meals is recommended.

Basal-bolus insulin therapy, one of the most advanced and flexible insulin replacement therapies, mimics endogenous insulin release and offers great advantages in diabetes care. Using mealtime bolus insulin permits variation in the amount of food eaten; more insulin can be taken with a larger meal and less with smaller meals. A bolus approach offers the flexibility of administering rapid-acting insulin immediately after meals when oral intake is variable.

Individualize insulin therapy

Optimizing glycemic control requires an understanding of the altered pharmacokinetics and pharmacodynamics of insulin in patients with diabetic nephropathy. Table 2 shows the pharmacokinetic profiles of insulin preparations in healthy people. Analogue insulins, which are manufactured by recombinant DNA technology, have conformational changes in the insulin molecule that alter their pharmacokinetics and pharmacodynamics. The rapid-acting analogue insulins are absorbed quickly, making them suitable for postprandial glucose control.

Changes in GFR are associated with altered pharmacokinetics and pharmacodynamics of insulin,^30,31 but unlike for oral antidiabetic agents, these properties are not well characterized for insulin preparations in patients with renal insufficiency.^13,32–36

CKD may reduce insulin clearance. Rave et al³² reported that the clearance of regular human insulin was reduced by 30% to 40% in patients with type 1 diabetes and a mean estimated GFR of 54 mL/min. They found that the metabolic activity of insulin lispro was more robust than that of short-acting regular human insulin in patients with diabetic nephropathy. In another study, patients with diabetes treated with insulin aspart did not show any significant change in the required insulin dosage in relation to the renal filtration rate.³⁴ Biesenbach et al³³ found a 38% reduction in insulin requirements in patients with type 1 diabetes as estimated GFR decreased from 80 mL/min to 10 mL/min. Further studies are required to better understand the safety of insulin in treating hospitalized patients with diabetes and renal insufficiency.

Few studies have compared the pharmacodynamics of long-acting insulins in relation to declining renal function. The long-acting analogue insulins have less of a peak than human insulin and thus better mimic endogenous insulin secretion. For insulin detemir, Lindholm and Jacobsen found no significant differences in the pharmacokinetics related to the stages of CKD.³⁵ When using the long-acting insulins glargine or detemir, one should consider giving much lower doses (half the initial starting dosage) and titrating the dosage until target fasting glucose concentrations are reached to prevent hypoglycemia.

Table 3 summarizes recommended insulin dosage adjustments in CKD based on the literature and our clinical experience.

Considerations for dialysis patients

Subcutaneously administered insulin is eliminated renally, unlike endogenous insulin, which undergoes first-pass metabolism in the liver.^13,37 As renal function declines, insulin clearance decreases and the insulin dosage must be reduced to prevent hypoglycemia.

Patients on hemodialysis or peritoneal dialysis pose a challenge for insulin dosing. Hemodialysis improves insulin sensitivity but also increases insulin clearance, making it difficult to determine insulin requirements. Sobngwi et al³⁸ conducted a study in diabetic patients with end-stage renal disease on hemodialysis, using a 24-hour euglycemic clamp. They found that exogenous basal insulin requirements were 25% lower on the day after hemodialysis compared with the day before, but premeal insulin requirements stayed the same.

Peritoneal dialysis exposes patients to a high glucose load via the peritoneum, which can worsen insulin resistance. Intraperitoneal administration of insulin during peritoneal dialysis provides a more physiologic effect than subcutaneous administration: it prevents fluctuations of blood glucose and the formation of insulin antibodies. But insulin requirements are higher owing to a dilutional effect and to insulin binding to the plastic surface of the dialysis fluid reservoir.³⁹

GLYCEMIC CONTROL FOR PROCEDURES

No guidelines have been established regarding the optimal blood glucose range for diabetic patients with CKD undergoing diagnostic or surgical procedures. Given the risk of hypoglycemia in such settings, less-stringent targets are reasonable, ie, premeal blood glucose levels of 140 mg/dL and random blood glucose levels of less than 180 mg/dL.

Before surgery, consideration should be given to the type of diabetes, surgical procedure, and metabolic control. Patients on insulin detemir or glargine as part of a basal-bolus regimen with rapid-acting insulin may safely be given the full dose of their basal insulin the night before or the morning of their procedure. However, patients on neutral protamine Hagedorn (NPH) insulin as a part of their basal-bolus regimen should receive half of their usual dose due to a difference in pharmacokinetic profile compared with insulin glargine or detemir.

In insulin-treated patients undergoing prolonged procedures (eg, coronary artery bypass grafting, transplant):

• Discontinue subcutaneous insulin and start an intravenous insulin infusion, titrated to maintain a blood glucose range of 140 to 180 mg/dL
• Subcutaneous insulin management may be acceptable for patients undergoing shorter outpatient procedures
• Supplemental subcutaneous doses of short- or rapid-acting insulin preparations can be given for blood glucose elevation greater than 180 mg/dL.

AVOID ORAL AGENTS AND NONINSULIN INJECTABLES

Oral antidiabetic agents and noninsulin injectables (Table 4) should generally be avoided in hospitalized patients, especially for those with decompensated heart failure, renal insufficiency, hypoperfusion, or chronic pulmonary disease, or for those given intravenous contrast. Most oral medications used to treat diabetes are affected by reduced kidney function, resulting in prolonged drug exposure and increased risk of hypoglycemia in patients with moderate to severe CKD (stages 3–5).

Metformin, a biguanide, is contraindicated in patients with high serum creatinine levels (> 1.5 mg/dL in men, > 1.4 mg/dL in women) because of the theoretical risk of lactic acidosis.⁴⁰

Sulfonylurea clearance depends on kidney function.⁴¹ Severe prolonged episodes of hypoglycemia have been reported in dialysis patients taking these drugs, except with glipizide, which carries a lower risk.^41,42

Repaglinide, a nonsulfonylurea insulin secretagogue, can be used in CKD stages 3 to 4 without any dosage adjustment.⁴³

Thiazolidinediones have been reported to slow the progression of diabetic kidney disease independent of glycemic control.⁴⁴ Adverse effects include fluid retention, edema, and congestive heart failure. Thiazolidinediones should not be used in patients with New York Heart Association class 3 or 4 heart failure,⁴⁵ and so should not be prescribed in the hospital except for patients who are clinically stable or ready for discharge.

Quick-release bromocriptine, a dopamine receptor agonist, has been shown to be effective in lowering fasting plasma glucose levels and hemoglobin A_1c, and improving glucose tolerance in obese patients with type 2 diabetes, although its usefulness in hospitalized patients with diabetes is not known.^46,47

Dipeptidyl peptidase inhibitors. Sitagliptin and saxagliptin have been shown to be safe and effective in hospitalized patients with type 2 diabetes.⁴⁸ However, except for linagliptin, dose reduction is recommended in patients with CKD stage 3 and higher.^49–52

GLP-1 receptor agonists. Drugs of this class are potent agents for the reduction of glucose in the outpatient setting but are relatively contraindicated if the GFR is less than 30 mL/min, and they are currently not used in the hospital.

BLOOD GLUCOSE MONITORING IN HOSPITALIZED PATIENTS

Bedside blood glucose monitoring is recommended for all hospitalized patients with known diabetes with or without CKD, those with newly recognized hyperglycemia, and those who receive therapy associated with high risk for hyperglycemia, such as glucocorticoid therapy and enteral and parenteral nutrition. For patients on scheduled diets, fingerstick blood glucose monitoring is recommended before meals and at bedtime. In patients with no oral intake or on continuous enteral or parenteral nutrition, blood glucose monitoring every 4 to 6 hours is recommended. More frequent monitoring (eg, adding a 3:00 am check) may be prudent in patients with CKD.

Continuous glucose monitoring systems use a sensor inserted under the skin and transmit information via radio to a wireless monitor. Such systems are more expensive than conventional glucose monitoring but may enable better glucose control by providing real-time glucose measurements, with levels displayed at 5-minute or 1-minute intervals. Marshall et al⁵³ confirmed this technology’s accuracy and precision in uremic patients on dialysis.

Considerations for peritoneal dialysis

For patients on peritoneal dialysis, glucose in the dialysate exacerbates hyperglycemia. Dialysis solutions with the glucose polymer icodextrin as the osmotic agent instead of glucose have been suggested to reduce glucose exposure.

Glucose monitoring systems measure interstitial fluid glucose by the glucose oxidase reaction and therefore are not affected by icodextrin. However, icodextrin is converted to maltose, a disaccharide composed of two glucose molecules, which can cause spuriously high readings in devices that use test strips containing the enzymes glucose dehydrogenase pyrroloquinoline quinone or glucose dye oxidoreductase. Spurious hyperglycemia may lead to giving too much insulin, in turn leading to symptomatic hypoglycemia.

Clinicians caring for patients receiving icodextrin should ensure that the glucose monitoring system uses only test strips that contain glucose oxidase, glucose dehydrogenase-nicotinamide adenine dinucleotide, or glucose dehydrogenase-flavin adenine dinucleotide, which are not affected by icodextrin.⁵⁴

IMPROVING QUALITY

Hospitalized patients face many barriers to optimal glycemic control. Less experienced practitioners tend to have insufficient knowledge of insulin preparations and appropriate insulin dosing. Also, diabetes is often listed as a secondary diagnosis and so may be overlooked by the inpatient care team.

Educational programs should be instituted to overcome these barriers and improve knowledge related to inpatient diabetes care. When necessary, the appropriate use of consultants is important in hospitalized settings to improve quality and make hospital care more efficient and cost-effective.

No national benchmarks currently exist for inpatient diabetes care, and they need to be developed to ensure best practices. Physicians should take the initiative to remedy this by collaborating with other healthcare providers, such as dedicated diabetes educators, nursing staff, pharmacists, registered dietitians, and physicians with expertise in diabetes management, with the aim of achieving optimum glycemic control and minimizing hypoglycemia. 

Managing glycemic control in hospitalized patients with chronic kidney disease (CKD) and diabetes mellitus is a challenge, with no published guidelines. In this setting, avoiding hypoglycemia takes precedence over meeting strict blood glucose targets. Optimal management is essential to reduce hypoglycemia and the risk of death from cardiovascular disease.¹

This article reviews the evidence to guide diabetes management in hospitalized patients with CKD, focusing on blood glucose monitoring, insulin dosing, and concerns about other diabetic agents.

FOCUS ON AVOIDING HYPOGLYCEMIA

CKD is common, estimated to affect more than 50 million people worldwide.² Diabetes mellitus is the primary cause of kidney failure in 45% of dialysis patients with CKD.

Tight control comes with a cost

Hyperglycemia in hospitalized patients is associated with a higher risk of death, a higher risk of infections, and a longer hospital stay.^3,4 In 2001, Van den Berghe et al⁵ found that intensive insulin therapy reduced the mortality rate in critically ill patients in the surgical intensive care unit. But subsequent studies^6,7 found that intensive insulin therapy to achieve tight glycemic control increased rates of morbidity and mortality without adding clinical benefit.

Randomized clinical trials in outpatients have shown that tight control of blood glucose levels reduces microvascular and macrovascular complications in patients with type 1 diabetes.^8–10 In the Diabetes Control and Complications Trial,⁹ compared with conventional therapy, intensive insulin therapy reduced the incidence of retinopathy progression (4.7 vs 1.2 cases per 100 patient-years, number needed to treat [NNT] = 3 for 10 years) and clinical neuropathy (9.8 vs 3.1 per 100 patient-years, NNT = 1.5 for 10 years). The long-term likelihood of a cardiovascular event was also significantly lower in the intensive treatment group (0.38 vs 0.80 events per 100 patient-years).⁹

Similarly, in the Epidemiology of Diabetes Interventions and Complications follow-up study, the intensive therapy group had fewer cardiovascular deaths.¹¹ On the other hand, the risk of severe hypoglycemia and subsequent coma or seizure was significantly higher in the intensive therapy group than in the conventional therapy group (16.3 vs 5.4 per 100 patient-years).⁸

CKD increases hypoglycemia risk

Moen et al¹² found that the incidence of hypoglycemia was significantly higher in patients with CKD (estimated glomerular filtration rate [GFR] < 60 mL/min) with or without diabetes, and that patients with both conditions were at greatest risk (Figure 1). Multiple factors contribute to the increased risk of hypoglycemia: patients with advanced CKD tend to have poor nutrition, resulting in reduced glycogen stores, and a smaller renal mass reduces renal gluconeogenesis and decreases the elimination of insulin and oral antidiabetic agents.

After the onset of diabetic nephropathy, progression of renal complications and overall life expectancy are influenced by earlier glycemic control.⁸ Development of diabetic nephropathy is commonly accompanied by changes in metabolic control, particularly an increased risk of hypoglycemia.¹³ In addition, episodes of severe hypoglycemia constitute an independent cardiovascular risk factor.¹⁴

Aggressive glycemic control in hospitalized patients, particularly those with advanced CKD, is associated with a risk of hypoglycemia without overall improvement in outcomes.¹⁵ Elderly patients with type 2 diabetes are similar to patients with CKD in that they have a reduced GFR and are thus more sensitive to insulin. In both groups, intensifying glycemic control, especially in the hospital, is associated with more frequent episodes of severe hypoglycemia.¹⁶ The focus should be not only on maintaining optimal blood glucose concentration, but also on preventing hypoglycemia.

‘Burnt-out’ diabetes

Paradoxically, patients with end-stage renal disease and type 2 diabetes often experience altered glucose homeostasis with markedly improved glycemic control. They may attain normoglycemia and normalization of hemoglobin A_1c, a condition known as “burnt-out” diabetes. Its precise mechanism is not understood and its significance remains unclear (Table 1).¹⁷

HEMOGLOBIN A_1c CAN BE FALSELY HIGH OR FALSELY LOW

Hemoglobin A_1c measurement is used to diagnose diabetes and to assess long-term glycemic control. It is a measure of the fraction of hemoglobin that has been glycated by exposure to glucose. Because the average lifespan of a red cell is 120 days, the hemoglobin A_1c value reflects the mean blood glucose concentration over the preceding 3 months.

But hemoglobin A_1c measurement has limitations: any condition that alters the lifespan of erythrocytes leads to higher or lower hemoglobin A_1c levels. Hemoglobin A_1c levels are also affected by kidney dysfunction, hemolysis, and acidosis.¹⁸

Falsely high hemoglobin A_1c levels are associated with conditions that prolong the lifespan of erythrocytes, such as asplenia. Iron deficiency also increases the average age of circulating red cells because of reduced red cell production. For patients in whom blood glucose measurements do not correlate with hemoglobin A_1c measurements, iron deficiency anemia should be considered before altering a treatment regimen.

Falsely low hemoglobin A_1c levels are associated with conditions of more rapid erythrocyte turnover, such as autoimmune hemolytic anemia, hereditary spherocytosis, and acute blood loss anemia. In patients with CKD, recombinant erythropoietin treatment lowers hemoglobin A_1c levels by increasing the number of immature red cells, which are less likely to glycosylate.¹⁹

Morgan et al²⁰ compared the association between hemoglobin A_1c and blood glucose levels in diabetic patients with moderate to severe CKD not requiring dialysis and in diabetic patients with normal renal function and found no difference between these two groups, suggesting that hemoglobin A_1c is reliable in this setting. But study results conflict for patients on dialysis, making the usefulness of hemoglobin A_1c testing for those patients less clear. In one study, hemoglobin A_1c testing underestimated glycemic control,²⁰ but other studies found that glycemic control was overestimated.^21,22

Alternatives to hemoglobin A_1c

Other measures of long-term glycemic control such as fructosamine and glycated albumin levels are sometimes used in conditions in which hemoglobin A_1c may not be reliable.

Albumin also undergoes glycation when exposed to glucose. Glycated albumin appears to be a better measure of glycemic control in patients with CKD and diabetes than serum fructosamine,²³ which has failed to show a significant correlation with blood glucose levels in patients with CKD.²⁴ However, because serum albumin has a short half-life, glycated albumin reflects glycemic control in only the approximately 1 to 2 weeks before sampling,²⁵ so monthly monitoring is required.

Glycated albumin levels may be reduced due to increased albumin turnover in patients with nephrotic-range proteinuria and in diabetic patients on peritoneal dialysis. Several issues remain unclear, such as the appropriate target level of glycated albumin and at what stage of CKD it should replace hemoglobin A_1c testing. If an improved assay that is unaffected by changes in serum albumin becomes available, it may be appropriate to use glycated albumin measurements to assess long-term glycemic control for patients with CKD.

In general, therapeutic decisions to achieve optimum glycemic control in patients with diabetes and CKD should be based on hemoglobin A_1c testing, multiple glucose measurements, and patient symptoms of hypoglycemia or hyperglycemia. The best measure for assessing glycemic control in hospitalized patients with CKD remains multiple blood glucose testing daily.

INSULIN THERAPY PREFERRED

Although several studies have evaluated inpatient glycemic control,^26–29 no guidelines have been published for hospitalized patients with diabetes and CKD. Insulin therapy is preferred for achieving glycemic control in acutely ill or hospitalized patients with diabetes. Oral hypoglycemic agents should be discontinued.

Regardless of the form of insulin chosen to treat diabetes, caution is needed for patients with kidney disease. During hospitalization, clinical changes are expected owing to illness and differences in caloric intake and physical activity, resulting in altered insulin sensitivity. Insulin-treated hospitalized patients require individualized care, including multiple daily blood glucose tests and insulin therapy modifications for ideal glycemic control.

For surgical or medical intensive care patients on insulin therapy, the target blood glucose level before meals should be 140 mg/dL, and the target random level should be less than 180 mg/dL.^15,26–29

Basal-bolus insulin

Sliding-scale therapy should be avoided as the only method for glycemic control. Instead, scheduled subcutaneous basal insulin once or twice daily combined with rapid- or short-acting insulin with meals is recommended.

Basal-bolus insulin therapy, one of the most advanced and flexible insulin replacement therapies, mimics endogenous insulin release and offers great advantages in diabetes care. Using mealtime bolus insulin permits variation in the amount of food eaten; more insulin can be taken with a larger meal and less with smaller meals. A bolus approach offers the flexibility of administering rapid-acting insulin immediately after meals when oral intake is variable.

Individualize insulin therapy

Optimizing glycemic control requires an understanding of the altered pharmacokinetics and pharmacodynamics of insulin in patients with diabetic nephropathy. Table 2 shows the pharmacokinetic profiles of insulin preparations in healthy people. Analogue insulins, which are manufactured by recombinant DNA technology, have conformational changes in the insulin molecule that alter their pharmacokinetics and pharmacodynamics. The rapid-acting analogue insulins are absorbed quickly, making them suitable for postprandial glucose control.

Changes in GFR are associated with altered pharmacokinetics and pharmacodynamics of insulin,^30,31 but unlike for oral antidiabetic agents, these properties are not well characterized for insulin preparations in patients with renal insufficiency.^13,32–36

CKD may reduce insulin clearance. Rave et al³² reported that the clearance of regular human insulin was reduced by 30% to 40% in patients with type 1 diabetes and a mean estimated GFR of 54 mL/min. They found that the metabolic activity of insulin lispro was more robust than that of short-acting regular human insulin in patients with diabetic nephropathy. In another study, patients with diabetes treated with insulin aspart did not show any significant change in the required insulin dosage in relation to the renal filtration rate.³⁴ Biesenbach et al³³ found a 38% reduction in insulin requirements in patients with type 1 diabetes as estimated GFR decreased from 80 mL/min to 10 mL/min. Further studies are required to better understand the safety of insulin in treating hospitalized patients with diabetes and renal insufficiency.

Few studies have compared the pharmacodynamics of long-acting insulins in relation to declining renal function. The long-acting analogue insulins have less of a peak than human insulin and thus better mimic endogenous insulin secretion. For insulin detemir, Lindholm and Jacobsen found no significant differences in the pharmacokinetics related to the stages of CKD.³⁵ When using the long-acting insulins glargine or detemir, one should consider giving much lower doses (half the initial starting dosage) and titrating the dosage until target fasting glucose concentrations are reached to prevent hypoglycemia.

Table 3 summarizes recommended insulin dosage adjustments in CKD based on the literature and our clinical experience.

Considerations for dialysis patients

Subcutaneously administered insulin is eliminated renally, unlike endogenous insulin, which undergoes first-pass metabolism in the liver.^13,37 As renal function declines, insulin clearance decreases and the insulin dosage must be reduced to prevent hypoglycemia.

Patients on hemodialysis or peritoneal dialysis pose a challenge for insulin dosing. Hemodialysis improves insulin sensitivity but also increases insulin clearance, making it difficult to determine insulin requirements. Sobngwi et al³⁸ conducted a study in diabetic patients with end-stage renal disease on hemodialysis, using a 24-hour euglycemic clamp. They found that exogenous basal insulin requirements were 25% lower on the day after hemodialysis compared with the day before, but premeal insulin requirements stayed the same.

Peritoneal dialysis exposes patients to a high glucose load via the peritoneum, which can worsen insulin resistance. Intraperitoneal administration of insulin during peritoneal dialysis provides a more physiologic effect than subcutaneous administration: it prevents fluctuations of blood glucose and the formation of insulin antibodies. But insulin requirements are higher owing to a dilutional effect and to insulin binding to the plastic surface of the dialysis fluid reservoir.³⁹

GLYCEMIC CONTROL FOR PROCEDURES

No guidelines have been established regarding the optimal blood glucose range for diabetic patients with CKD undergoing diagnostic or surgical procedures. Given the risk of hypoglycemia in such settings, less-stringent targets are reasonable, ie, premeal blood glucose levels of 140 mg/dL and random blood glucose levels of less than 180 mg/dL.

Before surgery, consideration should be given to the type of diabetes, surgical procedure, and metabolic control. Patients on insulin detemir or glargine as part of a basal-bolus regimen with rapid-acting insulin may safely be given the full dose of their basal insulin the night before or the morning of their procedure. However, patients on neutral protamine Hagedorn (NPH) insulin as a part of their basal-bolus regimen should receive half of their usual dose due to a difference in pharmacokinetic profile compared with insulin glargine or detemir.

In insulin-treated patients undergoing prolonged procedures (eg, coronary artery bypass grafting, transplant):

• Discontinue subcutaneous insulin and start an intravenous insulin infusion, titrated to maintain a blood glucose range of 140 to 180 mg/dL
• Subcutaneous insulin management may be acceptable for patients undergoing shorter outpatient procedures
• Supplemental subcutaneous doses of short- or rapid-acting insulin preparations can be given for blood glucose elevation greater than 180 mg/dL.

AVOID ORAL AGENTS AND NONINSULIN INJECTABLES

Oral antidiabetic agents and noninsulin injectables (Table 4) should generally be avoided in hospitalized patients, especially for those with decompensated heart failure, renal insufficiency, hypoperfusion, or chronic pulmonary disease, or for those given intravenous contrast. Most oral medications used to treat diabetes are affected by reduced kidney function, resulting in prolonged drug exposure and increased risk of hypoglycemia in patients with moderate to severe CKD (stages 3–5).

Metformin, a biguanide, is contraindicated in patients with high serum creatinine levels (> 1.5 mg/dL in men, > 1.4 mg/dL in women) because of the theoretical risk of lactic acidosis.⁴⁰

Sulfonylurea clearance depends on kidney function.⁴¹ Severe prolonged episodes of hypoglycemia have been reported in dialysis patients taking these drugs, except with glipizide, which carries a lower risk.^41,42

Repaglinide, a nonsulfonylurea insulin secretagogue, can be used in CKD stages 3 to 4 without any dosage adjustment.⁴³

Thiazolidinediones have been reported to slow the progression of diabetic kidney disease independent of glycemic control.⁴⁴ Adverse effects include fluid retention, edema, and congestive heart failure. Thiazolidinediones should not be used in patients with New York Heart Association class 3 or 4 heart failure,⁴⁵ and so should not be prescribed in the hospital except for patients who are clinically stable or ready for discharge.

Quick-release bromocriptine, a dopamine receptor agonist, has been shown to be effective in lowering fasting plasma glucose levels and hemoglobin A_1c, and improving glucose tolerance in obese patients with type 2 diabetes, although its usefulness in hospitalized patients with diabetes is not known.^46,47

Dipeptidyl peptidase inhibitors. Sitagliptin and saxagliptin have been shown to be safe and effective in hospitalized patients with type 2 diabetes.⁴⁸ However, except for linagliptin, dose reduction is recommended in patients with CKD stage 3 and higher.^49–52

GLP-1 receptor agonists. Drugs of this class are potent agents for the reduction of glucose in the outpatient setting but are relatively contraindicated if the GFR is less than 30 mL/min, and they are currently not used in the hospital.

BLOOD GLUCOSE MONITORING IN HOSPITALIZED PATIENTS

Bedside blood glucose monitoring is recommended for all hospitalized patients with known diabetes with or without CKD, those with newly recognized hyperglycemia, and those who receive therapy associated with high risk for hyperglycemia, such as glucocorticoid therapy and enteral and parenteral nutrition. For patients on scheduled diets, fingerstick blood glucose monitoring is recommended before meals and at bedtime. In patients with no oral intake or on continuous enteral or parenteral nutrition, blood glucose monitoring every 4 to 6 hours is recommended. More frequent monitoring (eg, adding a 3:00 am check) may be prudent in patients with CKD.

Continuous glucose monitoring systems use a sensor inserted under the skin and transmit information via radio to a wireless monitor. Such systems are more expensive than conventional glucose monitoring but may enable better glucose control by providing real-time glucose measurements, with levels displayed at 5-minute or 1-minute intervals. Marshall et al⁵³ confirmed this technology’s accuracy and precision in uremic patients on dialysis.

Considerations for peritoneal dialysis

For patients on peritoneal dialysis, glucose in the dialysate exacerbates hyperglycemia. Dialysis solutions with the glucose polymer icodextrin as the osmotic agent instead of glucose have been suggested to reduce glucose exposure.

Glucose monitoring systems measure interstitial fluid glucose by the glucose oxidase reaction and therefore are not affected by icodextrin. However, icodextrin is converted to maltose, a disaccharide composed of two glucose molecules, which can cause spuriously high readings in devices that use test strips containing the enzymes glucose dehydrogenase pyrroloquinoline quinone or glucose dye oxidoreductase. Spurious hyperglycemia may lead to giving too much insulin, in turn leading to symptomatic hypoglycemia.

Clinicians caring for patients receiving icodextrin should ensure that the glucose monitoring system uses only test strips that contain glucose oxidase, glucose dehydrogenase-nicotinamide adenine dinucleotide, or glucose dehydrogenase-flavin adenine dinucleotide, which are not affected by icodextrin.⁵⁴

IMPROVING QUALITY

Hospitalized patients face many barriers to optimal glycemic control. Less experienced practitioners tend to have insufficient knowledge of insulin preparations and appropriate insulin dosing. Also, diabetes is often listed as a secondary diagnosis and so may be overlooked by the inpatient care team.

Educational programs should be instituted to overcome these barriers and improve knowledge related to inpatient diabetes care. When necessary, the appropriate use of consultants is important in hospitalized settings to improve quality and make hospital care more efficient and cost-effective.

No national benchmarks currently exist for inpatient diabetes care, and they need to be developed to ensure best practices. Physicians should take the initiative to remedy this by collaborating with other healthcare providers, such as dedicated diabetes educators, nursing staff, pharmacists, registered dietitians, and physicians with expertise in diabetes management, with the aim of achieving optimum glycemic control and minimizing hypoglycemia.