John Timmerman, MD

Photo courtesy of UCLA

LUGANO—The PD-1 checkpoint inhibitor nivolumab produces rapid, durable, and, in some cases, “dramatic” responses in Hodgkin lymphoma (HL), according to a speaker at the 13th International Congress on Malignant Lymphoma.

The drug has also produced durable responses in follicular lymphoma (FL), cutaneous T-cell lymphoma (CTCL), and peripheral T-cell lymphoma (PTCL), although patient numbers for these malignancies are small.

John Timmerman, MD, of the University of California, Los Angeles, presented these results from a phase 1 study of patients with relapsed or refractory lymphoid malignancies and chronic HL (abstract 010).

Bristol-Myers Squibb and Ono Pharmaceutical Company are sponsors of the trial.

Original results of the study, with a data cutoff of June 2014, were reported at ASH 2014, with 40 weeks of median follow-up.

The update presented at 13-ICML, with a data lock in April 2015, includes an additional 10 months of data, for a median follow-up of 76 weeks.

Investigators enrolled 105 patients in this dose-escalation study to receive nivolumab at 1 mg/kg, then 3 mg/kg, every 2 weeks for 2 years.

Twenty-three patients had HL. Thirty-one had B-cell non-Hodgkin lymphoma (NHL), including 11 with FL and 10 with diffuse large B-cell lymphoma (DLBCL).

Twenty-three patients had T-cell NHL, including 5 with PTCL and 13 with CTCL/mycosis fungoides (MF). Twenty-seven patients had multiple myeloma (MM), and 1 had chronic myeloid leukemia.

Patients were heavily pretreated. Seventy-eight percent of HL patients and 26% of T-NHL patients had prior brentuximab vedotin. And 78% (HL), 14% (B-NHL), 9% (T-NHL), and 56% (MM) of patients had a prior autologous transplant.

The median number of prior therapies was 5 (range, 2-15) for HL patients and ranged from 1 to 16 for all patients.

The study’s primary endpoint was safety and tolerability, and the secondary endpoint was efficacy.

Safety and tolerability

Ninety-seven percent of patients had an adverse event, 69% of them related to study treatment and 21% of them treatment-related grade 3-4 events.

Fifteen patients (14%) discontinued treatment due to a related adverse event, including 3 with pneumonitis and 1 each with enteritis, stomatitis, pancreatitis, rash, conjunctivitis, sepsis, diplopia, myositis, neutropenia, myelodysplastic syndrome, increased creatinine phosphokinase, and peripheral neuropathy.

“Immune-related adverse events were generally seen early on and generally of low grade,” Dr Timmerman said. “However, it is notable that there were several grade 3 immune-related adverse events that can be seen as far as 6 months out after the start of therapy.”

These included skin, gastrointestinal, and pulmonary events. Most immune-related adverse events (83%) were resolved using protocol-prescribed procedures.

Efficacy

The overall response rate was 87% for HL, 36% for DLBCL, 40% for FL, 15% for CTCL/MF, 40% for PTCL, and 4% for MM.

Dr Timmerman pointed out that, since ASH, 2 additional conversions from partial response (PR) to complete response (CR) occurred in patients with HL. To date, 6 of 23 HL patients have achieved a CR and 14 a PR.

In B-cell NHL, there were additional conversions from PR to CR in DLBCL, while responses remained the same in FL and in the 4 responders with T-cell lymphomas.

“Intriguingly, there has been 1 late CR in the multiple myeloma cohort, which previously had shown no responses,” Dr Timmerman said.

Durability of response

This study suggests PD-1 blockade can produce durable responses in hematologic malignancies, as it does in melanoma and renal cell carcinoma.

In HL, the median response duration at a median follow-up of 86 weeks has not yet been reached, and half (n=10) of the responses are still ongoing.

In FL, CTCL, and PTCL, the median response duration has not been reached at a median follow-up of 81, 43, and 31 weeks, respectively. Of note, there are ongoing responses in at least half of patients in these tumor types.

In HL, none of the 6 patients in CR has progressed, although there have been some progressions in the PR group.

The rapidity of responses is also notable, Dr Timmerman said.

“[I]t’s very interesting that some patients have resolution of symptoms and improvement of symptoms within even 1 day of starting nivolumab therapy,” he said.

And responses to nivolumab in HL “can be very dramatic,” he added, as illustrated in the following case from the Mayo Clinic.

A patient with multiple sites of bulky FDG-avid tumors was scheduled to enter hospice. But first, he entered the nivolumab trial. Within 6 weeks of initiating treatment, he had achieved a near-CR. This response has been maintained for 2 years.

“The occurrence of very durable responses in the PR and CR groups has led us to question whether patients should go on to allogeneic stem cell transplantation after achieving responses with nivolumab or, rather, continue on nivolumab as long as their response remains,” Dr Timmerman said.

He added that an international, phase 2 trial in HL is underway and is accruing briskly.

Nivolumab was awarded breakthrough designation by the US Food and Drug Administration last year. Breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.

John Timmerman, MD

Photo courtesy of UCLA

LUGANO—The PD-1 checkpoint inhibitor nivolumab produces rapid, durable, and, in some cases, “dramatic” responses in Hodgkin lymphoma (HL), according to a speaker at the 13th International Congress on Malignant Lymphoma.

The drug has also produced durable responses in follicular lymphoma (FL), cutaneous T-cell lymphoma (CTCL), and peripheral T-cell lymphoma (PTCL), although patient numbers for these malignancies are small.

John Timmerman, MD, of the University of California, Los Angeles, presented these results from a phase 1 study of patients with relapsed or refractory lymphoid malignancies and chronic HL (abstract 010).

Bristol-Myers Squibb and Ono Pharmaceutical Company are sponsors of the trial.

Original results of the study, with a data cutoff of June 2014, were reported at ASH 2014, with 40 weeks of median follow-up.

The update presented at 13-ICML, with a data lock in April 2015, includes an additional 10 months of data, for a median follow-up of 76 weeks.

Investigators enrolled 105 patients in this dose-escalation study to receive nivolumab at 1 mg/kg, then 3 mg/kg, every 2 weeks for 2 years.

Twenty-three patients had HL. Thirty-one had B-cell non-Hodgkin lymphoma (NHL), including 11 with FL and 10 with diffuse large B-cell lymphoma (DLBCL).

Twenty-three patients had T-cell NHL, including 5 with PTCL and 13 with CTCL/mycosis fungoides (MF). Twenty-seven patients had multiple myeloma (MM), and 1 had chronic myeloid leukemia.

Patients were heavily pretreated. Seventy-eight percent of HL patients and 26% of T-NHL patients had prior brentuximab vedotin. And 78% (HL), 14% (B-NHL), 9% (T-NHL), and 56% (MM) of patients had a prior autologous transplant.

The median number of prior therapies was 5 (range, 2-15) for HL patients and ranged from 1 to 16 for all patients.

The study’s primary endpoint was safety and tolerability, and the secondary endpoint was efficacy.

Safety and tolerability

Ninety-seven percent of patients had an adverse event, 69% of them related to study treatment and 21% of them treatment-related grade 3-4 events.

Fifteen patients (14%) discontinued treatment due to a related adverse event, including 3 with pneumonitis and 1 each with enteritis, stomatitis, pancreatitis, rash, conjunctivitis, sepsis, diplopia, myositis, neutropenia, myelodysplastic syndrome, increased creatinine phosphokinase, and peripheral neuropathy.

“Immune-related adverse events were generally seen early on and generally of low grade,” Dr Timmerman said. “However, it is notable that there were several grade 3 immune-related adverse events that can be seen as far as 6 months out after the start of therapy.”

These included skin, gastrointestinal, and pulmonary events. Most immune-related adverse events (83%) were resolved using protocol-prescribed procedures.

Efficacy

The overall response rate was 87% for HL, 36% for DLBCL, 40% for FL, 15% for CTCL/MF, 40% for PTCL, and 4% for MM.

Dr Timmerman pointed out that, since ASH, 2 additional conversions from partial response (PR) to complete response (CR) occurred in patients with HL. To date, 6 of 23 HL patients have achieved a CR and 14 a PR.

In B-cell NHL, there were additional conversions from PR to CR in DLBCL, while responses remained the same in FL and in the 4 responders with T-cell lymphomas.

“Intriguingly, there has been 1 late CR in the multiple myeloma cohort, which previously had shown no responses,” Dr Timmerman said.

Durability of response

This study suggests PD-1 blockade can produce durable responses in hematologic malignancies, as it does in melanoma and renal cell carcinoma.

In HL, the median response duration at a median follow-up of 86 weeks has not yet been reached, and half (n=10) of the responses are still ongoing.

In FL, CTCL, and PTCL, the median response duration has not been reached at a median follow-up of 81, 43, and 31 weeks, respectively. Of note, there are ongoing responses in at least half of patients in these tumor types.

In HL, none of the 6 patients in CR has progressed, although there have been some progressions in the PR group.

The rapidity of responses is also notable, Dr Timmerman said.

“[I]t’s very interesting that some patients have resolution of symptoms and improvement of symptoms within even 1 day of starting nivolumab therapy,” he said.

And responses to nivolumab in HL “can be very dramatic,” he added, as illustrated in the following case from the Mayo Clinic.

A patient with multiple sites of bulky FDG-avid tumors was scheduled to enter hospice. But first, he entered the nivolumab trial. Within 6 weeks of initiating treatment, he had achieved a near-CR. This response has been maintained for 2 years.

“The occurrence of very durable responses in the PR and CR groups has led us to question whether patients should go on to allogeneic stem cell transplantation after achieving responses with nivolumab or, rather, continue on nivolumab as long as their response remains,” Dr Timmerman said.

He added that an international, phase 2 trial in HL is underway and is accruing briskly.

Nivolumab was awarded breakthrough designation by the US Food and Drug Administration last year. Breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.

John Timmerman, MD

Photo courtesy of UCLA

LUGANO—The PD-1 checkpoint inhibitor nivolumab produces rapid, durable, and, in some cases, “dramatic” responses in Hodgkin lymphoma (HL), according to a speaker at the 13th International Congress on Malignant Lymphoma.

The drug has also produced durable responses in follicular lymphoma (FL), cutaneous T-cell lymphoma (CTCL), and peripheral T-cell lymphoma (PTCL), although patient numbers for these malignancies are small.

John Timmerman, MD, of the University of California, Los Angeles, presented these results from a phase 1 study of patients with relapsed or refractory lymphoid malignancies and chronic HL (abstract 010).

Bristol-Myers Squibb and Ono Pharmaceutical Company are sponsors of the trial.

Original results of the study, with a data cutoff of June 2014, were reported at ASH 2014, with 40 weeks of median follow-up.

The update presented at 13-ICML, with a data lock in April 2015, includes an additional 10 months of data, for a median follow-up of 76 weeks.

Investigators enrolled 105 patients in this dose-escalation study to receive nivolumab at 1 mg/kg, then 3 mg/kg, every 2 weeks for 2 years.

Twenty-three patients had HL. Thirty-one had B-cell non-Hodgkin lymphoma (NHL), including 11 with FL and 10 with diffuse large B-cell lymphoma (DLBCL).

Twenty-three patients had T-cell NHL, including 5 with PTCL and 13 with CTCL/mycosis fungoides (MF). Twenty-seven patients had multiple myeloma (MM), and 1 had chronic myeloid leukemia.

Patients were heavily pretreated. Seventy-eight percent of HL patients and 26% of T-NHL patients had prior brentuximab vedotin. And 78% (HL), 14% (B-NHL), 9% (T-NHL), and 56% (MM) of patients had a prior autologous transplant.

The median number of prior therapies was 5 (range, 2-15) for HL patients and ranged from 1 to 16 for all patients.

The study’s primary endpoint was safety and tolerability, and the secondary endpoint was efficacy.

Safety and tolerability

Ninety-seven percent of patients had an adverse event, 69% of them related to study treatment and 21% of them treatment-related grade 3-4 events.

Fifteen patients (14%) discontinued treatment due to a related adverse event, including 3 with pneumonitis and 1 each with enteritis, stomatitis, pancreatitis, rash, conjunctivitis, sepsis, diplopia, myositis, neutropenia, myelodysplastic syndrome, increased creatinine phosphokinase, and peripheral neuropathy.

“Immune-related adverse events were generally seen early on and generally of low grade,” Dr Timmerman said. “However, it is notable that there were several grade 3 immune-related adverse events that can be seen as far as 6 months out after the start of therapy.”

These included skin, gastrointestinal, and pulmonary events. Most immune-related adverse events (83%) were resolved using protocol-prescribed procedures.

Efficacy

The overall response rate was 87% for HL, 36% for DLBCL, 40% for FL, 15% for CTCL/MF, 40% for PTCL, and 4% for MM.

Dr Timmerman pointed out that, since ASH, 2 additional conversions from partial response (PR) to complete response (CR) occurred in patients with HL. To date, 6 of 23 HL patients have achieved a CR and 14 a PR.

In B-cell NHL, there were additional conversions from PR to CR in DLBCL, while responses remained the same in FL and in the 4 responders with T-cell lymphomas.

“Intriguingly, there has been 1 late CR in the multiple myeloma cohort, which previously had shown no responses,” Dr Timmerman said.

Durability of response

This study suggests PD-1 blockade can produce durable responses in hematologic malignancies, as it does in melanoma and renal cell carcinoma.

In HL, the median response duration at a median follow-up of 86 weeks has not yet been reached, and half (n=10) of the responses are still ongoing.

In FL, CTCL, and PTCL, the median response duration has not been reached at a median follow-up of 81, 43, and 31 weeks, respectively. Of note, there are ongoing responses in at least half of patients in these tumor types.

In HL, none of the 6 patients in CR has progressed, although there have been some progressions in the PR group.

The rapidity of responses is also notable, Dr Timmerman said.

“[I]t’s very interesting that some patients have resolution of symptoms and improvement of symptoms within even 1 day of starting nivolumab therapy,” he said.

And responses to nivolumab in HL “can be very dramatic,” he added, as illustrated in the following case from the Mayo Clinic.

A patient with multiple sites of bulky FDG-avid tumors was scheduled to enter hospice. But first, he entered the nivolumab trial. Within 6 weeks of initiating treatment, he had achieved a near-CR. This response has been maintained for 2 years.

“The occurrence of very durable responses in the PR and CR groups has led us to question whether patients should go on to allogeneic stem cell transplantation after achieving responses with nivolumab or, rather, continue on nivolumab as long as their response remains,” Dr Timmerman said.

He added that an international, phase 2 trial in HL is underway and is accruing briskly.

Nivolumab was awarded breakthrough designation by the US Food and Drug Administration last year. Breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.

Patient undergoing CT scan

Photo by Angela Mary Butler

TORONTO—A CT scan of the abdomen and pelvis does not improve cancer detection in people with unexplained venous thromboembolism (VTE), results of the SOME trial suggest.

“Unexplained blood clots have long been thought of as a possible early warning sign of cancer, with previous studies suggesting that up to 10% of patients with unexplained clots will be diagnosed with cancer within the year,” said Marc Carrier, MD, of Ottawa Hospital Research Institute in Ontario, Canada.

“Some clinical guidelines recommend a CT scan of the abdomen and pelvis in these patients, in addition to other cancer screening, but there has been very little evidence to know if the added CT scan is helpful. We did this study to find out.”

Dr Carrier and his colleagues described this research in an article published in NEJM and in a presentation given at the 2015 ISTH Congress (abstract LB001*).

The trial involved 854 patients treated at 9 Canadian centers who had an unexplained VTE—deep vein thrombosis, pulmonary embolism, or both.

The patients were randomized to receive basic cancer screening or basic cancer screening plus a CT scan of the abdomen and pelvis. Basic cancer screening included blood work and a chest X-ray, in addition to gender-specific screening (such as a breast exam, Pap smear, and prostate exam) if it had not been conducted in the last year.

Overall, 33 patients (3.9%) had a new diagnosis of occult cancer during the 1-year follow-up period.

There was no significant difference in the rate of diagnosis between the patients who received only basic screening and the patients who underwent CT as well—3.2% (14/431) and 4.5% (19/423), respectively (P=0.28).

Likewise, there was no significant difference in the number of cancers that were not diagnosed by the screening strategies. Basic screening failed to uncover 4 cancers (29%), and basic screening plus CT failed to reveal 5 cancers (26%, P=1.0).

In addition, there was no significant difference between the screening strategies in the time to cancer diagnosis or cancer-related mortality. The mean time to cancer diagnosis was 4.2 months in the basic screening group and 4.0 months in the CT group (P=0.88). And the rate of cancer-related mortality was 1.4% and 0.9%, respectively (P=0.75).

“Although it is tempting to believe that more cancer screening is always better, our study shows that this is not necessarily the case,” Dr Carrier said. “And in fact, unnecessary CT scanning has real risks. It can cause stress and anxiety in patients, as well as radiation exposure, and it can lead to over-investigation of false-positive findings. Our study means many patients will now be able to avoid this.”

That could lead to significant savings for the healthcare system, according to the researchers. For example, approximately 30,000 Canadians suffer from an unexplained VTE every year, and a CT scan costs approximately $300. So avoiding unnecessary CT scans could result in a potential saving of $9 million per year in Canada alone.

*Information in the abstract differs from that presented at the meeting.

Patient undergoing CT scan

Photo by Angela Mary Butler

TORONTO—A CT scan of the abdomen and pelvis does not improve cancer detection in people with unexplained venous thromboembolism (VTE), results of the SOME trial suggest.

“Unexplained blood clots have long been thought of as a possible early warning sign of cancer, with previous studies suggesting that up to 10% of patients with unexplained clots will be diagnosed with cancer within the year,” said Marc Carrier, MD, of Ottawa Hospital Research Institute in Ontario, Canada.

“Some clinical guidelines recommend a CT scan of the abdomen and pelvis in these patients, in addition to other cancer screening, but there has been very little evidence to know if the added CT scan is helpful. We did this study to find out.”

Dr Carrier and his colleagues described this research in an article published in NEJM and in a presentation given at the 2015 ISTH Congress (abstract LB001*).

The trial involved 854 patients treated at 9 Canadian centers who had an unexplained VTE—deep vein thrombosis, pulmonary embolism, or both.

The patients were randomized to receive basic cancer screening or basic cancer screening plus a CT scan of the abdomen and pelvis. Basic cancer screening included blood work and a chest X-ray, in addition to gender-specific screening (such as a breast exam, Pap smear, and prostate exam) if it had not been conducted in the last year.

Overall, 33 patients (3.9%) had a new diagnosis of occult cancer during the 1-year follow-up period.

There was no significant difference in the rate of diagnosis between the patients who received only basic screening and the patients who underwent CT as well—3.2% (14/431) and 4.5% (19/423), respectively (P=0.28).

Likewise, there was no significant difference in the number of cancers that were not diagnosed by the screening strategies. Basic screening failed to uncover 4 cancers (29%), and basic screening plus CT failed to reveal 5 cancers (26%, P=1.0).

In addition, there was no significant difference between the screening strategies in the time to cancer diagnosis or cancer-related mortality. The mean time to cancer diagnosis was 4.2 months in the basic screening group and 4.0 months in the CT group (P=0.88). And the rate of cancer-related mortality was 1.4% and 0.9%, respectively (P=0.75).

“Although it is tempting to believe that more cancer screening is always better, our study shows that this is not necessarily the case,” Dr Carrier said. “And in fact, unnecessary CT scanning has real risks. It can cause stress and anxiety in patients, as well as radiation exposure, and it can lead to over-investigation of false-positive findings. Our study means many patients will now be able to avoid this.”

That could lead to significant savings for the healthcare system, according to the researchers. For example, approximately 30,000 Canadians suffer from an unexplained VTE every year, and a CT scan costs approximately $300. So avoiding unnecessary CT scans could result in a potential saving of $9 million per year in Canada alone.

*Information in the abstract differs from that presented at the meeting.

Patient undergoing CT scan

Photo by Angela Mary Butler

TORONTO—A CT scan of the abdomen and pelvis does not improve cancer detection in people with unexplained venous thromboembolism (VTE), results of the SOME trial suggest.

“Unexplained blood clots have long been thought of as a possible early warning sign of cancer, with previous studies suggesting that up to 10% of patients with unexplained clots will be diagnosed with cancer within the year,” said Marc Carrier, MD, of Ottawa Hospital Research Institute in Ontario, Canada.

“Some clinical guidelines recommend a CT scan of the abdomen and pelvis in these patients, in addition to other cancer screening, but there has been very little evidence to know if the added CT scan is helpful. We did this study to find out.”

Dr Carrier and his colleagues described this research in an article published in NEJM and in a presentation given at the 2015 ISTH Congress (abstract LB001*).

The trial involved 854 patients treated at 9 Canadian centers who had an unexplained VTE—deep vein thrombosis, pulmonary embolism, or both.

The patients were randomized to receive basic cancer screening or basic cancer screening plus a CT scan of the abdomen and pelvis. Basic cancer screening included blood work and a chest X-ray, in addition to gender-specific screening (such as a breast exam, Pap smear, and prostate exam) if it had not been conducted in the last year.

Overall, 33 patients (3.9%) had a new diagnosis of occult cancer during the 1-year follow-up period.

There was no significant difference in the rate of diagnosis between the patients who received only basic screening and the patients who underwent CT as well—3.2% (14/431) and 4.5% (19/423), respectively (P=0.28).

Likewise, there was no significant difference in the number of cancers that were not diagnosed by the screening strategies. Basic screening failed to uncover 4 cancers (29%), and basic screening plus CT failed to reveal 5 cancers (26%, P=1.0).

In addition, there was no significant difference between the screening strategies in the time to cancer diagnosis or cancer-related mortality. The mean time to cancer diagnosis was 4.2 months in the basic screening group and 4.0 months in the CT group (P=0.88). And the rate of cancer-related mortality was 1.4% and 0.9%, respectively (P=0.75).

“Although it is tempting to believe that more cancer screening is always better, our study shows that this is not necessarily the case,” Dr Carrier said. “And in fact, unnecessary CT scanning has real risks. It can cause stress and anxiety in patients, as well as radiation exposure, and it can lead to over-investigation of false-positive findings. Our study means many patients will now be able to avoid this.”

That could lead to significant savings for the healthcare system, according to the researchers. For example, approximately 30,000 Canadians suffer from an unexplained VTE every year, and a CT scan costs approximately $300. So avoiding unnecessary CT scans could result in a potential saving of $9 million per year in Canada alone.

*Information in the abstract differs from that presented at the meeting.

 

 

Micrograph showing

follicular lymphoma

 

LUGANO—An anti-CD37 antibody-radionuclide conjugate provides sustained efficacy and a manageable safety profile in patients with relapsed, CD37⁺ non-Hodgkin lymphoma (NHL), according to researchers.

The drug, ¹⁷⁷Lu-DOTA-HH1 (Betalutin), consists of the tumor-specific antibody HH1, which targets the CD37 antigen on the surface of NHL cells, conjugated to the β-emitting isotope lutetium-177 (Lu-177) via the chemical linker DOTA.

In an ongoing, phase 1/2 trial, Betalutin has produced responses in 7 of 12 evaluable patients with relapsed NHL, and 5 of those responses are ongoing.

Grade 3/4 adverse events (AEs) were largely hematologic in nature, and many were transient and reversible. However, grade 3/4 AEs occurred at all 3 dose levels investigated in this study, as did serious AEs.

Arne Kolstad, MD, PhD, of Oslo University Hospital in Norway, and his colleagues reported these results at the 13th International Conference on Malignant Lymphoma (abstract 287*). The study was sponsored by Nordic Nanovector, the company developing Betalutin.

Thus far, the researchers have evaluated 13 patients with relapsed, CD37⁺ NHL. Twelve patients had a primary diagnosis of follicular lymphoma, and 1 had mantle cell lymphoma (MCL). The patients’ median age was 68 (range, 41-78), and they had received 1 to 8 prior treatments.

In this dose-finding study, the researchers investigated 3 dose levels of Betalutin. Four patients received Betalutin at 10 MBq/kg biweekly, 6 received 15 MBq/kg biweekly, and 3 (including the MCL patient) received 20 MBq/kg biweekly.

All patients received 50 mg of HH1 prior to Betalutin. Patients also received rituximab at 375 mg/m² on days -28 and -21 (prior to Betalutin on day 0).

Safety and dosing

Dose-limiting toxicities occurred at the 20 MBq/kg biweekly dose, so researchers said 15 MBq/kg biweekly, with HH1 pre-dosing, is the current recommended dose of Betalutin.

Treatment-emergent grade 3 AEs in the 10 MBq/kg group included thrombocytopenia (n=1), neutropenia (n=2), pneumonia (n=1), and pulmonary embolism (n=1). There were no grade 4 AEs in this group.

In the 15 MBq/kg group, 2 patients had grade 3 thrombocytopenia, and 1 had grade 4. One patient each had grade 3 and 4 neutropenia.

Grade 3/4 AEs in the 20 MBq/kg group included grade 4 thrombocytopenia (n=3), grade 3 (n=1) and grade 4 (n=2) neutropenia, and grade 3 epistaxis (n=1).

Serious AEs included pulmonary embolism (1 in the 10 MBq/kg group), pneumonia (1 in the 10 MBq/kg group), atrial fibrillation (2 in the 15 MBq/kg group), thrombocytopenia (1 in the 20 MBq/kg group), and epistaxis (1 in the 20 MBq/kg group).

The researchers said all hematologic AEs were transient and reversible. They also pointed out that 6 patients in this trial have been followed for a year or more, and there have been no secondary malignancies or other events that would suggest long-term toxicity.

Efficacy and next steps

Twelve patients were evaluable for efficacy. Seven patients responded to treatment, including 4 complete responses (CRs) and 3 partial responses. Two patients had stable disease, and 3 progressed. Eight patients had a 50% or greater reduction in tumor volume.

The median response duration has not been reached, and 5 patients’ responses are ongoing. The duration of response in these patients ranges from 6 months to more than 21 months. All 4 patients who achieved a CR (including the MCL patient) are still in CR.

The researchers concluded that Betalutin delivers a highly favorable response rate, with durable clinical responses, and the drug has a predictable and manageable safety profile.

They have opened a new arm of this study to evaluate the safety and efficacy of Betalutin at 15 MBq/kg biweekly and 17.5 MBq/kg biweekly without HH1 pre-dosing.

*Information in the abstract differs from that presented at the meeting.

 

 

Micrograph showing

follicular lymphoma

 

LUGANO—An anti-CD37 antibody-radionuclide conjugate provides sustained efficacy and a manageable safety profile in patients with relapsed, CD37⁺ non-Hodgkin lymphoma (NHL), according to researchers.

The drug, ¹⁷⁷Lu-DOTA-HH1 (Betalutin), consists of the tumor-specific antibody HH1, which targets the CD37 antigen on the surface of NHL cells, conjugated to the β-emitting isotope lutetium-177 (Lu-177) via the chemical linker DOTA.

In an ongoing, phase 1/2 trial, Betalutin has produced responses in 7 of 12 evaluable patients with relapsed NHL, and 5 of those responses are ongoing.

Grade 3/4 adverse events (AEs) were largely hematologic in nature, and many were transient and reversible. However, grade 3/4 AEs occurred at all 3 dose levels investigated in this study, as did serious AEs.

Arne Kolstad, MD, PhD, of Oslo University Hospital in Norway, and his colleagues reported these results at the 13th International Conference on Malignant Lymphoma (abstract 287*). The study was sponsored by Nordic Nanovector, the company developing Betalutin.

Thus far, the researchers have evaluated 13 patients with relapsed, CD37⁺ NHL. Twelve patients had a primary diagnosis of follicular lymphoma, and 1 had mantle cell lymphoma (MCL). The patients’ median age was 68 (range, 41-78), and they had received 1 to 8 prior treatments.

In this dose-finding study, the researchers investigated 3 dose levels of Betalutin. Four patients received Betalutin at 10 MBq/kg biweekly, 6 received 15 MBq/kg biweekly, and 3 (including the MCL patient) received 20 MBq/kg biweekly.

All patients received 50 mg of HH1 prior to Betalutin. Patients also received rituximab at 375 mg/m² on days -28 and -21 (prior to Betalutin on day 0).

Safety and dosing

Dose-limiting toxicities occurred at the 20 MBq/kg biweekly dose, so researchers said 15 MBq/kg biweekly, with HH1 pre-dosing, is the current recommended dose of Betalutin.

Treatment-emergent grade 3 AEs in the 10 MBq/kg group included thrombocytopenia (n=1), neutropenia (n=2), pneumonia (n=1), and pulmonary embolism (n=1). There were no grade 4 AEs in this group.

In the 15 MBq/kg group, 2 patients had grade 3 thrombocytopenia, and 1 had grade 4. One patient each had grade 3 and 4 neutropenia.

Grade 3/4 AEs in the 20 MBq/kg group included grade 4 thrombocytopenia (n=3), grade 3 (n=1) and grade 4 (n=2) neutropenia, and grade 3 epistaxis (n=1).

Serious AEs included pulmonary embolism (1 in the 10 MBq/kg group), pneumonia (1 in the 10 MBq/kg group), atrial fibrillation (2 in the 15 MBq/kg group), thrombocytopenia (1 in the 20 MBq/kg group), and epistaxis (1 in the 20 MBq/kg group).

The researchers said all hematologic AEs were transient and reversible. They also pointed out that 6 patients in this trial have been followed for a year or more, and there have been no secondary malignancies or other events that would suggest long-term toxicity.

Efficacy and next steps

Twelve patients were evaluable for efficacy. Seven patients responded to treatment, including 4 complete responses (CRs) and 3 partial responses. Two patients had stable disease, and 3 progressed. Eight patients had a 50% or greater reduction in tumor volume.

The median response duration has not been reached, and 5 patients’ responses are ongoing. The duration of response in these patients ranges from 6 months to more than 21 months. All 4 patients who achieved a CR (including the MCL patient) are still in CR.

The researchers concluded that Betalutin delivers a highly favorable response rate, with durable clinical responses, and the drug has a predictable and manageable safety profile.

They have opened a new arm of this study to evaluate the safety and efficacy of Betalutin at 15 MBq/kg biweekly and 17.5 MBq/kg biweekly without HH1 pre-dosing.

*Information in the abstract differs from that presented at the meeting.

 

 

Micrograph showing

follicular lymphoma

 

LUGANO—An anti-CD37 antibody-radionuclide conjugate provides sustained efficacy and a manageable safety profile in patients with relapsed, CD37⁺ non-Hodgkin lymphoma (NHL), according to researchers.

The drug, ¹⁷⁷Lu-DOTA-HH1 (Betalutin), consists of the tumor-specific antibody HH1, which targets the CD37 antigen on the surface of NHL cells, conjugated to the β-emitting isotope lutetium-177 (Lu-177) via the chemical linker DOTA.

In an ongoing, phase 1/2 trial, Betalutin has produced responses in 7 of 12 evaluable patients with relapsed NHL, and 5 of those responses are ongoing.

Grade 3/4 adverse events (AEs) were largely hematologic in nature, and many were transient and reversible. However, grade 3/4 AEs occurred at all 3 dose levels investigated in this study, as did serious AEs.

Arne Kolstad, MD, PhD, of Oslo University Hospital in Norway, and his colleagues reported these results at the 13th International Conference on Malignant Lymphoma (abstract 287*). The study was sponsored by Nordic Nanovector, the company developing Betalutin.

Thus far, the researchers have evaluated 13 patients with relapsed, CD37⁺ NHL. Twelve patients had a primary diagnosis of follicular lymphoma, and 1 had mantle cell lymphoma (MCL). The patients’ median age was 68 (range, 41-78), and they had received 1 to 8 prior treatments.

In this dose-finding study, the researchers investigated 3 dose levels of Betalutin. Four patients received Betalutin at 10 MBq/kg biweekly, 6 received 15 MBq/kg biweekly, and 3 (including the MCL patient) received 20 MBq/kg biweekly.

All patients received 50 mg of HH1 prior to Betalutin. Patients also received rituximab at 375 mg/m² on days -28 and -21 (prior to Betalutin on day 0).

Safety and dosing

Dose-limiting toxicities occurred at the 20 MBq/kg biweekly dose, so researchers said 15 MBq/kg biweekly, with HH1 pre-dosing, is the current recommended dose of Betalutin.

Treatment-emergent grade 3 AEs in the 10 MBq/kg group included thrombocytopenia (n=1), neutropenia (n=2), pneumonia (n=1), and pulmonary embolism (n=1). There were no grade 4 AEs in this group.

In the 15 MBq/kg group, 2 patients had grade 3 thrombocytopenia, and 1 had grade 4. One patient each had grade 3 and 4 neutropenia.

Grade 3/4 AEs in the 20 MBq/kg group included grade 4 thrombocytopenia (n=3), grade 3 (n=1) and grade 4 (n=2) neutropenia, and grade 3 epistaxis (n=1).

Serious AEs included pulmonary embolism (1 in the 10 MBq/kg group), pneumonia (1 in the 10 MBq/kg group), atrial fibrillation (2 in the 15 MBq/kg group), thrombocytopenia (1 in the 20 MBq/kg group), and epistaxis (1 in the 20 MBq/kg group).

The researchers said all hematologic AEs were transient and reversible. They also pointed out that 6 patients in this trial have been followed for a year or more, and there have been no secondary malignancies or other events that would suggest long-term toxicity.

Efficacy and next steps

Twelve patients were evaluable for efficacy. Seven patients responded to treatment, including 4 complete responses (CRs) and 3 partial responses. Two patients had stable disease, and 3 progressed. Eight patients had a 50% or greater reduction in tumor volume.

The median response duration has not been reached, and 5 patients’ responses are ongoing. The duration of response in these patients ranges from 6 months to more than 21 months. All 4 patients who achieved a CR (including the MCL patient) are still in CR.

The researchers concluded that Betalutin delivers a highly favorable response rate, with durable clinical responses, and the drug has a predictable and manageable safety profile.

They have opened a new arm of this study to evaluate the safety and efficacy of Betalutin at 15 MBq/kg biweekly and 17.5 MBq/kg biweekly without HH1 pre-dosing.

*Information in the abstract differs from that presented at the meeting.

Lab mouse

Preclinical research suggests that inactivating a single enzyme could eradicate or prevent T-cell acute lymphoblastic leukemia (T-ALL).

The researchers knew that T-ALL onset is linked to microRNAs, and most are generated with the help of the enzyme Dicer1.

Now, the team has found evidence to suggest that Dicer1 is crucial for the development of T-ALL, and inhibiting Dicer1 can actually prevent the disease altogether.

They reported these findings in Blood.

The researchers used mice that were genetically modified to develop T-ALL and in which Dicer1 could be abrogated. The team “switched off” Dicer1 in the mice at different stages of T-ALL development to see what role the enzyme plays in disease evolution.

Switching Dicer1 off at an early stage completely prevented T-ALL. In mice where Dicer1 was completely abrogated, T-ALL cells were entirely eliminated, allowing all the mice to survive.

The researchers were able to confirm this effect by monitoring the few residual leukemic cells taken from these animals.

“You can actually see the cancer cells dying off after Dicer1 has been abrogated,” said study author Freddy Radtke, PhD, of Ecole Polytechnique Fédérale de Lausanne in Lausanne, Switzerland.

He and his colleagues found that the key to this cell death is Dicer1’s role in producing microRNAs. The team discovered that a previously unrecognized microRNA, miR-21, was deregulated in both mouse and human T-ALL.

In the context of T-ALL, miR-21 inhibits the tumor suppressor gene Pdcd4. Without Dicer1, there is no miR-21 to do this, which allows Pdcd4 to fight the disease.

This study is the first to conclusively demonstrate that Dicer1 plays a role in T-ALL, the researchers said. The work paves the way for a new set of treatment for this malignancy and possibly others.

However, the team also noted that it can be challenging to target cells of interest when dealing with molecules that are so fundamental to the cell’s life.

“We can’t just go shutting down Dicer1 across the board,” Dr Radtke explained. “Otherwise, we’ll end up killing healthy cells as well.”

His lab is now focused on tackling this obstacle.

Lab mouse

Preclinical research suggests that inactivating a single enzyme could eradicate or prevent T-cell acute lymphoblastic leukemia (T-ALL).

The researchers knew that T-ALL onset is linked to microRNAs, and most are generated with the help of the enzyme Dicer1.

Now, the team has found evidence to suggest that Dicer1 is crucial for the development of T-ALL, and inhibiting Dicer1 can actually prevent the disease altogether.

They reported these findings in Blood.

The researchers used mice that were genetically modified to develop T-ALL and in which Dicer1 could be abrogated. The team “switched off” Dicer1 in the mice at different stages of T-ALL development to see what role the enzyme plays in disease evolution.

Switching Dicer1 off at an early stage completely prevented T-ALL. In mice where Dicer1 was completely abrogated, T-ALL cells were entirely eliminated, allowing all the mice to survive.

The researchers were able to confirm this effect by monitoring the few residual leukemic cells taken from these animals.

“You can actually see the cancer cells dying off after Dicer1 has been abrogated,” said study author Freddy Radtke, PhD, of Ecole Polytechnique Fédérale de Lausanne in Lausanne, Switzerland.

He and his colleagues found that the key to this cell death is Dicer1’s role in producing microRNAs. The team discovered that a previously unrecognized microRNA, miR-21, was deregulated in both mouse and human T-ALL.

In the context of T-ALL, miR-21 inhibits the tumor suppressor gene Pdcd4. Without Dicer1, there is no miR-21 to do this, which allows Pdcd4 to fight the disease.

This study is the first to conclusively demonstrate that Dicer1 plays a role in T-ALL, the researchers said. The work paves the way for a new set of treatment for this malignancy and possibly others.

However, the team also noted that it can be challenging to target cells of interest when dealing with molecules that are so fundamental to the cell’s life.

“We can’t just go shutting down Dicer1 across the board,” Dr Radtke explained. “Otherwise, we’ll end up killing healthy cells as well.”

His lab is now focused on tackling this obstacle.

Lab mouse

Preclinical research suggests that inactivating a single enzyme could eradicate or prevent T-cell acute lymphoblastic leukemia (T-ALL).

The researchers knew that T-ALL onset is linked to microRNAs, and most are generated with the help of the enzyme Dicer1.

Now, the team has found evidence to suggest that Dicer1 is crucial for the development of T-ALL, and inhibiting Dicer1 can actually prevent the disease altogether.

They reported these findings in Blood.

The researchers used mice that were genetically modified to develop T-ALL and in which Dicer1 could be abrogated. The team “switched off” Dicer1 in the mice at different stages of T-ALL development to see what role the enzyme plays in disease evolution.

Switching Dicer1 off at an early stage completely prevented T-ALL. In mice where Dicer1 was completely abrogated, T-ALL cells were entirely eliminated, allowing all the mice to survive.

The researchers were able to confirm this effect by monitoring the few residual leukemic cells taken from these animals.

“You can actually see the cancer cells dying off after Dicer1 has been abrogated,” said study author Freddy Radtke, PhD, of Ecole Polytechnique Fédérale de Lausanne in Lausanne, Switzerland.

He and his colleagues found that the key to this cell death is Dicer1’s role in producing microRNAs. The team discovered that a previously unrecognized microRNA, miR-21, was deregulated in both mouse and human T-ALL.

In the context of T-ALL, miR-21 inhibits the tumor suppressor gene Pdcd4. Without Dicer1, there is no miR-21 to do this, which allows Pdcd4 to fight the disease.

This study is the first to conclusively demonstrate that Dicer1 plays a role in T-ALL, the researchers said. The work paves the way for a new set of treatment for this malignancy and possibly others.

However, the team also noted that it can be challenging to target cells of interest when dealing with molecules that are so fundamental to the cell’s life.

“We can’t just go shutting down Dicer1 across the board,” Dr Radtke explained. “Otherwise, we’ll end up killing healthy cells as well.”

His lab is now focused on tackling this obstacle.

One of the perks that comes with being a grandparent is that you may get the chance to watch your grandchildren practice, play, and perform in a variety of organized activities. If you are retired and are fortunate enough to live in the same town, the opportunities are limitless and change with the season.

Each event is a kaleidoscope of interpersonal and developmental tableaux. First, of course, you are interested to see how your grandchild is doing. Are her skills improving? How do they compare with her peers’? Is she having fun? But then, what is the goal of the activity? Are the coaches/instructors/organizers doing a good job of reaching that goal?

Last week, I was watching my 8-year-old grandson play the last baseball game of his career (“Grampy, baseball is boring. I’m only playing lacrosse next spring.”) Between innings, I thumbed through the June 2015 Pediatrics. I encountered an article that confirmed my suspicions about some of the organized youth activities I had been watching for the last decade, “Physical Activity in Youth Dance Classes” (Pediatrics 2015;135:1067-73). Using accelerometers, researchers from San Diego State University recorded the activity of more than 250 girls, both children and adolescents, in 21 dance studios, both private and community based.

They discovered that the young dancers were, on average, engaged in moderate to vigorous activity 17.2 minutes (plus or minus 8.9 minutes), which amounted to about 36% of the usual class session. Only 8% of the children and 6% of the adolescents met the Centers for Disease Control and Prevention 30-minute guideline for after-school physical activity during dance.

I’ve watched a fair share of dance classes, and these findings come as no surprise. Typically, there is a lot of sitting around cross-legged in a circle, “listening” to “instruction.” There is even more lining up and waiting, and, then of course, adjusting the line, and an abundance of relining up, followed by a 6-second burst of activity. There is considerable poking and/or hugging fellow line mates, that I suspect wouldn’t have budged an accelerometer.

Unfortunately, this degree of inactivity is not unique to little girls’ dance classes. I have observed the same phenomenon during soccer, baseball, lacrosse, and swim classes – in which the ratio of inactivity to activity often exceeds 4:1. Although it may be slightly more prevalent when the instructors are parent/volunteers, professional physical educators also are guilty of injecting too little physical activity into the activities they are managing. Remember gym class. How much time was spent having your attendance taken, being instructed on how to do the activity, and then standing in line waiting your turn?

There are simple solutions, but they require thinking outside the box. Why have two lines of participants? Wouldn’t six lines mean three times as many children would be active at one time? For example, it has taken a while for soccer and hockey programs to catch on, but now both have games on smaller surfaces with less than the usual number of team members, in hopes that more children will be involved and active. Most great coaches have a knack for creating drills that keep the maximum number of participants active, foster the necessary skills, and at the same time are fun for the participants. The bottom line is that most children, particularly the younger ones, learn by imitating, not by being lectured to. They learn even more quickly if they have older children from which to model their behavior.

You could ask, “What’s the big deal?” Am I just venting the frustrations of an efficiency-obsessed former athlete? Does every minute of a child’s organized activity need to be packed with physical activity? No, not if children were allowed more opportunities for free play at other times during the day. No, not if parents were more diligent in restricting screen time. But if parents are going to count on dance classes and organized sports as physically active time for their children, they need to look more carefully at how that time is being used. An hour of dance class or soccer practice may be better than an hour in front of the tube, but it may fall far short of what the child needs.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “Coping with a Picky Eater.”

One of the perks that comes with being a grandparent is that you may get the chance to watch your grandchildren practice, play, and perform in a variety of organized activities. If you are retired and are fortunate enough to live in the same town, the opportunities are limitless and change with the season.

Each event is a kaleidoscope of interpersonal and developmental tableaux. First, of course, you are interested to see how your grandchild is doing. Are her skills improving? How do they compare with her peers’? Is she having fun? But then, what is the goal of the activity? Are the coaches/instructors/organizers doing a good job of reaching that goal?

Last week, I was watching my 8-year-old grandson play the last baseball game of his career (“Grampy, baseball is boring. I’m only playing lacrosse next spring.”) Between innings, I thumbed through the June 2015 Pediatrics. I encountered an article that confirmed my suspicions about some of the organized youth activities I had been watching for the last decade, “Physical Activity in Youth Dance Classes” (Pediatrics 2015;135:1067-73). Using accelerometers, researchers from San Diego State University recorded the activity of more than 250 girls, both children and adolescents, in 21 dance studios, both private and community based.

They discovered that the young dancers were, on average, engaged in moderate to vigorous activity 17.2 minutes (plus or minus 8.9 minutes), which amounted to about 36% of the usual class session. Only 8% of the children and 6% of the adolescents met the Centers for Disease Control and Prevention 30-minute guideline for after-school physical activity during dance.

I’ve watched a fair share of dance classes, and these findings come as no surprise. Typically, there is a lot of sitting around cross-legged in a circle, “listening” to “instruction.” There is even more lining up and waiting, and, then of course, adjusting the line, and an abundance of relining up, followed by a 6-second burst of activity. There is considerable poking and/or hugging fellow line mates, that I suspect wouldn’t have budged an accelerometer.

Unfortunately, this degree of inactivity is not unique to little girls’ dance classes. I have observed the same phenomenon during soccer, baseball, lacrosse, and swim classes – in which the ratio of inactivity to activity often exceeds 4:1. Although it may be slightly more prevalent when the instructors are parent/volunteers, professional physical educators also are guilty of injecting too little physical activity into the activities they are managing. Remember gym class. How much time was spent having your attendance taken, being instructed on how to do the activity, and then standing in line waiting your turn?

There are simple solutions, but they require thinking outside the box. Why have two lines of participants? Wouldn’t six lines mean three times as many children would be active at one time? For example, it has taken a while for soccer and hockey programs to catch on, but now both have games on smaller surfaces with less than the usual number of team members, in hopes that more children will be involved and active. Most great coaches have a knack for creating drills that keep the maximum number of participants active, foster the necessary skills, and at the same time are fun for the participants. The bottom line is that most children, particularly the younger ones, learn by imitating, not by being lectured to. They learn even more quickly if they have older children from which to model their behavior.

You could ask, “What’s the big deal?” Am I just venting the frustrations of an efficiency-obsessed former athlete? Does every minute of a child’s organized activity need to be packed with physical activity? No, not if children were allowed more opportunities for free play at other times during the day. No, not if parents were more diligent in restricting screen time. But if parents are going to count on dance classes and organized sports as physically active time for their children, they need to look more carefully at how that time is being used. An hour of dance class or soccer practice may be better than an hour in front of the tube, but it may fall far short of what the child needs.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “Coping with a Picky Eater.”

One of the perks that comes with being a grandparent is that you may get the chance to watch your grandchildren practice, play, and perform in a variety of organized activities. If you are retired and are fortunate enough to live in the same town, the opportunities are limitless and change with the season.

Each event is a kaleidoscope of interpersonal and developmental tableaux. First, of course, you are interested to see how your grandchild is doing. Are her skills improving? How do they compare with her peers’? Is she having fun? But then, what is the goal of the activity? Are the coaches/instructors/organizers doing a good job of reaching that goal?

Last week, I was watching my 8-year-old grandson play the last baseball game of his career (“Grampy, baseball is boring. I’m only playing lacrosse next spring.”) Between innings, I thumbed through the June 2015 Pediatrics. I encountered an article that confirmed my suspicions about some of the organized youth activities I had been watching for the last decade, “Physical Activity in Youth Dance Classes” (Pediatrics 2015;135:1067-73). Using accelerometers, researchers from San Diego State University recorded the activity of more than 250 girls, both children and adolescents, in 21 dance studios, both private and community based.

They discovered that the young dancers were, on average, engaged in moderate to vigorous activity 17.2 minutes (plus or minus 8.9 minutes), which amounted to about 36% of the usual class session. Only 8% of the children and 6% of the adolescents met the Centers for Disease Control and Prevention 30-minute guideline for after-school physical activity during dance.

I’ve watched a fair share of dance classes, and these findings come as no surprise. Typically, there is a lot of sitting around cross-legged in a circle, “listening” to “instruction.” There is even more lining up and waiting, and, then of course, adjusting the line, and an abundance of relining up, followed by a 6-second burst of activity. There is considerable poking and/or hugging fellow line mates, that I suspect wouldn’t have budged an accelerometer.

Unfortunately, this degree of inactivity is not unique to little girls’ dance classes. I have observed the same phenomenon during soccer, baseball, lacrosse, and swim classes – in which the ratio of inactivity to activity often exceeds 4:1. Although it may be slightly more prevalent when the instructors are parent/volunteers, professional physical educators also are guilty of injecting too little physical activity into the activities they are managing. Remember gym class. How much time was spent having your attendance taken, being instructed on how to do the activity, and then standing in line waiting your turn?

There are simple solutions, but they require thinking outside the box. Why have two lines of participants? Wouldn’t six lines mean three times as many children would be active at one time? For example, it has taken a while for soccer and hockey programs to catch on, but now both have games on smaller surfaces with less than the usual number of team members, in hopes that more children will be involved and active. Most great coaches have a knack for creating drills that keep the maximum number of participants active, foster the necessary skills, and at the same time are fun for the participants. The bottom line is that most children, particularly the younger ones, learn by imitating, not by being lectured to. They learn even more quickly if they have older children from which to model their behavior.

You could ask, “What’s the big deal?” Am I just venting the frustrations of an efficiency-obsessed former athlete? Does every minute of a child’s organized activity need to be packed with physical activity? No, not if children were allowed more opportunities for free play at other times during the day. No, not if parents were more diligent in restricting screen time. But if parents are going to count on dance classes and organized sports as physically active time for their children, they need to look more carefully at how that time is being used. An hour of dance class or soccer practice may be better than an hour in front of the tube, but it may fall far short of what the child needs.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “Coping with a Picky Eater.”

For patients who have femoropopliteal peripheral artery disease, percutaneous transluminal angioplasty with a paclitaxel-coated balloon achieves better 1-year patency than does using a standard balloon, according to a report published online June 24 in the New England Journal of Medicine.

Angioplasty initially restores blood flow in most patients with this type of PAD, but more than 60% develop restenosis from vessel recoil and neointimal hyperplasia within 1 year. The LEVANT2 (Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis) clinical trial assessed the performance of a drug-coated balloon (316 patients) against a standard balloon (160 patients) in participants treated at 54 sites in the U.S. and Europe, said Dr. Kenneth Rosenfield of Massachusetts General Hospital, Boston, and his associates.

The primary efficacy endpoint – the rate of patency of the target lesion at 1 year – was significantly higher with the paclitaxel-coated balloon (65.2%) than with the standard balloon (52.6%), the investigators said (N. Engl. J. Med. 2015 June 24 [doi:10.1056/NEJMoa1406235]).

However, secondary efficacy endpoints including the rates of event-free survival (86.7% vs. 81.5%), target-lesion revascularizations (12.3% vs. 16.8%), overall mortality (2.4% vs. 2.8%), amputation (0.3% vs. 0.0%) and thrombosis (0.4% vs. 0.7%) were not significantly different between the two study groups. Scores on a measure of walking distance improved significantly more with the paclitaxel-coated balloon, but ankle-brachial index and Rutherford scores measuring pain and symptoms of intermittent claudication did not differ significantly between the two study groups.

The primary safety endpoint – a composite of the proportion of patients free from perioperative death from any cause plus the proportion free from amputation, reintervention, or PAD-associated death at 1 year – was 83.9% with the paclitaxel-coated balloon and 79.0% with the standard balloon. This met the criterion for noninferiority.

“Our trial does not provide definitive guidance concerning the potential role of this paclitaxel-coated balloon in clinical practice. Although the findings are encouraging, long-term follow-up will be useful in determining whether the benefit of this intervention is sustained, increased, or attenuated over time,” Dr. Rosenfield and his associates said.

This study was funded by Lutonix-Bard, maker of the paclitaxel-coated balloon. Dr. Rosenfield reported ties to Lutonix/Bard, Cordis, Atrium, Abbott Vascular, and VIVA Physicians; his associates reported ties to numerous industry sources.

For patients who have femoropopliteal peripheral artery disease, percutaneous transluminal angioplasty with a paclitaxel-coated balloon achieves better 1-year patency than does using a standard balloon, according to a report published online June 24 in the New England Journal of Medicine.

Angioplasty initially restores blood flow in most patients with this type of PAD, but more than 60% develop restenosis from vessel recoil and neointimal hyperplasia within 1 year. The LEVANT2 (Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis) clinical trial assessed the performance of a drug-coated balloon (316 patients) against a standard balloon (160 patients) in participants treated at 54 sites in the U.S. and Europe, said Dr. Kenneth Rosenfield of Massachusetts General Hospital, Boston, and his associates.

The primary efficacy endpoint – the rate of patency of the target lesion at 1 year – was significantly higher with the paclitaxel-coated balloon (65.2%) than with the standard balloon (52.6%), the investigators said (N. Engl. J. Med. 2015 June 24 [doi:10.1056/NEJMoa1406235]).

However, secondary efficacy endpoints including the rates of event-free survival (86.7% vs. 81.5%), target-lesion revascularizations (12.3% vs. 16.8%), overall mortality (2.4% vs. 2.8%), amputation (0.3% vs. 0.0%) and thrombosis (0.4% vs. 0.7%) were not significantly different between the two study groups. Scores on a measure of walking distance improved significantly more with the paclitaxel-coated balloon, but ankle-brachial index and Rutherford scores measuring pain and symptoms of intermittent claudication did not differ significantly between the two study groups.

The primary safety endpoint – a composite of the proportion of patients free from perioperative death from any cause plus the proportion free from amputation, reintervention, or PAD-associated death at 1 year – was 83.9% with the paclitaxel-coated balloon and 79.0% with the standard balloon. This met the criterion for noninferiority.

“Our trial does not provide definitive guidance concerning the potential role of this paclitaxel-coated balloon in clinical practice. Although the findings are encouraging, long-term follow-up will be useful in determining whether the benefit of this intervention is sustained, increased, or attenuated over time,” Dr. Rosenfield and his associates said.

This study was funded by Lutonix-Bard, maker of the paclitaxel-coated balloon. Dr. Rosenfield reported ties to Lutonix/Bard, Cordis, Atrium, Abbott Vascular, and VIVA Physicians; his associates reported ties to numerous industry sources.

For patients who have femoropopliteal peripheral artery disease, percutaneous transluminal angioplasty with a paclitaxel-coated balloon achieves better 1-year patency than does using a standard balloon, according to a report published online June 24 in the New England Journal of Medicine.

Angioplasty initially restores blood flow in most patients with this type of PAD, but more than 60% develop restenosis from vessel recoil and neointimal hyperplasia within 1 year. The LEVANT2 (Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis) clinical trial assessed the performance of a drug-coated balloon (316 patients) against a standard balloon (160 patients) in participants treated at 54 sites in the U.S. and Europe, said Dr. Kenneth Rosenfield of Massachusetts General Hospital, Boston, and his associates.

The primary efficacy endpoint – the rate of patency of the target lesion at 1 year – was significantly higher with the paclitaxel-coated balloon (65.2%) than with the standard balloon (52.6%), the investigators said (N. Engl. J. Med. 2015 June 24 [doi:10.1056/NEJMoa1406235]).

However, secondary efficacy endpoints including the rates of event-free survival (86.7% vs. 81.5%), target-lesion revascularizations (12.3% vs. 16.8%), overall mortality (2.4% vs. 2.8%), amputation (0.3% vs. 0.0%) and thrombosis (0.4% vs. 0.7%) were not significantly different between the two study groups. Scores on a measure of walking distance improved significantly more with the paclitaxel-coated balloon, but ankle-brachial index and Rutherford scores measuring pain and symptoms of intermittent claudication did not differ significantly between the two study groups.

The primary safety endpoint – a composite of the proportion of patients free from perioperative death from any cause plus the proportion free from amputation, reintervention, or PAD-associated death at 1 year – was 83.9% with the paclitaxel-coated balloon and 79.0% with the standard balloon. This met the criterion for noninferiority.

“Our trial does not provide definitive guidance concerning the potential role of this paclitaxel-coated balloon in clinical practice. Although the findings are encouraging, long-term follow-up will be useful in determining whether the benefit of this intervention is sustained, increased, or attenuated over time,” Dr. Rosenfield and his associates said.

This study was funded by Lutonix-Bard, maker of the paclitaxel-coated balloon. Dr. Rosenfield reported ties to Lutonix/Bard, Cordis, Atrium, Abbott Vascular, and VIVA Physicians; his associates reported ties to numerous industry sources.

Spending time in front of a screen may increase adolescents’ risks of suffering from depression and anxiety, according to a study of 2,482 Canadian middle and high schoolers.

To assess the mental status of the participants, the researchers used self-report questionnaires, the Children’s Depression Inventory, and the Multidimensional Anxiety Scale for Children-10. The more time a student spent viewing a screen was significantly associated with depressive symptoms and the severity of anxiety symptoms, after controlling for the covariates of age, sex, ethnicity, parental education, body mass index, and physical activity. More severe depressive symptoms were significantly associated with the increased amounts of time a student played video games and used a computer, but not with the hours spent watching television. The duration of video game playing also was significantly associated with more severe symptoms of anxiety.

The study’s findings suggest that “screen time may represent a risk factor for, or a marker” of depression and anxiety disorders in adolescents, according to Danijela Maras of Carleton University, Ottawa, and her colleagues. The researchers recommended that future studies determine if “reducing screen time can have a significant impact on the prevention and treatment of anxiety and depression in adolescents.”

Read the full study in Preventive Medicine (doi:10.1016/j.ypmed2015.01.029).

[email protected]

Spending time in front of a screen may increase adolescents’ risks of suffering from depression and anxiety, according to a study of 2,482 Canadian middle and high schoolers.

To assess the mental status of the participants, the researchers used self-report questionnaires, the Children’s Depression Inventory, and the Multidimensional Anxiety Scale for Children-10. The more time a student spent viewing a screen was significantly associated with depressive symptoms and the severity of anxiety symptoms, after controlling for the covariates of age, sex, ethnicity, parental education, body mass index, and physical activity. More severe depressive symptoms were significantly associated with the increased amounts of time a student played video games and used a computer, but not with the hours spent watching television. The duration of video game playing also was significantly associated with more severe symptoms of anxiety.

The study’s findings suggest that “screen time may represent a risk factor for, or a marker” of depression and anxiety disorders in adolescents, according to Danijela Maras of Carleton University, Ottawa, and her colleagues. The researchers recommended that future studies determine if “reducing screen time can have a significant impact on the prevention and treatment of anxiety and depression in adolescents.”

Read the full study in Preventive Medicine (doi:10.1016/j.ypmed2015.01.029).

[email protected]

Spending time in front of a screen may increase adolescents’ risks of suffering from depression and anxiety, according to a study of 2,482 Canadian middle and high schoolers.

To assess the mental status of the participants, the researchers used self-report questionnaires, the Children’s Depression Inventory, and the Multidimensional Anxiety Scale for Children-10. The more time a student spent viewing a screen was significantly associated with depressive symptoms and the severity of anxiety symptoms, after controlling for the covariates of age, sex, ethnicity, parental education, body mass index, and physical activity. More severe depressive symptoms were significantly associated with the increased amounts of time a student played video games and used a computer, but not with the hours spent watching television. The duration of video game playing also was significantly associated with more severe symptoms of anxiety.

The study’s findings suggest that “screen time may represent a risk factor for, or a marker” of depression and anxiety disorders in adolescents, according to Danijela Maras of Carleton University, Ottawa, and her colleagues. The researchers recommended that future studies determine if “reducing screen time can have a significant impact on the prevention and treatment of anxiety and depression in adolescents.”

Read the full study in Preventive Medicine (doi:10.1016/j.ypmed2015.01.029).

[email protected]

At least half of all cases of maternal morbidity and mortality could be prevented, or so studies suggest.^1,2

The main stumbling block?

Faulty communication.

That’s the word from the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, the American College of Nurse-Midwives, and the Association of Women’s Health, Obstetric and Neonatal Nurses.³

In a joint “blueprint” to transform communication and enhance the safety culture in intrapartum care, these organizations, led by Audrey Lyndon, PhD, RN, from the University of California, San Francisco, School of Nursing, describe the extent of the problem, steps that various team members can take to improve safety, notable success stories, and communication strategies.³ In this article, the joint blueprint is summarized, with a focus on steps obstetricians can take to improve the intrapartum safety culture.

Scope of the problem
A study of more than 3,282 physicians, midwives, and registered nurses produced a troubling statistic: More than 90% of respondents said that they had “witnessed shortcuts, missing competencies, disrespect, or performance problems” during the preceding year of practice.⁴ Few of these clinicians reported that they had discussed their concerns with the parties involved.

A second study of 1,932 clinicians found that 34% of physicians, 40% of midwives, and 56% of registered nurses had witnessed patients being put at risk within the preceding 2 years by other team members’ inattentiveness or lack of responsiveness.⁵

These findings suggest that health care providers often witness weak links in intrapartum safety but do not always address or report them. Among the reasons team members may be hesitant to speak up when they perceive a potential problem:

Although Lyndon and colleagues acknowledge that it is impossible to eliminate adverse outcomes entirely or completely eradicate human error, they argue that significant improvements can be made by adopting a number of manageable strategies.³

Recommended strategies
Lyndon and colleagues describe some of the challenges of effective communication in a health care setting:

Lyndon and colleagues go on to mention a number of strategies to improve communication, boost safety, and reduce medical errors.³

1. Remember that the patient is part of the team
The patient and her family play a key role in identifying the potential for harm during labor and delivery, Lyndon and colleagues assert. Patients should be considered members of the intrapartum team, care should be patient-focused, and any communications from the patient should not only be heard but fully considered. In fact, explicit elicitation of her experience and concerns is recommended.³

2. Consider that you might be part of the problem
It is human nature to attribute a communication problem to the other people involved, rather than take responsibility for it oneself. One potential solution to this mindset is team training, where all members are encouraged to communicate clearly and listen attentively. Organizations that have been successful at improving their culture of safety have implemented such training, as well as the use of checklists, training in fetal heart-rate monitoring, formation of a patient safety committee, external review of safety practices, and designation of a key clinicianto lead the safety program and oversee team training.

3. Structure handoffs
The team should standardize handoffs so that they occur smoothly and all channels of communication remain open and clear.

“Having structured formats for debriefing and handoffs are steps in the right direction, but solving the problem of communication breakdowns is more complicated than standardizing the flow and format of information transfer,” Lyndon and colleagues assert. “Indeed, solving communication breakdowns is a matter of individual, group, organizational, and professional responsibility for creating and sustaining an environment of mutual respect, curiosity, and accountability for behavior and performance.”³

4. Learn to communicate responsibly
“Differences of opinion about clinical assessments, goals of care, and the pathway to optimal outcomes are bound to occur with some regularity in the dynamic environment of labor and delivery,” note Lyndon and colleagues. “Every person has the responsibility to contribute to improving how we relate to and communicate with each other. Collectively, we must create environments in which every team member (woman, family member, physician, midwife, nurse, unit clerk, patient care assistant, or scrub tech) is comfortable expressing and discussing concerns about safety or performance, is encouraged to do so, and has the support of the team to articulate the rationale for and urgency of the concern without fear of put-downs, retribution, or receiving poor-quality care.”³

5. Be persistent and proactive
When team members have differing expectations and communication styles, useful approaches include structured communication tools such as situation, background, assessment, recommendation (SBAR); structured handoffs; board rounds; huddles; attentive listening; and explicit elicitation of the patient’s concerns and desires.³

If someone fails to pay attention to a concern you raise, be persistent about restating that concern until you elicit a response.

If someone exhibits disruptive behavior, point to or establish a code of conduct that clearly describes professional behavior.

If there is a difference of opinion on patient management, such as fetal monitoring and interpretation, conduct regular case reviews and standardize a plan for notification of complications.

6. If you’re a team leader, set clear goals
Then ask team members what will be needed to achieve the outcomes desired.

“Team leaders need to develop outstanding skills for listening and eliciting feedback and cross-monitoring (being aware of each other’s actions and performance) from other team members,” note Lyndon and colleagues.³

7. Increase public awareness of safety concepts
When these concepts and best practices are made known to the public, women and families become “empowered” to speak up when they have concerns about care.

And when they do speak up, it pays to listen.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

At least half of all cases of maternal morbidity and mortality could be prevented, or so studies suggest.^1,2

The main stumbling block?

Faulty communication.

That’s the word from the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, the American College of Nurse-Midwives, and the Association of Women’s Health, Obstetric and Neonatal Nurses.³

In a joint “blueprint” to transform communication and enhance the safety culture in intrapartum care, these organizations, led by Audrey Lyndon, PhD, RN, from the University of California, San Francisco, School of Nursing, describe the extent of the problem, steps that various team members can take to improve safety, notable success stories, and communication strategies.³ In this article, the joint blueprint is summarized, with a focus on steps obstetricians can take to improve the intrapartum safety culture.

Scope of the problem
A study of more than 3,282 physicians, midwives, and registered nurses produced a troubling statistic: More than 90% of respondents said that they had “witnessed shortcuts, missing competencies, disrespect, or performance problems” during the preceding year of practice.⁴ Few of these clinicians reported that they had discussed their concerns with the parties involved.

A second study of 1,932 clinicians found that 34% of physicians, 40% of midwives, and 56% of registered nurses had witnessed patients being put at risk within the preceding 2 years by other team members’ inattentiveness or lack of responsiveness.⁵

These findings suggest that health care providers often witness weak links in intrapartum safety but do not always address or report them. Among the reasons team members may be hesitant to speak up when they perceive a potential problem:

Although Lyndon and colleagues acknowledge that it is impossible to eliminate adverse outcomes entirely or completely eradicate human error, they argue that significant improvements can be made by adopting a number of manageable strategies.³

Recommended strategies
Lyndon and colleagues describe some of the challenges of effective communication in a health care setting:

Lyndon and colleagues go on to mention a number of strategies to improve communication, boost safety, and reduce medical errors.³

1. Remember that the patient is part of the team
The patient and her family play a key role in identifying the potential for harm during labor and delivery, Lyndon and colleagues assert. Patients should be considered members of the intrapartum team, care should be patient-focused, and any communications from the patient should not only be heard but fully considered. In fact, explicit elicitation of her experience and concerns is recommended.³

2. Consider that you might be part of the problem
It is human nature to attribute a communication problem to the other people involved, rather than take responsibility for it oneself. One potential solution to this mindset is team training, where all members are encouraged to communicate clearly and listen attentively. Organizations that have been successful at improving their culture of safety have implemented such training, as well as the use of checklists, training in fetal heart-rate monitoring, formation of a patient safety committee, external review of safety practices, and designation of a key clinicianto lead the safety program and oversee team training.

3. Structure handoffs
The team should standardize handoffs so that they occur smoothly and all channels of communication remain open and clear.

“Having structured formats for debriefing and handoffs are steps in the right direction, but solving the problem of communication breakdowns is more complicated than standardizing the flow and format of information transfer,” Lyndon and colleagues assert. “Indeed, solving communication breakdowns is a matter of individual, group, organizational, and professional responsibility for creating and sustaining an environment of mutual respect, curiosity, and accountability for behavior and performance.”³

4. Learn to communicate responsibly
“Differences of opinion about clinical assessments, goals of care, and the pathway to optimal outcomes are bound to occur with some regularity in the dynamic environment of labor and delivery,” note Lyndon and colleagues. “Every person has the responsibility to contribute to improving how we relate to and communicate with each other. Collectively, we must create environments in which every team member (woman, family member, physician, midwife, nurse, unit clerk, patient care assistant, or scrub tech) is comfortable expressing and discussing concerns about safety or performance, is encouraged to do so, and has the support of the team to articulate the rationale for and urgency of the concern without fear of put-downs, retribution, or receiving poor-quality care.”³

5. Be persistent and proactive
When team members have differing expectations and communication styles, useful approaches include structured communication tools such as situation, background, assessment, recommendation (SBAR); structured handoffs; board rounds; huddles; attentive listening; and explicit elicitation of the patient’s concerns and desires.³

If someone fails to pay attention to a concern you raise, be persistent about restating that concern until you elicit a response.

If someone exhibits disruptive behavior, point to or establish a code of conduct that clearly describes professional behavior.

If there is a difference of opinion on patient management, such as fetal monitoring and interpretation, conduct regular case reviews and standardize a plan for notification of complications.

6. If you’re a team leader, set clear goals
Then ask team members what will be needed to achieve the outcomes desired.

“Team leaders need to develop outstanding skills for listening and eliciting feedback and cross-monitoring (being aware of each other’s actions and performance) from other team members,” note Lyndon and colleagues.³

7. Increase public awareness of safety concepts
When these concepts and best practices are made known to the public, women and families become “empowered” to speak up when they have concerns about care.

And when they do speak up, it pays to listen.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

At least half of all cases of maternal morbidity and mortality could be prevented, or so studies suggest.^1,2

The main stumbling block?

Faulty communication.

That’s the word from the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, the American College of Nurse-Midwives, and the Association of Women’s Health, Obstetric and Neonatal Nurses.³

In a joint “blueprint” to transform communication and enhance the safety culture in intrapartum care, these organizations, led by Audrey Lyndon, PhD, RN, from the University of California, San Francisco, School of Nursing, describe the extent of the problem, steps that various team members can take to improve safety, notable success stories, and communication strategies.³ In this article, the joint blueprint is summarized, with a focus on steps obstetricians can take to improve the intrapartum safety culture.

Scope of the problem
A study of more than 3,282 physicians, midwives, and registered nurses produced a troubling statistic: More than 90% of respondents said that they had “witnessed shortcuts, missing competencies, disrespect, or performance problems” during the preceding year of practice.⁴ Few of these clinicians reported that they had discussed their concerns with the parties involved.

A second study of 1,932 clinicians found that 34% of physicians, 40% of midwives, and 56% of registered nurses had witnessed patients being put at risk within the preceding 2 years by other team members’ inattentiveness or lack of responsiveness.⁵

These findings suggest that health care providers often witness weak links in intrapartum safety but do not always address or report them. Among the reasons team members may be hesitant to speak up when they perceive a potential problem:

Although Lyndon and colleagues acknowledge that it is impossible to eliminate adverse outcomes entirely or completely eradicate human error, they argue that significant improvements can be made by adopting a number of manageable strategies.³

Recommended strategies
Lyndon and colleagues describe some of the challenges of effective communication in a health care setting:

Lyndon and colleagues go on to mention a number of strategies to improve communication, boost safety, and reduce medical errors.³

1. Remember that the patient is part of the team
The patient and her family play a key role in identifying the potential for harm during labor and delivery, Lyndon and colleagues assert. Patients should be considered members of the intrapartum team, care should be patient-focused, and any communications from the patient should not only be heard but fully considered. In fact, explicit elicitation of her experience and concerns is recommended.³

2. Consider that you might be part of the problem
It is human nature to attribute a communication problem to the other people involved, rather than take responsibility for it oneself. One potential solution to this mindset is team training, where all members are encouraged to communicate clearly and listen attentively. Organizations that have been successful at improving their culture of safety have implemented such training, as well as the use of checklists, training in fetal heart-rate monitoring, formation of a patient safety committee, external review of safety practices, and designation of a key clinicianto lead the safety program and oversee team training.

3. Structure handoffs
The team should standardize handoffs so that they occur smoothly and all channels of communication remain open and clear.

“Having structured formats for debriefing and handoffs are steps in the right direction, but solving the problem of communication breakdowns is more complicated than standardizing the flow and format of information transfer,” Lyndon and colleagues assert. “Indeed, solving communication breakdowns is a matter of individual, group, organizational, and professional responsibility for creating and sustaining an environment of mutual respect, curiosity, and accountability for behavior and performance.”³

4. Learn to communicate responsibly
“Differences of opinion about clinical assessments, goals of care, and the pathway to optimal outcomes are bound to occur with some regularity in the dynamic environment of labor and delivery,” note Lyndon and colleagues. “Every person has the responsibility to contribute to improving how we relate to and communicate with each other. Collectively, we must create environments in which every team member (woman, family member, physician, midwife, nurse, unit clerk, patient care assistant, or scrub tech) is comfortable expressing and discussing concerns about safety or performance, is encouraged to do so, and has the support of the team to articulate the rationale for and urgency of the concern without fear of put-downs, retribution, or receiving poor-quality care.”³

5. Be persistent and proactive
When team members have differing expectations and communication styles, useful approaches include structured communication tools such as situation, background, assessment, recommendation (SBAR); structured handoffs; board rounds; huddles; attentive listening; and explicit elicitation of the patient’s concerns and desires.³

If someone fails to pay attention to a concern you raise, be persistent about restating that concern until you elicit a response.

If someone exhibits disruptive behavior, point to or establish a code of conduct that clearly describes professional behavior.

If there is a difference of opinion on patient management, such as fetal monitoring and interpretation, conduct regular case reviews and standardize a plan for notification of complications.

6. If you’re a team leader, set clear goals
Then ask team members what will be needed to achieve the outcomes desired.

“Team leaders need to develop outstanding skills for listening and eliciting feedback and cross-monitoring (being aware of each other’s actions and performance) from other team members,” note Lyndon and colleagues.³

7. Increase public awareness of safety concepts
When these concepts and best practices are made known to the public, women and families become “empowered” to speak up when they have concerns about care.

And when they do speak up, it pays to listen.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

From the Department of Health Behavior and Health Education, School of Public Health (Dr. Janevic) and the Medical School (Dr. Sanders), University of Michigan Ann Arbor, MI.

Abstract

• Objective: Asthma prevalence, morbidity, and mortality are all greater among adult women compared to men. Appropriate asthma self-management can improve asthma control. We reviewed published literature about sex- and gender-related factors that influence asthma self-management among women, as well as evidence-based interventions to promote effective asthma self-management in this population.
• Design: Based on evidence from the published literature, factors influencing women’s asthma self-management were categorized as follows: social roles and socioeconomic status, comorbidities, obesity, hormonal factors, and aging-related changes.
• Results: A number of factors were identified that affect women’s asthma self-management. These include: exposure to asthma triggers associated with gender roles, such as cleaning products; financial barriers to asthma management; comorbidities that divert attention or otherwise interfere with asthma management; a link between obesity and poor asthma outcomes; the effects of hormonal shifts associated with menstrual cycles and menopause on asthma control; and aging-associated barriers to effective self-management such as functional limitations and caregiving. Certain groups, such as African-American women, are at higher risk for poor asthma outcomes linked to many of the above factors. At least 1 health coaching intervention designed for women with asthma has been shown in a randomized trial to reduce symptoms and health care use.
• Conclusion: Future research on women and asthma self-management should include a focus on the relationship between hormonal changes and asthma symptoms. Interventions are also needed that address the separate and interacting effects of risk factors for poor asthma control that tend to cluster in women, such as obesity, depression, and gastroesophageal reflux disease.

In childhood, asthma is more prevalent in boys than in girls. In adolescence and adulthood, however, asthma becomes a predominantly female disease, with hormonal factors likely playing a role in this shift [1,2]. Fu et al [3] reviewed daily asthma symptom diaries of 418 children. From age 5 to 7, boys had more severe symptoms, but by age 10 girls’ symptoms were becoming more severe. By age 14, the girls’ symptoms continued increasing while the boys’ symptoms began to decline. A meta-analysis by Lieberoth et al [4] found a 37% increased risk of post-menarchal asthma in girls with onset of menarche < 12 years. Together, these studies implicate female sex hormones in both the increased incidence and severity of asthma after puberty. In 2012, nearly 10% of adult women reported current asthma, compared to only 6% of men [5]. Among adults with asthma, women have a 30% higher mortality rate than men [6]. Disparities that disadvantage women are also evident across a range of other asthma-related outcomes, including disease severity, rescue inhaler use, activity limitations, asthma-related quality of life, and health care utilization [7–12].

Factors Influencing Asthma Self-Management in Women

Social Roles and Socioeconomic Status

Traditional gender roles involve various responsibilities, such as household cleaning, cooking, and care of young children, that are associated with exposures to precipitants of asthma symptoms [17]. Gender norms also promote the use of personal care products, like fragrances and hair sprays, which are potential asthma triggers [17]. Recent observational studies in Europe have examined the link between women’s use of cleaning products and asthma. Bédard and colleagues [18] found an association between weekly use of cleaning sprays at home and asthma among women, and Dumas and colleagues [19] found that workplace exposure to cleaning products among women with asthma was related to increased symptoms and severity of asthma. These researchers conclude that “while domestic exposure is much more frequent in the general population, exposure levels are probably higher at the workplace” and therefore both contribute to asthma disease burden [19]. Although little-discussed in the literature, sexual activity is another common trigger of asthma symptoms in women. Clark et al [15] found that more than one-third of women taking part in a randomized controlled trial (RCT) of an asthma self-management intervention reported being bothered by symptoms of asthma during sexual activity. This topic was rarely discussed, however, by their health care providers [20].

Socioeconomic factors also play a significant role in asthma management. There is a well-recognized and persistent gender gap in income in the U.S. population such that women who work full-time only earn three-quarters of what their male counterparts earn [21]. Challenges related to low socioeconomic status (SES) may contribute to poor medication adherence among asthma patients [22]. Although a comprehensive review of the impact of SES-related factors on asthma prevalence, severity, and disease-management behaviors is beyond the scope of this article, recent research demonstrates the impact of financial stress on women’s asthma self-management. Patel et al (2014) studied health-related financial burden among African-American women with asthma [23]. Despite the fact that the majority of women in this qualitative study had health insurance, they felt greatly burdened by out-of-pocket expenses such as high co-pays for medications or ambulance use, lost wages due to sick time, and gaps in insurance coverage. These financial concerns—and related issues such as time spent navigating health care insurance and cycling through private and public insurance programs—were described as a significant source of ongoing stress by this group of vulnerable asthma patients [23]. Focus group participants reported several strategies for dealing with asthma-related financial challenges, including stockpiling medications when feasible (eg, when covered by current insurance plan) for future use by the patient or a family member, seeking out and using community assistance programs, and foregoing medications altogether during periods when they could not afford them [23].

Comorbidities

The 2010 publication of Multiple chronic conditions: a strategic framework by the US Department of Health and Human Services [24] brought the attention of the medical and research communities to the scope and significance of multimorbidity in the US population, including the challenges that individuals face in managing multiple chronic health conditions. Although the prevalence of specific comorbidities with asthma differs by age, some that are most commonly associated with asthma and that may complicate asthma control are obstructive sleep apnea, gastroesophageal reflux disease (GERD), rhinitis, and sinusitis [25,26]. Among women with asthma, multimorbidity appears to be the rule, not the exception. Using nationally-representative data from the US National Health and Nutrition Examination Survey (NHANES), Patel et al [27] found that more than half of adults with asthma reported also being diagnosed with at least 1 additional major chronic condition. A recent study found that asthma/arthritis and asthma/hypertension were the second and third most prevalent disease dyads among all US women aged 18–44 years [28]. Studies have found that comorbidities among asthma patients are associated with worse asthma outcomes, including increased symptoms, activity limitations and sleep disturbance due to asthma [27], and ED use for asthma [15,27].

Qualitative research yields insight into the patient perspective of multimorbidity, that is, how women with asthma and coexisting chronic diseases perceive the effect of their health conditions on their ability to engage in self-management. Janevic and colleagues [29] conducted face-to-face interviews with African-American women participating in a randomized controlled trial of a culturally and gender-tailored asthma-management intervention to learn about their experiences managing asthma and concurrent health conditions. Interviewees had an average of 5.7 chronic conditions in addition to asthma. Women reported that managing their asthma often “took a backseat” to other chronic conditions. Participants also discussed reduced motivation or capacity for asthma self-management due to depression, chronic pain, mobility limitations or combinations of these, and reduced adherence to asthma medications due to the psychological and logistical burdens of polypharmacy.

Depression and anxiety are common comorbidities that are associated with worse asthma outcomes [26,30–32] and reduced asthma medication adherence [33,34]. In general population studies as well as among asthma patients, women are more likely than men to report depression and anxiety [30,35–37]. Screening for and treating depression and anxiety are indicated in women with asthma and may lead to improved adherence and outcomes [30].

Obesity

Adults with asthma are at increased risk of obesity [38]. Obesity is a possible risk factor for development of asthma in women [2] and for resting dyspnea in women with asthma [39]. It is associated with poor asthma-related QOL and use of emergency/urgent services [40]. Evidence is mixed regarding the link between BMI and asthma control [41–43], but the following studies suggest that women who are overweight/obese face unique asthma management challenges. Valerio and colleagues found that in a sample of 808 women enrolled in a randomized trial of an asthma-education intervention, nearly 7 out of 10 were overweight (BMI ≥ 25) or obese (BMI ≥ 30), and nearly a quarter were “extremely obese” (BMI > 35) [44]. This subgroup of women was more likely to have persistent asthma, comorbid GERD and urinary incontinence, to be non-white, and to have lower levels of education and income. Being overweight was also associated with greater use of health care services and having greater psychosocial challenges (ie, a higher need for asthma-related social support and lower asthma-related quality of life). These authors suggest the need to design communications for overweight women with asthma that recognize “the specific cultural and social influences on their asthma management behaviors” [44] with a focus on psychosocial needs, while incorporating existing social support networks. In the previously discussed study by Janevic and colleagues [29] the average BMI of the interview participants was 36.0, and a number of respondents identified weight loss as the self-care behavior that they thought would benefit them the most across multimorbid conditions. Therefore, health care providers should provide appropriate counseling and/or referrals to help women with asthma achieve weight loss goals. Given trends over time showing increasing prevalence of asthma and obesity [45,46], interest is growing in the asthma research community about the interaction of the 2 conditions.

Hormonal Factors

Hormones exert a significant effect on asthma in women, and must be considered in clinical and self-management of the disease. Hormone levels fluctuate during the menstrual cycle, with a surge of estradiol (a type of estrogen) at the time of ovulation around day 14, accompanied by low levels of progesterone. During the luteal phase (day 14–28 of the menstrual cycle), estrogens decrease while progesterone levels increase then decrease again before onset of menstruation [47]. During pregnancy, levels of estrogens and progesterone increase and are the highest during the third trimester, when women usually experience good asthma control. Then, during menopause both estradiol and progesterone levels drop to lower levels than those during any phase of menstruation. In addition to the role in the menstrual cycle, there are estrogen receptors (ER-α and ER-β) which are expressed in the human lung and have a role in both airway responsiveness (relaxation) and inflammation [48]. Estrogen also acts directly on cells of the immune system to stimulate airway inflammation, particularly when allergens are present [48]. Further discussion about these contrasting actions of estrogen can be found in a recent review [48].

During the reproductive years, 30% to 40% of women with asthma report perimenstrual symptoms. Forced expiratory volume in 1 second and forced vital capacity are lowest in the periovulatory period, when estrogen levels are high. In contrast, during the luteal phase, studies have shown increased airway hyperreactivity, especially in the premenstrual period when estrogen levels are low [49]. However, when asthma patients with and without perimenstrual symptoms are evaluated, there is no significant difference in their perimenstrual estrogen and progesterone levels [50]. Clark et al [15] found women participating in a self-management intervention, which included checking daily peak flow rates, reported significantly more menstrual and perimenstrual asthma symptomatology than the control group. This suggests that some women with asthma have may have, but do not recognize, perimenstrual symptoms. Further elucidation of the incidence of symptomatology related to the menstrual cycle as well as the role of hormonal variation is an area for future research efforts.

At the time of menopause and continuing to postmenopause, levels of both estrogen and progesterone drop to below those during the reproductive years, leading to uncomfortable symptoms in many women. Hormone replacement therapy (HRT) with either estrogen alone or estrogen-progesterone combination effectively improves these, but there is concern for potential effects on asthma prevalence and severity. Two recent large studies support this concern. Postmenopausal women followed for 10 years in the Nurses’ Health Study with a history of HRT had an increased risk of new onset asthma when compared to postmenopausal women with no history of estrogen use (RR = 2.30, 95% CI 1.69–3.14) [51]. This persisted in estrogen-progesterone users. A large French cohort confirmed the increased onset of new asthma in users of estrogen-alone replacement therapy (HR = 1.54, 95% CI 1.13–2.09). However, this effect decreased with time if estrogen had been discontinued, and they did not find a similar increase in users of estrogen-progesterone combination therapy [52]. In contrast, Bonelykke et al [53] found an association between ever using HRT and first-ever hospital admission for asthma, in postmenopausal women (HR 1.46, CI 1.21–1.76), and this risk increased with duration of HRT use. It is clear that physicians need to be aware of these potential respiratory complications, inform their patients, and consider new-onset asthma when women on HRT bring complaints of dyspnea, cough, or wheeze. Future randomized trials are needed to clarify the relationship between HRT and asthma, and to test ways to optimize asthma self-management in women experiencing these transitions.

Older Women and Asthma

Although the bulk of research on asthma focuses on children and young adults, asthma in the elderly is receiving increased attention [54], in part because this demographic group has the highest asthma mortality rate and the most frequent hospitalizations [6,55]. In a sample of midlife and older women from the Nurses’ Health Study who had been diagnosed with persistent asthma, Barr et al found that adherence to asthma medication guidelines decreased with age [54]. In this study, women with more severe asthma and those with multimorbidity were less adherent than those without comorbidities, as were women who spent more hours caregiving for an ill spouse. The authors concluded that asthma is undertreated among older women.

Baptist et al (2014) describe several challenges to asthma management of older women by clinicians and by the women themselves [55]. For example, elderly women may be at increased risk for adverse effects of inhaled corticosteroids. Certain medications used to treat comorbidities, such as beta-blockers and aspirin, may also exacerbate asthma symptoms. In terms of self-management, older women may have a decreased ability to perceive breathlessness, requiring monitoring with a peak flow meter to detect reductions in airflow. Comorbidities are particularly prevalent in this age group, and asthma symptoms may be confused with symptoms of other conditions, such as heart disease [56]. Baptist and colleagues note factors common among elderly women that pose potential barriers to successful self-management of asthma, including limited income, poverty, depression, and caregiving [55]. They also mention that functional limitations such as those due to arthritis, visual difficulties, or weakened inspiratory strength can make inhaler use more difficult. It should also be noted that some behaviors may promote asthma self-management in this group; for example, Valerio and colleagues [57] found that women over age 50 were more likely than younger women to keep a daily asthma diary when asked to do so as part of a self-management intervention [57].

Evidence-Based Asthma Self-Management Interventions for Women

For women to achieve optimal asthma control, the unique factors as described above that influence their symptoms and management need to be addressed [58]. Several examples can be found in the literature of behavioral interventions that focus on the particular self-management challenges faced by women. Clark and colleagues reported the results of an RCT of the Women Breathe Free (WBF) program [15,16]. This intervention consisted of asthma self-management education delivered over 5 telephone sessions by a health educator. WBF content was based on self-regulation theory, which involves observing one’s behavior and making judgments on the observations, testing strategies to improve asthma management, and reacting to positive results of these strategies with enhanced self-efficacy and outcome expectations, ie, the belief that a given strategy will produce the desired results [59]. In WBF, participants used a problem-solving process based on this framework to carry out recommendations in their physician’s therapeutic plan. WBF also incorporated special attention to sex- and gender-based factors in asthma management.

Over a 12-month period, women who participated in the intervention relative to controls experienced significant reductions in nighttime symptoms, days of missed work/school, emergency department visits, and both scheduled and urgent office visits. Intervention group women also reported decreased asthma symptoms during sexual activity, improved asthma-related quality of life, and increased confidence to manage asthma. At long-term follow-up (2 years from baseline), persistent positive effects of the intervention were found on outpatient visits for asthma symptom level during sexual activity, days of missed work/school, asthma-related quality of life, and confidence to manage asthma [60].

In a follow-up study, Clark and colleagues [61] developed the “Women of Color and Asthma Control” (WCAC) program. WCAC incorporates the theoretical orientation and many of the program elements of Women Breathe Free, but has been adapted to be responsive to the needs and preferences of African-American women. Poverty and race are associated with greater asthma morbidity and mortality [5,62,63]. African-American women and women of low socioeconomic status are particularly vulnerable to asthma and associated morbidity and mortality, making this an important group for intervention. Culturally responsive components in the WCAC intervention include use of culturally relevant activities and beliefs when discussing triggers and barriers to asthma management, as well as culturally appropriate visuals. This ongoing trial will test WCAC’s effect on ED visits, hospitalizations, and urgent care; asthma symptoms; and asthma-related quality of life at 1 year and 18 months from baseline.

In a small RCT among women with asthma, Bidwell and colleagues tested a program consisting of 10 weeks of yoga instruction (including breathing practices, poses, and meditation/relaxation skills) in a group setting followed by 10 weeks of home practice [64]. Women in the intervention group reported improved quality of life, as measured by the St. George’s Respiratory Quality of Life questionnaire [65], and participants also had decreased parasympathetic modulation in response to an isometric forearm exercise. They conclude that yoga is a promising modality for improving quality of life among asthma patients and that these changes may be linked to better autonomic modulation. Although this program was not designed specifically for women, yoga is practiced significantly more frequently among women compared to men [66,67], and thus has the potential to be widely used in this group.

Based on our experience conducting self-management research among women with asthma, and unpublished process data from these studies, we observe that the following elements appear to contribute to high participant engagement in these programs and successful outcomes. First, in participant feedback questionnaires from the Women Breathe Free and Women of Color and Asthma Control studies, women have singled out the importance of their relationship with their assigned telephone asthma educator as motivating them to make positive changes in their asthma self-management behaviors. The popularity of health and wellness coaching, including for chronic disease management, is rapidly growing [68]. This is a patient-centered approach that guides patients in setting their own goals for disease management and devising their own strategies for achieving them [68]. Strong interpersonal relationships are thought to enhance the coaching process and this may be especially important for women [68]. Participants have also indicated that they are able to apply the goal-setting and problem-solving skills they have learned as part of the intervention to management of other health or psychosocial issues in their lives; therefore this component seems especially critical for women with asthma who are typically managing multiple health issues as well as those of others. Finally, maximizing the flexibility of interventions is important for working-age women who typically are engaged in part- or full-time employment and also have significant responsibilities caring for others. This flexibility can come in the form of telephone-based or “mHealth” interventions that use mobile technologies such as text messaging [69], as well as internet-based or smartphone/tablet “apps” that can be completed at a pace and schedule that is convenient for the participant [70]. Such interventions could be easily tailored to address sex- and gender-specific issues in asthma management.

Future Research and Practice Directions

This review points to several promising directions for research and practice in the area of supporting women’s asthma self-management. The first is a systematic exploration of the added value of gender-tailoring asthma self-management support interventions to determine which subgroups of women benefit from which type of sex- and gender-specific information, and in which form. More research is needed on the relationship between hormone levels and changes and asthma symptoms, and how this affects women’s self-management. This includes recognition of new or worsening asthma with the use of hormone replacement therapy in menopausal and post-menopausal women, a group that is rapidly increasing in number in the US population. Another direction for research is a family-systems approach to asthma education and supporting asthma management. Asthma in one or more first-degree relatives has been shown across diverse populations to be a risk factor for asthma [71]. Women with asthma are therefore more likely to have children with asthma, and vice-versa; however, no prior research was identified that addresses asthma self-management in mother/child dyads. For example, it is possible that teaching women to better manage their own asthma could have “trickle down” effects to how they help a child manage asthma. Last, as the above discussion of factors affecting women’s asthma makes clear, many risk factors for poor asthma management and control in women cluster together, such as obesity, depression, and GERD. Interventions that attempt to address the separate and interacting effects of these factors and comorbidities, may yield better outcomes among the most vulnerable asthma patients.

Corresponding author: Mary R. Janevic, PhD, Center for Managing Chronic Disease, University of Michigan School of Public Health, 1425 Washington Heights, Ann Arbor, MI 48109, [email protected].

Financial disclosures: None.

From the Department of Health Behavior and Health Education, School of Public Health (Dr. Janevic) and the Medical School (Dr. Sanders), University of Michigan Ann Arbor, MI.

Abstract

• Objective: Asthma prevalence, morbidity, and mortality are all greater among adult women compared to men. Appropriate asthma self-management can improve asthma control. We reviewed published literature about sex- and gender-related factors that influence asthma self-management among women, as well as evidence-based interventions to promote effective asthma self-management in this population.
• Design: Based on evidence from the published literature, factors influencing women’s asthma self-management were categorized as follows: social roles and socioeconomic status, comorbidities, obesity, hormonal factors, and aging-related changes.
• Results: A number of factors were identified that affect women’s asthma self-management. These include: exposure to asthma triggers associated with gender roles, such as cleaning products; financial barriers to asthma management; comorbidities that divert attention or otherwise interfere with asthma management; a link between obesity and poor asthma outcomes; the effects of hormonal shifts associated with menstrual cycles and menopause on asthma control; and aging-associated barriers to effective self-management such as functional limitations and caregiving. Certain groups, such as African-American women, are at higher risk for poor asthma outcomes linked to many of the above factors. At least 1 health coaching intervention designed for women with asthma has been shown in a randomized trial to reduce symptoms and health care use.
• Conclusion: Future research on women and asthma self-management should include a focus on the relationship between hormonal changes and asthma symptoms. Interventions are also needed that address the separate and interacting effects of risk factors for poor asthma control that tend to cluster in women, such as obesity, depression, and gastroesophageal reflux disease.

In childhood, asthma is more prevalent in boys than in girls. In adolescence and adulthood, however, asthma becomes a predominantly female disease, with hormonal factors likely playing a role in this shift [1,2]. Fu et al [3] reviewed daily asthma symptom diaries of 418 children. From age 5 to 7, boys had more severe symptoms, but by age 10 girls’ symptoms were becoming more severe. By age 14, the girls’ symptoms continued increasing while the boys’ symptoms began to decline. A meta-analysis by Lieberoth et al [4] found a 37% increased risk of post-menarchal asthma in girls with onset of menarche < 12 years. Together, these studies implicate female sex hormones in both the increased incidence and severity of asthma after puberty. In 2012, nearly 10% of adult women reported current asthma, compared to only 6% of men [5]. Among adults with asthma, women have a 30% higher mortality rate than men [6]. Disparities that disadvantage women are also evident across a range of other asthma-related outcomes, including disease severity, rescue inhaler use, activity limitations, asthma-related quality of life, and health care utilization [7–12].

Factors Influencing Asthma Self-Management in Women

Social Roles and Socioeconomic Status

Traditional gender roles involve various responsibilities, such as household cleaning, cooking, and care of young children, that are associated with exposures to precipitants of asthma symptoms [17]. Gender norms also promote the use of personal care products, like fragrances and hair sprays, which are potential asthma triggers [17]. Recent observational studies in Europe have examined the link between women’s use of cleaning products and asthma. Bédard and colleagues [18] found an association between weekly use of cleaning sprays at home and asthma among women, and Dumas and colleagues [19] found that workplace exposure to cleaning products among women with asthma was related to increased symptoms and severity of asthma. These researchers conclude that “while domestic exposure is much more frequent in the general population, exposure levels are probably higher at the workplace” and therefore both contribute to asthma disease burden [19]. Although little-discussed in the literature, sexual activity is another common trigger of asthma symptoms in women. Clark et al [15] found that more than one-third of women taking part in a randomized controlled trial (RCT) of an asthma self-management intervention reported being bothered by symptoms of asthma during sexual activity. This topic was rarely discussed, however, by their health care providers [20].

Socioeconomic factors also play a significant role in asthma management. There is a well-recognized and persistent gender gap in income in the U.S. population such that women who work full-time only earn three-quarters of what their male counterparts earn [21]. Challenges related to low socioeconomic status (SES) may contribute to poor medication adherence among asthma patients [22]. Although a comprehensive review of the impact of SES-related factors on asthma prevalence, severity, and disease-management behaviors is beyond the scope of this article, recent research demonstrates the impact of financial stress on women’s asthma self-management. Patel et al (2014) studied health-related financial burden among African-American women with asthma [23]. Despite the fact that the majority of women in this qualitative study had health insurance, they felt greatly burdened by out-of-pocket expenses such as high co-pays for medications or ambulance use, lost wages due to sick time, and gaps in insurance coverage. These financial concerns—and related issues such as time spent navigating health care insurance and cycling through private and public insurance programs—were described as a significant source of ongoing stress by this group of vulnerable asthma patients [23]. Focus group participants reported several strategies for dealing with asthma-related financial challenges, including stockpiling medications when feasible (eg, when covered by current insurance plan) for future use by the patient or a family member, seeking out and using community assistance programs, and foregoing medications altogether during periods when they could not afford them [23].

Comorbidities

The 2010 publication of Multiple chronic conditions: a strategic framework by the US Department of Health and Human Services [24] brought the attention of the medical and research communities to the scope and significance of multimorbidity in the US population, including the challenges that individuals face in managing multiple chronic health conditions. Although the prevalence of specific comorbidities with asthma differs by age, some that are most commonly associated with asthma and that may complicate asthma control are obstructive sleep apnea, gastroesophageal reflux disease (GERD), rhinitis, and sinusitis [25,26]. Among women with asthma, multimorbidity appears to be the rule, not the exception. Using nationally-representative data from the US National Health and Nutrition Examination Survey (NHANES), Patel et al [27] found that more than half of adults with asthma reported also being diagnosed with at least 1 additional major chronic condition. A recent study found that asthma/arthritis and asthma/hypertension were the second and third most prevalent disease dyads among all US women aged 18–44 years [28]. Studies have found that comorbidities among asthma patients are associated with worse asthma outcomes, including increased symptoms, activity limitations and sleep disturbance due to asthma [27], and ED use for asthma [15,27].

Qualitative research yields insight into the patient perspective of multimorbidity, that is, how women with asthma and coexisting chronic diseases perceive the effect of their health conditions on their ability to engage in self-management. Janevic and colleagues [29] conducted face-to-face interviews with African-American women participating in a randomized controlled trial of a culturally and gender-tailored asthma-management intervention to learn about their experiences managing asthma and concurrent health conditions. Interviewees had an average of 5.7 chronic conditions in addition to asthma. Women reported that managing their asthma often “took a backseat” to other chronic conditions. Participants also discussed reduced motivation or capacity for asthma self-management due to depression, chronic pain, mobility limitations or combinations of these, and reduced adherence to asthma medications due to the psychological and logistical burdens of polypharmacy.

Depression and anxiety are common comorbidities that are associated with worse asthma outcomes [26,30–32] and reduced asthma medication adherence [33,34]. In general population studies as well as among asthma patients, women are more likely than men to report depression and anxiety [30,35–37]. Screening for and treating depression and anxiety are indicated in women with asthma and may lead to improved adherence and outcomes [30].

Obesity

Adults with asthma are at increased risk of obesity [38]. Obesity is a possible risk factor for development of asthma in women [2] and for resting dyspnea in women with asthma [39]. It is associated with poor asthma-related QOL and use of emergency/urgent services [40]. Evidence is mixed regarding the link between BMI and asthma control [41–43], but the following studies suggest that women who are overweight/obese face unique asthma management challenges. Valerio and colleagues found that in a sample of 808 women enrolled in a randomized trial of an asthma-education intervention, nearly 7 out of 10 were overweight (BMI ≥ 25) or obese (BMI ≥ 30), and nearly a quarter were “extremely obese” (BMI > 35) [44]. This subgroup of women was more likely to have persistent asthma, comorbid GERD and urinary incontinence, to be non-white, and to have lower levels of education and income. Being overweight was also associated with greater use of health care services and having greater psychosocial challenges (ie, a higher need for asthma-related social support and lower asthma-related quality of life). These authors suggest the need to design communications for overweight women with asthma that recognize “the specific cultural and social influences on their asthma management behaviors” [44] with a focus on psychosocial needs, while incorporating existing social support networks. In the previously discussed study by Janevic and colleagues [29] the average BMI of the interview participants was 36.0, and a number of respondents identified weight loss as the self-care behavior that they thought would benefit them the most across multimorbid conditions. Therefore, health care providers should provide appropriate counseling and/or referrals to help women with asthma achieve weight loss goals. Given trends over time showing increasing prevalence of asthma and obesity [45,46], interest is growing in the asthma research community about the interaction of the 2 conditions.

Hormonal Factors

Hormones exert a significant effect on asthma in women, and must be considered in clinical and self-management of the disease. Hormone levels fluctuate during the menstrual cycle, with a surge of estradiol (a type of estrogen) at the time of ovulation around day 14, accompanied by low levels of progesterone. During the luteal phase (day 14–28 of the menstrual cycle), estrogens decrease while progesterone levels increase then decrease again before onset of menstruation [47]. During pregnancy, levels of estrogens and progesterone increase and are the highest during the third trimester, when women usually experience good asthma control. Then, during menopause both estradiol and progesterone levels drop to lower levels than those during any phase of menstruation. In addition to the role in the menstrual cycle, there are estrogen receptors (ER-α and ER-β) which are expressed in the human lung and have a role in both airway responsiveness (relaxation) and inflammation [48]. Estrogen also acts directly on cells of the immune system to stimulate airway inflammation, particularly when allergens are present [48]. Further discussion about these contrasting actions of estrogen can be found in a recent review [48].

During the reproductive years, 30% to 40% of women with asthma report perimenstrual symptoms. Forced expiratory volume in 1 second and forced vital capacity are lowest in the periovulatory period, when estrogen levels are high. In contrast, during the luteal phase, studies have shown increased airway hyperreactivity, especially in the premenstrual period when estrogen levels are low [49]. However, when asthma patients with and without perimenstrual symptoms are evaluated, there is no significant difference in their perimenstrual estrogen and progesterone levels [50]. Clark et al [15] found women participating in a self-management intervention, which included checking daily peak flow rates, reported significantly more menstrual and perimenstrual asthma symptomatology than the control group. This suggests that some women with asthma have may have, but do not recognize, perimenstrual symptoms. Further elucidation of the incidence of symptomatology related to the menstrual cycle as well as the role of hormonal variation is an area for future research efforts.

At the time of menopause and continuing to postmenopause, levels of both estrogen and progesterone drop to below those during the reproductive years, leading to uncomfortable symptoms in many women. Hormone replacement therapy (HRT) with either estrogen alone or estrogen-progesterone combination effectively improves these, but there is concern for potential effects on asthma prevalence and severity. Two recent large studies support this concern. Postmenopausal women followed for 10 years in the Nurses’ Health Study with a history of HRT had an increased risk of new onset asthma when compared to postmenopausal women with no history of estrogen use (RR = 2.30, 95% CI 1.69–3.14) [51]. This persisted in estrogen-progesterone users. A large French cohort confirmed the increased onset of new asthma in users of estrogen-alone replacement therapy (HR = 1.54, 95% CI 1.13–2.09). However, this effect decreased with time if estrogen had been discontinued, and they did not find a similar increase in users of estrogen-progesterone combination therapy [52]. In contrast, Bonelykke et al [53] found an association between ever using HRT and first-ever hospital admission for asthma, in postmenopausal women (HR 1.46, CI 1.21–1.76), and this risk increased with duration of HRT use. It is clear that physicians need to be aware of these potential respiratory complications, inform their patients, and consider new-onset asthma when women on HRT bring complaints of dyspnea, cough, or wheeze. Future randomized trials are needed to clarify the relationship between HRT and asthma, and to test ways to optimize asthma self-management in women experiencing these transitions.

Older Women and Asthma

Although the bulk of research on asthma focuses on children and young adults, asthma in the elderly is receiving increased attention [54], in part because this demographic group has the highest asthma mortality rate and the most frequent hospitalizations [6,55]. In a sample of midlife and older women from the Nurses’ Health Study who had been diagnosed with persistent asthma, Barr et al found that adherence to asthma medication guidelines decreased with age [54]. In this study, women with more severe asthma and those with multimorbidity were less adherent than those without comorbidities, as were women who spent more hours caregiving for an ill spouse. The authors concluded that asthma is undertreated among older women.

Baptist et al (2014) describe several challenges to asthma management of older women by clinicians and by the women themselves [55]. For example, elderly women may be at increased risk for adverse effects of inhaled corticosteroids. Certain medications used to treat comorbidities, such as beta-blockers and aspirin, may also exacerbate asthma symptoms. In terms of self-management, older women may have a decreased ability to perceive breathlessness, requiring monitoring with a peak flow meter to detect reductions in airflow. Comorbidities are particularly prevalent in this age group, and asthma symptoms may be confused with symptoms of other conditions, such as heart disease [56]. Baptist and colleagues note factors common among elderly women that pose potential barriers to successful self-management of asthma, including limited income, poverty, depression, and caregiving [55]. They also mention that functional limitations such as those due to arthritis, visual difficulties, or weakened inspiratory strength can make inhaler use more difficult. It should also be noted that some behaviors may promote asthma self-management in this group; for example, Valerio and colleagues [57] found that women over age 50 were more likely than younger women to keep a daily asthma diary when asked to do so as part of a self-management intervention [57].

Evidence-Based Asthma Self-Management Interventions for Women

For women to achieve optimal asthma control, the unique factors as described above that influence their symptoms and management need to be addressed [58]. Several examples can be found in the literature of behavioral interventions that focus on the particular self-management challenges faced by women. Clark and colleagues reported the results of an RCT of the Women Breathe Free (WBF) program [15,16]. This intervention consisted of asthma self-management education delivered over 5 telephone sessions by a health educator. WBF content was based on self-regulation theory, which involves observing one’s behavior and making judgments on the observations, testing strategies to improve asthma management, and reacting to positive results of these strategies with enhanced self-efficacy and outcome expectations, ie, the belief that a given strategy will produce the desired results [59]. In WBF, participants used a problem-solving process based on this framework to carry out recommendations in their physician’s therapeutic plan. WBF also incorporated special attention to sex- and gender-based factors in asthma management.

Over a 12-month period, women who participated in the intervention relative to controls experienced significant reductions in nighttime symptoms, days of missed work/school, emergency department visits, and both scheduled and urgent office visits. Intervention group women also reported decreased asthma symptoms during sexual activity, improved asthma-related quality of life, and increased confidence to manage asthma. At long-term follow-up (2 years from baseline), persistent positive effects of the intervention were found on outpatient visits for asthma symptom level during sexual activity, days of missed work/school, asthma-related quality of life, and confidence to manage asthma [60].

In a follow-up study, Clark and colleagues [61] developed the “Women of Color and Asthma Control” (WCAC) program. WCAC incorporates the theoretical orientation and many of the program elements of Women Breathe Free, but has been adapted to be responsive to the needs and preferences of African-American women. Poverty and race are associated with greater asthma morbidity and mortality [5,62,63]. African-American women and women of low socioeconomic status are particularly vulnerable to asthma and associated morbidity and mortality, making this an important group for intervention. Culturally responsive components in the WCAC intervention include use of culturally relevant activities and beliefs when discussing triggers and barriers to asthma management, as well as culturally appropriate visuals. This ongoing trial will test WCAC’s effect on ED visits, hospitalizations, and urgent care; asthma symptoms; and asthma-related quality of life at 1 year and 18 months from baseline.

In a small RCT among women with asthma, Bidwell and colleagues tested a program consisting of 10 weeks of yoga instruction (including breathing practices, poses, and meditation/relaxation skills) in a group setting followed by 10 weeks of home practice [64]. Women in the intervention group reported improved quality of life, as measured by the St. George’s Respiratory Quality of Life questionnaire [65], and participants also had decreased parasympathetic modulation in response to an isometric forearm exercise. They conclude that yoga is a promising modality for improving quality of life among asthma patients and that these changes may be linked to better autonomic modulation. Although this program was not designed specifically for women, yoga is practiced significantly more frequently among women compared to men [66,67], and thus has the potential to be widely used in this group.

Based on our experience conducting self-management research among women with asthma, and unpublished process data from these studies, we observe that the following elements appear to contribute to high participant engagement in these programs and successful outcomes. First, in participant feedback questionnaires from the Women Breathe Free and Women of Color and Asthma Control studies, women have singled out the importance of their relationship with their assigned telephone asthma educator as motivating them to make positive changes in their asthma self-management behaviors. The popularity of health and wellness coaching, including for chronic disease management, is rapidly growing [68]. This is a patient-centered approach that guides patients in setting their own goals for disease management and devising their own strategies for achieving them [68]. Strong interpersonal relationships are thought to enhance the coaching process and this may be especially important for women [68]. Participants have also indicated that they are able to apply the goal-setting and problem-solving skills they have learned as part of the intervention to management of other health or psychosocial issues in their lives; therefore this component seems especially critical for women with asthma who are typically managing multiple health issues as well as those of others. Finally, maximizing the flexibility of interventions is important for working-age women who typically are engaged in part- or full-time employment and also have significant responsibilities caring for others. This flexibility can come in the form of telephone-based or “mHealth” interventions that use mobile technologies such as text messaging [69], as well as internet-based or smartphone/tablet “apps” that can be completed at a pace and schedule that is convenient for the participant [70]. Such interventions could be easily tailored to address sex- and gender-specific issues in asthma management.

Future Research and Practice Directions

This review points to several promising directions for research and practice in the area of supporting women’s asthma self-management. The first is a systematic exploration of the added value of gender-tailoring asthma self-management support interventions to determine which subgroups of women benefit from which type of sex- and gender-specific information, and in which form. More research is needed on the relationship between hormone levels and changes and asthma symptoms, and how this affects women’s self-management. This includes recognition of new or worsening asthma with the use of hormone replacement therapy in menopausal and post-menopausal women, a group that is rapidly increasing in number in the US population. Another direction for research is a family-systems approach to asthma education and supporting asthma management. Asthma in one or more first-degree relatives has been shown across diverse populations to be a risk factor for asthma [71]. Women with asthma are therefore more likely to have children with asthma, and vice-versa; however, no prior research was identified that addresses asthma self-management in mother/child dyads. For example, it is possible that teaching women to better manage their own asthma could have “trickle down” effects to how they help a child manage asthma. Last, as the above discussion of factors affecting women’s asthma makes clear, many risk factors for poor asthma management and control in women cluster together, such as obesity, depression, and GERD. Interventions that attempt to address the separate and interacting effects of these factors and comorbidities, may yield better outcomes among the most vulnerable asthma patients.

Corresponding author: Mary R. Janevic, PhD, Center for Managing Chronic Disease, University of Michigan School of Public Health, 1425 Washington Heights, Ann Arbor, MI 48109, [email protected].

Financial disclosures: None.

From the Department of Health Behavior and Health Education, School of Public Health (Dr. Janevic) and the Medical School (Dr. Sanders), University of Michigan Ann Arbor, MI.

Abstract

• Objective: Asthma prevalence, morbidity, and mortality are all greater among adult women compared to men. Appropriate asthma self-management can improve asthma control. We reviewed published literature about sex- and gender-related factors that influence asthma self-management among women, as well as evidence-based interventions to promote effective asthma self-management in this population.
• Design: Based on evidence from the published literature, factors influencing women’s asthma self-management were categorized as follows: social roles and socioeconomic status, comorbidities, obesity, hormonal factors, and aging-related changes.
• Results: A number of factors were identified that affect women’s asthma self-management. These include: exposure to asthma triggers associated with gender roles, such as cleaning products; financial barriers to asthma management; comorbidities that divert attention or otherwise interfere with asthma management; a link between obesity and poor asthma outcomes; the effects of hormonal shifts associated with menstrual cycles and menopause on asthma control; and aging-associated barriers to effective self-management such as functional limitations and caregiving. Certain groups, such as African-American women, are at higher risk for poor asthma outcomes linked to many of the above factors. At least 1 health coaching intervention designed for women with asthma has been shown in a randomized trial to reduce symptoms and health care use.
• Conclusion: Future research on women and asthma self-management should include a focus on the relationship between hormonal changes and asthma symptoms. Interventions are also needed that address the separate and interacting effects of risk factors for poor asthma control that tend to cluster in women, such as obesity, depression, and gastroesophageal reflux disease.

In childhood, asthma is more prevalent in boys than in girls. In adolescence and adulthood, however, asthma becomes a predominantly female disease, with hormonal factors likely playing a role in this shift [1,2]. Fu et al [3] reviewed daily asthma symptom diaries of 418 children. From age 5 to 7, boys had more severe symptoms, but by age 10 girls’ symptoms were becoming more severe. By age 14, the girls’ symptoms continued increasing while the boys’ symptoms began to decline. A meta-analysis by Lieberoth et al [4] found a 37% increased risk of post-menarchal asthma in girls with onset of menarche < 12 years. Together, these studies implicate female sex hormones in both the increased incidence and severity of asthma after puberty. In 2012, nearly 10% of adult women reported current asthma, compared to only 6% of men [5]. Among adults with asthma, women have a 30% higher mortality rate than men [6]. Disparities that disadvantage women are also evident across a range of other asthma-related outcomes, including disease severity, rescue inhaler use, activity limitations, asthma-related quality of life, and health care utilization [7–12].

Factors Influencing Asthma Self-Management in Women

Social Roles and Socioeconomic Status

Traditional gender roles involve various responsibilities, such as household cleaning, cooking, and care of young children, that are associated with exposures to precipitants of asthma symptoms [17]. Gender norms also promote the use of personal care products, like fragrances and hair sprays, which are potential asthma triggers [17]. Recent observational studies in Europe have examined the link between women’s use of cleaning products and asthma. Bédard and colleagues [18] found an association between weekly use of cleaning sprays at home and asthma among women, and Dumas and colleagues [19] found that workplace exposure to cleaning products among women with asthma was related to increased symptoms and severity of asthma. These researchers conclude that “while domestic exposure is much more frequent in the general population, exposure levels are probably higher at the workplace” and therefore both contribute to asthma disease burden [19]. Although little-discussed in the literature, sexual activity is another common trigger of asthma symptoms in women. Clark et al [15] found that more than one-third of women taking part in a randomized controlled trial (RCT) of an asthma self-management intervention reported being bothered by symptoms of asthma during sexual activity. This topic was rarely discussed, however, by their health care providers [20].

Socioeconomic factors also play a significant role in asthma management. There is a well-recognized and persistent gender gap in income in the U.S. population such that women who work full-time only earn three-quarters of what their male counterparts earn [21]. Challenges related to low socioeconomic status (SES) may contribute to poor medication adherence among asthma patients [22]. Although a comprehensive review of the impact of SES-related factors on asthma prevalence, severity, and disease-management behaviors is beyond the scope of this article, recent research demonstrates the impact of financial stress on women’s asthma self-management. Patel et al (2014) studied health-related financial burden among African-American women with asthma [23]. Despite the fact that the majority of women in this qualitative study had health insurance, they felt greatly burdened by out-of-pocket expenses such as high co-pays for medications or ambulance use, lost wages due to sick time, and gaps in insurance coverage. These financial concerns—and related issues such as time spent navigating health care insurance and cycling through private and public insurance programs—were described as a significant source of ongoing stress by this group of vulnerable asthma patients [23]. Focus group participants reported several strategies for dealing with asthma-related financial challenges, including stockpiling medications when feasible (eg, when covered by current insurance plan) for future use by the patient or a family member, seeking out and using community assistance programs, and foregoing medications altogether during periods when they could not afford them [23].

Comorbidities

The 2010 publication of Multiple chronic conditions: a strategic framework by the US Department of Health and Human Services [24] brought the attention of the medical and research communities to the scope and significance of multimorbidity in the US population, including the challenges that individuals face in managing multiple chronic health conditions. Although the prevalence of specific comorbidities with asthma differs by age, some that are most commonly associated with asthma and that may complicate asthma control are obstructive sleep apnea, gastroesophageal reflux disease (GERD), rhinitis, and sinusitis [25,26]. Among women with asthma, multimorbidity appears to be the rule, not the exception. Using nationally-representative data from the US National Health and Nutrition Examination Survey (NHANES), Patel et al [27] found that more than half of adults with asthma reported also being diagnosed with at least 1 additional major chronic condition. A recent study found that asthma/arthritis and asthma/hypertension were the second and third most prevalent disease dyads among all US women aged 18–44 years [28]. Studies have found that comorbidities among asthma patients are associated with worse asthma outcomes, including increased symptoms, activity limitations and sleep disturbance due to asthma [27], and ED use for asthma [15,27].

Qualitative research yields insight into the patient perspective of multimorbidity, that is, how women with asthma and coexisting chronic diseases perceive the effect of their health conditions on their ability to engage in self-management. Janevic and colleagues [29] conducted face-to-face interviews with African-American women participating in a randomized controlled trial of a culturally and gender-tailored asthma-management intervention to learn about their experiences managing asthma and concurrent health conditions. Interviewees had an average of 5.7 chronic conditions in addition to asthma. Women reported that managing their asthma often “took a backseat” to other chronic conditions. Participants also discussed reduced motivation or capacity for asthma self-management due to depression, chronic pain, mobility limitations or combinations of these, and reduced adherence to asthma medications due to the psychological and logistical burdens of polypharmacy.

Depression and anxiety are common comorbidities that are associated with worse asthma outcomes [26,30–32] and reduced asthma medication adherence [33,34]. In general population studies as well as among asthma patients, women are more likely than men to report depression and anxiety [30,35–37]. Screening for and treating depression and anxiety are indicated in women with asthma and may lead to improved adherence and outcomes [30].

Obesity

Adults with asthma are at increased risk of obesity [38]. Obesity is a possible risk factor for development of asthma in women [2] and for resting dyspnea in women with asthma [39]. It is associated with poor asthma-related QOL and use of emergency/urgent services [40]. Evidence is mixed regarding the link between BMI and asthma control [41–43], but the following studies suggest that women who are overweight/obese face unique asthma management challenges. Valerio and colleagues found that in a sample of 808 women enrolled in a randomized trial of an asthma-education intervention, nearly 7 out of 10 were overweight (BMI ≥ 25) or obese (BMI ≥ 30), and nearly a quarter were “extremely obese” (BMI > 35) [44]. This subgroup of women was more likely to have persistent asthma, comorbid GERD and urinary incontinence, to be non-white, and to have lower levels of education and income. Being overweight was also associated with greater use of health care services and having greater psychosocial challenges (ie, a higher need for asthma-related social support and lower asthma-related quality of life). These authors suggest the need to design communications for overweight women with asthma that recognize “the specific cultural and social influences on their asthma management behaviors” [44] with a focus on psychosocial needs, while incorporating existing social support networks. In the previously discussed study by Janevic and colleagues [29] the average BMI of the interview participants was 36.0, and a number of respondents identified weight loss as the self-care behavior that they thought would benefit them the most across multimorbid conditions. Therefore, health care providers should provide appropriate counseling and/or referrals to help women with asthma achieve weight loss goals. Given trends over time showing increasing prevalence of asthma and obesity [45,46], interest is growing in the asthma research community about the interaction of the 2 conditions.

Hormonal Factors

Hormones exert a significant effect on asthma in women, and must be considered in clinical and self-management of the disease. Hormone levels fluctuate during the menstrual cycle, with a surge of estradiol (a type of estrogen) at the time of ovulation around day 14, accompanied by low levels of progesterone. During the luteal phase (day 14–28 of the menstrual cycle), estrogens decrease while progesterone levels increase then decrease again before onset of menstruation [47]. During pregnancy, levels of estrogens and progesterone increase and are the highest during the third trimester, when women usually experience good asthma control. Then, during menopause both estradiol and progesterone levels drop to lower levels than those during any phase of menstruation. In addition to the role in the menstrual cycle, there are estrogen receptors (ER-α and ER-β) which are expressed in the human lung and have a role in both airway responsiveness (relaxation) and inflammation [48]. Estrogen also acts directly on cells of the immune system to stimulate airway inflammation, particularly when allergens are present [48]. Further discussion about these contrasting actions of estrogen can be found in a recent review [48].

During the reproductive years, 30% to 40% of women with asthma report perimenstrual symptoms. Forced expiratory volume in 1 second and forced vital capacity are lowest in the periovulatory period, when estrogen levels are high. In contrast, during the luteal phase, studies have shown increased airway hyperreactivity, especially in the premenstrual period when estrogen levels are low [49]. However, when asthma patients with and without perimenstrual symptoms are evaluated, there is no significant difference in their perimenstrual estrogen and progesterone levels [50]. Clark et al [15] found women participating in a self-management intervention, which included checking daily peak flow rates, reported significantly more menstrual and perimenstrual asthma symptomatology than the control group. This suggests that some women with asthma have may have, but do not recognize, perimenstrual symptoms. Further elucidation of the incidence of symptomatology related to the menstrual cycle as well as the role of hormonal variation is an area for future research efforts.

At the time of menopause and continuing to postmenopause, levels of both estrogen and progesterone drop to below those during the reproductive years, leading to uncomfortable symptoms in many women. Hormone replacement therapy (HRT) with either estrogen alone or estrogen-progesterone combination effectively improves these, but there is concern for potential effects on asthma prevalence and severity. Two recent large studies support this concern. Postmenopausal women followed for 10 years in the Nurses’ Health Study with a history of HRT had an increased risk of new onset asthma when compared to postmenopausal women with no history of estrogen use (RR = 2.30, 95% CI 1.69–3.14) [51]. This persisted in estrogen-progesterone users. A large French cohort confirmed the increased onset of new asthma in users of estrogen-alone replacement therapy (HR = 1.54, 95% CI 1.13–2.09). However, this effect decreased with time if estrogen had been discontinued, and they did not find a similar increase in users of estrogen-progesterone combination therapy [52]. In contrast, Bonelykke et al [53] found an association between ever using HRT and first-ever hospital admission for asthma, in postmenopausal women (HR 1.46, CI 1.21–1.76), and this risk increased with duration of HRT use. It is clear that physicians need to be aware of these potential respiratory complications, inform their patients, and consider new-onset asthma when women on HRT bring complaints of dyspnea, cough, or wheeze. Future randomized trials are needed to clarify the relationship between HRT and asthma, and to test ways to optimize asthma self-management in women experiencing these transitions.

Older Women and Asthma

Although the bulk of research on asthma focuses on children and young adults, asthma in the elderly is receiving increased attention [54], in part because this demographic group has the highest asthma mortality rate and the most frequent hospitalizations [6,55]. In a sample of midlife and older women from the Nurses’ Health Study who had been diagnosed with persistent asthma, Barr et al found that adherence to asthma medication guidelines decreased with age [54]. In this study, women with more severe asthma and those with multimorbidity were less adherent than those without comorbidities, as were women who spent more hours caregiving for an ill spouse. The authors concluded that asthma is undertreated among older women.

Baptist et al (2014) describe several challenges to asthma management of older women by clinicians and by the women themselves [55]. For example, elderly women may be at increased risk for adverse effects of inhaled corticosteroids. Certain medications used to treat comorbidities, such as beta-blockers and aspirin, may also exacerbate asthma symptoms. In terms of self-management, older women may have a decreased ability to perceive breathlessness, requiring monitoring with a peak flow meter to detect reductions in airflow. Comorbidities are particularly prevalent in this age group, and asthma symptoms may be confused with symptoms of other conditions, such as heart disease [56]. Baptist and colleagues note factors common among elderly women that pose potential barriers to successful self-management of asthma, including limited income, poverty, depression, and caregiving [55]. They also mention that functional limitations such as those due to arthritis, visual difficulties, or weakened inspiratory strength can make inhaler use more difficult. It should also be noted that some behaviors may promote asthma self-management in this group; for example, Valerio and colleagues [57] found that women over age 50 were more likely than younger women to keep a daily asthma diary when asked to do so as part of a self-management intervention [57].

Evidence-Based Asthma Self-Management Interventions for Women

For women to achieve optimal asthma control, the unique factors as described above that influence their symptoms and management need to be addressed [58]. Several examples can be found in the literature of behavioral interventions that focus on the particular self-management challenges faced by women. Clark and colleagues reported the results of an RCT of the Women Breathe Free (WBF) program [15,16]. This intervention consisted of asthma self-management education delivered over 5 telephone sessions by a health educator. WBF content was based on self-regulation theory, which involves observing one’s behavior and making judgments on the observations, testing strategies to improve asthma management, and reacting to positive results of these strategies with enhanced self-efficacy and outcome expectations, ie, the belief that a given strategy will produce the desired results [59]. In WBF, participants used a problem-solving process based on this framework to carry out recommendations in their physician’s therapeutic plan. WBF also incorporated special attention to sex- and gender-based factors in asthma management.

Over a 12-month period, women who participated in the intervention relative to controls experienced significant reductions in nighttime symptoms, days of missed work/school, emergency department visits, and both scheduled and urgent office visits. Intervention group women also reported decreased asthma symptoms during sexual activity, improved asthma-related quality of life, and increased confidence to manage asthma. At long-term follow-up (2 years from baseline), persistent positive effects of the intervention were found on outpatient visits for asthma symptom level during sexual activity, days of missed work/school, asthma-related quality of life, and confidence to manage asthma [60].

In a follow-up study, Clark and colleagues [61] developed the “Women of Color and Asthma Control” (WCAC) program. WCAC incorporates the theoretical orientation and many of the program elements of Women Breathe Free, but has been adapted to be responsive to the needs and preferences of African-American women. Poverty and race are associated with greater asthma morbidity and mortality [5,62,63]. African-American women and women of low socioeconomic status are particularly vulnerable to asthma and associated morbidity and mortality, making this an important group for intervention. Culturally responsive components in the WCAC intervention include use of culturally relevant activities and beliefs when discussing triggers and barriers to asthma management, as well as culturally appropriate visuals. This ongoing trial will test WCAC’s effect on ED visits, hospitalizations, and urgent care; asthma symptoms; and asthma-related quality of life at 1 year and 18 months from baseline.

In a small RCT among women with asthma, Bidwell and colleagues tested a program consisting of 10 weeks of yoga instruction (including breathing practices, poses, and meditation/relaxation skills) in a group setting followed by 10 weeks of home practice [64]. Women in the intervention group reported improved quality of life, as measured by the St. George’s Respiratory Quality of Life questionnaire [65], and participants also had decreased parasympathetic modulation in response to an isometric forearm exercise. They conclude that yoga is a promising modality for improving quality of life among asthma patients and that these changes may be linked to better autonomic modulation. Although this program was not designed specifically for women, yoga is practiced significantly more frequently among women compared to men [66,67], and thus has the potential to be widely used in this group.

Based on our experience conducting self-management research among women with asthma, and unpublished process data from these studies, we observe that the following elements appear to contribute to high participant engagement in these programs and successful outcomes. First, in participant feedback questionnaires from the Women Breathe Free and Women of Color and Asthma Control studies, women have singled out the importance of their relationship with their assigned telephone asthma educator as motivating them to make positive changes in their asthma self-management behaviors. The popularity of health and wellness coaching, including for chronic disease management, is rapidly growing [68]. This is a patient-centered approach that guides patients in setting their own goals for disease management and devising their own strategies for achieving them [68]. Strong interpersonal relationships are thought to enhance the coaching process and this may be especially important for women [68]. Participants have also indicated that they are able to apply the goal-setting and problem-solving skills they have learned as part of the intervention to management of other health or psychosocial issues in their lives; therefore this component seems especially critical for women with asthma who are typically managing multiple health issues as well as those of others. Finally, maximizing the flexibility of interventions is important for working-age women who typically are engaged in part- or full-time employment and also have significant responsibilities caring for others. This flexibility can come in the form of telephone-based or “mHealth” interventions that use mobile technologies such as text messaging [69], as well as internet-based or smartphone/tablet “apps” that can be completed at a pace and schedule that is convenient for the participant [70]. Such interventions could be easily tailored to address sex- and gender-specific issues in asthma management.

Future Research and Practice Directions

This review points to several promising directions for research and practice in the area of supporting women’s asthma self-management. The first is a systematic exploration of the added value of gender-tailoring asthma self-management support interventions to determine which subgroups of women benefit from which type of sex- and gender-specific information, and in which form. More research is needed on the relationship between hormone levels and changes and asthma symptoms, and how this affects women’s self-management. This includes recognition of new or worsening asthma with the use of hormone replacement therapy in menopausal and post-menopausal women, a group that is rapidly increasing in number in the US population. Another direction for research is a family-systems approach to asthma education and supporting asthma management. Asthma in one or more first-degree relatives has been shown across diverse populations to be a risk factor for asthma [71]. Women with asthma are therefore more likely to have children with asthma, and vice-versa; however, no prior research was identified that addresses asthma self-management in mother/child dyads. For example, it is possible that teaching women to better manage their own asthma could have “trickle down” effects to how they help a child manage asthma. Last, as the above discussion of factors affecting women’s asthma makes clear, many risk factors for poor asthma management and control in women cluster together, such as obesity, depression, and GERD. Interventions that attempt to address the separate and interacting effects of these factors and comorbidities, may yield better outcomes among the most vulnerable asthma patients.

Corresponding author: Mary R. Janevic, PhD, Center for Managing Chronic Disease, University of Michigan School of Public Health, 1425 Washington Heights, Ann Arbor, MI 48109, [email protected].

Financial disclosures: None.

From the MetroHealth System, Cleveland, OH.

Abstract

• Objective: To describe risk factors for unplanned extubation (UE) among critically ill adults requiring mechanical ventilation and to identify strategies to reduce the occurrence of this adverse event.
• Methods: Review of the literature.
• Results: Inadvertent removal of an endotracheal tube, or a UE, occurs in 7% to 22.5% of mechanically ventilated adult patients and is often due to deliberate patient removal. Despite the multitude of research examining risk factors and predictors of UE, rates have remained unchanged for the past 2 decades. Risk factors can be classified by intensive care unit (ICU) type, including medical ICUs, surgical ICUs, and mixed medical-surgical ICUs. The majority of risk factors for UEs across ICUs may be amenable to changes in unit processes, such as programs for agitation management, use of weaning protocols, increased surveillance of patients, and ongoing education for patients and health care staff.
• Conclusion: Prevention of UE remains an elusive target. Changes in unit processes that target identified risk factors may be an effective method to decrease prevalence of UE.

Unplanned extubation (UE) is the inadvertent removal of an endotracheal tube, either by a patient (deliberate self-extubation), or by a member of the health care team providing routine care such as repositioning, suctioning, or procedures (accidental extubation). Approximately 7% to 22.5% of mechanically ventilated patients in the intensive care unit (ICU) experience UE [1–7]. Estimates are likely higher, as current regulatory and accreditation standards do not include mandatory reporting of this event. Despite numerous studies investigating risk factors associated with UE, it remains a prevalent problem with adverse outcomes for patients and hospitals. The purpose of this review is to provide a summary of the literature on risk factors for UE, review effects on patient and organizational outcomes, and identify evidence-based strategies for reducing occurrence of UE among mechanically ventilated patients.

Prevalence of Unplanned Exubation

There is substantial heterogeneity in how UE is calculated and reported in the research literature. UE is calculated as the number of UE events per 100 or 1000 patient days, or the number of UE per total ventilator days. Rates of UE are also reported as the proportion of patients who experience UE out of all intubated patients over a set time period [8]. Despite efforts aimed at mitigating risk factors for UE, rates have remained static over the past 2 decades. Reported UE rates from 1994–2002 were 2.6% to 14% [3,6,9–11], while rates from 2004–2014 ranged from 1% to 22% [3–5,8,12–15]. Interventions utilizing a multidisciplinary approach have been implemented with the aim of decreasing UE, yet few have proven successful on improving rates nationally.

Unplanned self-extubation by the patient (deliberate self-extubation) is the most common type of UE [3,10,12,16–18]. A multicenter trial of 426 patients from 11 medical centers indicates that 46 patients experienced UE, with 36 of these (78.2%) caused by patient self-extubation [6]. Prospective single-site studies report similar or higher estimates of patient self-extubation, ranging from 75.8% to 91.7% [3,5], while a multisite study of 10,112 patients revealed 32 of 35 UE (91.4%) were due to patient self-extubation [12]. Similarly, a 4-year analysis of 85 UEs reported 82 incidences (96.5%) were a result of deliberate patient removal [13]. Patients either physically pull out the endotracheal tube or use their tongue or coughing/gagging maneuvers to displace or intentionally remove the endotracheal tube [5]. Only 3% to 8% of UEs are caused by inadvertent removal by health care staff [3,5,12,13].

Effects on Patient and Organizational Outcomes

Regardless of the cause of the UE, there are adverse consequences for both patients and hospitals. Some patients who experience UE have higher rates of in-hospital mortality; however, this is often due to contributing factors associated with severity of injury, the need for reintubation, and underlying chronic diseases [13]. Patients who experience accidental UE have higher incidence of nosocomial pneumonia (27.6% vs. 138%, P = 0.002) [11], longer duration of mechanical ventilation, and increased length of stay (LOS) [7,13]. While some studies report UE can result in serious consequences such as respiratory distress, hypoxia [13], and even death [6,12], others report lower mortality and length of stay when UE occurs, likely due to the fact that many patients are ready for liberation from mechanical ventilation at the time of UE [5,15].

Despite the emergent nature of UE, not all patients experience immediate reintubation. Many instances of UE occur during patient weaning trials or in preparation for planned extubations [5,11], which explains why only 10% to 60% of patients require reintubation [3,5,10,11,15,19,20]. When reintubation is necessary, it results in increased number of ventilator days [10,11], and increased ICU and hospital LOS [1,11]. There is little evidence directly linking reintubation with in-hospital mortality; however, it can cause serious complications such as hypotension, hypertension, arrhythmias, and airway trauma [21]. For hospitals and health care organizations, the need for reintubation results in increased hospital costs, estimated to be $1000 per reintubation event [17,22]. This estimate does not take into account additional costs incurred with increased ICU care, longer periods of mechanical ventilation, and increased LOS. Estimates of these additional costs in pediatric patients are approximately $36,000 [23]. Costs are likely higher in adult patients, due to multiple comorbidities that often accompany the need for mechanical ventilation, as well as increased pharmacy, lab, and diagnostic charges [1].

Risk Factors for Unplanned Extubation

Medical ICU Risk Factors

MICUs traditionally have the highest rates of UE [4,8]. Data from a national prevalence study indicated that there were 23.4 episodes of UE in MICUs per 1000 ventilator days [4]. Approximately 9.5% to 15% of all ventilated patients in the MICU experience UE [4,5,8]. Patients in the MICU who require mechanical ventilation often have complex chronic illness with underlying respiratory disease, which can result in prolonged periods of ventilation and increased risk of UE. Specific risk factors investigated in UE research include patient specific factors (age, gender, diagnosis, comorbidities, agitation, level of consciousness, laboratory values), ventilatory factors (ventilator type and setting, type of tracheal tube, method of tube fixation), as well as type of sedation and use of protocols [5,6,24]. Surprisingly, few variables emerge as significant risk factors for UE among MICU patients. Risk factors associated with UE have included male gender [24], presence of chronic obstructive pulmonary disease (COPD) [24], increased level of consciousness [25], and use of weaning protocols [5]. While gender, COPD, and level of consciousness increase risk of UE, the presence of weaning protocols is shown to decrease risk of UE [5]. Although UE are reported most often in MICUs, few risk factors consistently emerge for this specific cohort, making definitive recommendations for prevention of UE difficult.

Surgical ICU Risk Factors

The prevalence of UE for mechanically ventilated patients in the SICU tend to be lower than those for MICU cohorts. Prevalence of UE in the SICU is reported at 1.41 episodes per 100 ventilator days [13], or 6.8 episodes per 1000 ventilator days [4]. Percentages of UE in the SICU range from 2% to 6% [4,8,19]. Similar to MICU patients, critically ill patients in the SICU often have specific risk factors placing them at risk for UE. Causative factors examined in research studies with this population include gender, age, sedation scale scores, need for reintubation, time from intubation to extubation, use of sedatives/analgesics, restraints, ICU nurse experience, location of staff at time of UE, and criteria for extubation [17,19]. Similar to MICU cohorts, few variables are identified as predictors of UE. Significant predictors include use of restraints, decreased sedation [17], and meeting criteria for extubation [19]. Among patients who experienced an UE, 87% were restrained at the time of the UE [17], and most had low levels of sedation (mean Ramsay sedation scale score = 2.42 in the hour preceding the UE). Approximately 64% of patients who experienced UE met criteria for planned extubation and did not require re-intubation [19], suggesting many patients were essentially ready for planned extubation.

Mixed ICU Risk Factors

The majority of research investigating risk factors for UE is conducted within medical-surgical or mixed/general ICUs. The prevalence of UE within this type of unit is reported at 1.59 episodes per 100 patient days [6], or approximately 2% to 10% [4,6,7]. Among this population, potential risk factors are similar to those included in solely MICU or SICU studies. Because of the high number of studies investigating UE in a mixed ICU setting, there are significantly more variables included in as potential risk factors. Variables include patient age, gender, admission diagnosis, injury severity using Acute Physiological and Chronic Health Evaluation (APACHE II), ICU and hospital LOS, patient level of consciousness, agitation, days of mechanical ventilation, ventilator settings, nosocomial infection, sedation, physical restraints, vital signs [7,14,26], laboratory values, medication types, and body mass index [15,26]. One study also included time of UE and ICU nurse level of experience [3]. Among all factors, several were significant predictors of UE: male gender [15], decreased sedation and increased level of consciousness [8], agitation [3,19,26], use of restraints [3,7], sedation practices (particularly use of benzodiazapines) [3,7,15,26,27], lack of strong tube fixation, absence of IV sedation, and orotracheal intubation [6]. UE were more likely to occur on the night shift and among staff that included nurses with fewer years of experience [3]. Many episodes of UE occurred during weaning [10] or among patients who could communicate and were alert [3]. One study reports 57% of patients who intentionally self-extubated explained they simply removed the tube because it was uncomfortable [3].

Strategies for Reducing Adverse Events

Agitation Management

The majority of studies cited agitation, altered level of consciousness, or inadequate sedation as risk factors for UE [3,6–8,15,17,18,25,26,28,29]. These factors directly impact restraint use, another common risk factor for UE [3,7,17]. A key recommendation for agitation management is to identify the source of agitation, which is often caused by delirium onset in the ICU [30–32]. Prevalence of delirium in the ICU ranges from 20% to 80% [33–35]. ICU patients are at high risk for delirium due to sleep deprivation, older age, restraints, abnormal lab values, medications, infection, and respiratory complications [31]. Treatment for delirium centers on prevention, early recognition, interdisciplinary and pharmacologic protocols, increased nursing presence, and use of short-acting sedation when necessary [30–32,36]. While there is no research specifically linking delirium to UE, a quality analysis of risk factors present at the time of UE using bow-tie analysis methods identified delirium as a key factor present in the majority of UE cases [36]. It is possible that agitation reported in other studies investigating risk factors for UE may actually be reflective of underlying delirium. Routine screening using validated tools, such as the Confusion Assessment Method-ICU (CAM-ICU) [37] would aid in early detection and management of delirium, and would provide a standardized method for exploring the relationship of delirium and UE in future trials.

Integration of Weaning Protocols

Protocol-directed weaning is beneficial for decreasing ventilator days, time to wean from mechanical ventilation, and ICU LOS [38]. A systematic review including 7 trials (2434 patients) comparing protocol/non-protocol for weaning from mechanical ventilation reported a 26% decrease in the mean duration of mechanical ventilation for the protocol groups (95% CI 13%–37%, P < 0.001), a 70% reduction in time to wean, (95% CI 27%–88%, P = 0.009), and a decrease in ICU LOS by 11% (95% CI 3%–19%, P = 0.01). Weaning protocols are also an important risk factor for UE [5]. Findings from a prospective cohort study specifically identify the presence of weaning protocols as an important factor for reducing UE; patients who had weaning protocols ordered and followed were least likely to experience UE (P = 0.02) [5]. A separate quality improvement initiative demonstrated an overall decrease in the number of UEs (from 5.2% to 0.9%) after implementing weaning protocols as standard of care [39]. Considering many UEs occur during weaning [10], integration of weaning protocols aids in expediting the process and ensuring timely extubation.

Increased Surveillance

Increasing surveillance and monitoring of ventilated patients is a recommendation based on risk factors presented at the time of UE. Specifically, staffing levels and shifts and the use of physical restraints are variables associated with UE that are amendable to changes in unit processes based on increased surveillance. It is reported that 40% to 76% of UEs occurred during the night shift [14,17,24,40]; many more occur during change of shift or when there is not a nurse present at the bedside [3,17]. Recent trends towards mandatory bedside reporting is a specific intervention that may positively impact UE among patients in the ICU [41]. Meta-analyses of observational studies investigating the effect of nurse staffing on hospital outcomes indicate that increasing the number of RNs is associated with decreased risk of adverse patient outcomes, including UE [42,43]. The addition of 1 additional nurse per patient day can result in a 51% decrease in UE, while a decrease in nursing workload could result in a 45% decrease in UE [42]. Data from a national prevalence study reports ICUs with fewer available resources, including staff, experienced a higher number of UEs [4].

Increasing surveillance by nursing and health care staff may also impact prevalence of physical restraint use. A significant number of patients who experience UE are physically restrained at the time of the incident, ranging from 40% to 90% of intubated patients [5–7,14,17,40]. It is well documented that UE continue to occur despite the use of restraints [5,7,28,29,44] Patients who are physically restrained often experience higher rates of unplanned extubation (42.9% vs. 16.5% , P < 0.001 in Chang et al’s study [7]), and longer ICU LOS (20.3 days vs. 15.8 days, P = 0.009) [7]. Soft wrist restraints are commonly used to prevent pulling of the endotracheal tube; however, research evidence on UE demonstrates this is not always an effective intervention. Increasing surveillance of ventilated patients, treating their agitation and screening for underlying delirium, and integration of weaning protocols are all interventions that may decrease UE and the need for routine use of physical restraints.

Ongoing Education for Patients and Health Care Staff

Initial and ongoing education about UE, risk factors, and effective interventions is beneficial for patients and health care staff. Although there are no trials investigating effects of educational interventions for patients on UE outcomes, pre-education of surgical patients regarding what to expect while intubated may aid in decreasing delirium risk, agitation, physical restraint use, and possibly UE. Verbal and written educational information during pre-admission testing is a feasible method easily integrated into pre-operative programs.

Because UEs often occur more frequently among less experienced staff, initial education about risk factors for UE is crucial to include in ICU staff orientation programs [3,7]. Educational initiatives should incorporate training on routine delirium screening and avoidance of agitation, use of protocols, and increased surveillance of patients receiving mechanical ventilation [5,15,17,39,45]. Ongoing education of staff regarding ventilatory equipment and risk factors for UE can be particularly effective in decreasing UE [46]. Initial educational efforts should be followed by routine updates for all members of the healthcare team about ongoing quality improvement efforts to monitor UE. Associated factors for UE that may be unit- or process-specific, including methods for endotracheal tube securement and intra-hospital transport, should be communicated with all individuals involved in patient care. Integration of continuous quality improvement programs can decrease UE rates by 22% to 53% [16]. Quality efforts typically focus on standardization of reporting and tracking tools, protocol implementations, and ongoing monitoring, auditing, and recording of UE.

Current Trends and Future Directions

Recent trends in critical care recommendations may mitigate potential risk factors identified in UE research. Integration of lightened sedation and daily wake up periods for intubated patients may decrease prevalence of risk factors for UE, specifically agitation, physical restraint use, and altered level of consciousness [30], while routine weaning protocols may improve ventilatory outcomes, including UE [5,38,40]. Nursing bedside report and purposeful hourly rounding are quickly emerging as mainstays of professional nursing care [41]. Inherent in these 2 initiatives are increased surveillance and vigilance by health care staff, which can result in timely extubation of those who indicate readiness, as well as decreased incidence of adverse events. Delirium remains a key factor that may be a likely cause for UE; recent trends towards early detection and proper management of delirium among ICU staff may result in improved ventilatory outcomes, including weaning, planned extubation, and the prevalence of UE.

Another important trend in critical care is the emergence of a neurocritical care specialty and routine admission of neurocritically ill patients to neuroscience ICUs [47,48]. However, there are no studies investigating prevalence of UE among these patients, who often have higher rates of agitation or restlessness due to cognitive impairment. Among general ICUs, patients with a primary respiratory diagnosis accounted for 23% of all UE in one study, while those with a neurological diagnosis accounted for the second highest percentage (12%) among the study population [15]. A separate study concluded that presence of neurological injury with a concomitant nosocomial infection increased risk of UE among patients in a mixed ICU [7]. A recent systematic review of weaning protocols highlights positive effects on ventilatory outcomes but cites lack of evidence for effectiveness of protocols among those with neurological injury [38]. Areas for future UE research should include factors specific to this patient population, as they may be at higher risk for adverse ventilatory outcomes due to the nature of the neurological injury.

Conclusion

Prevention of UE remains an elusive target, evidenced by little change in reported rates over 2 decades. Research provides data on risk factors that may be patient, unit, or process related. Structuring prevention efforts around modifiable risk factors for UE is a feasible approach amenable to ongoing monitoring for effectiveness. Integration of current trends in health care safety and quality may produce an added benefit of reducing the occurrence of UE in critical care units. Future research evaluating these trends and the prevalence of UE in subspecialty populations is warranted.

Corresponding author: Molly McNett, PhD, RN, CNRN, Attn: NBO, MetroHealth Medical Center, 2500 MetroHealth Drive; Cleveland, OH 44109, [email protected].

Financial disclosures: None.

From the MetroHealth System, Cleveland, OH.

Abstract

• Objective: To describe risk factors for unplanned extubation (UE) among critically ill adults requiring mechanical ventilation and to identify strategies to reduce the occurrence of this adverse event.
• Methods: Review of the literature.
• Results: Inadvertent removal of an endotracheal tube, or a UE, occurs in 7% to 22.5% of mechanically ventilated adult patients and is often due to deliberate patient removal. Despite the multitude of research examining risk factors and predictors of UE, rates have remained unchanged for the past 2 decades. Risk factors can be classified by intensive care unit (ICU) type, including medical ICUs, surgical ICUs, and mixed medical-surgical ICUs. The majority of risk factors for UEs across ICUs may be amenable to changes in unit processes, such as programs for agitation management, use of weaning protocols, increased surveillance of patients, and ongoing education for patients and health care staff.
• Conclusion: Prevention of UE remains an elusive target. Changes in unit processes that target identified risk factors may be an effective method to decrease prevalence of UE.

Unplanned extubation (UE) is the inadvertent removal of an endotracheal tube, either by a patient (deliberate self-extubation), or by a member of the health care team providing routine care such as repositioning, suctioning, or procedures (accidental extubation). Approximately 7% to 22.5% of mechanically ventilated patients in the intensive care unit (ICU) experience UE [1–7]. Estimates are likely higher, as current regulatory and accreditation standards do not include mandatory reporting of this event. Despite numerous studies investigating risk factors associated with UE, it remains a prevalent problem with adverse outcomes for patients and hospitals. The purpose of this review is to provide a summary of the literature on risk factors for UE, review effects on patient and organizational outcomes, and identify evidence-based strategies for reducing occurrence of UE among mechanically ventilated patients.

Prevalence of Unplanned Exubation

There is substantial heterogeneity in how UE is calculated and reported in the research literature. UE is calculated as the number of UE events per 100 or 1000 patient days, or the number of UE per total ventilator days. Rates of UE are also reported as the proportion of patients who experience UE out of all intubated patients over a set time period [8]. Despite efforts aimed at mitigating risk factors for UE, rates have remained static over the past 2 decades. Reported UE rates from 1994–2002 were 2.6% to 14% [3,6,9–11], while rates from 2004–2014 ranged from 1% to 22% [3–5,8,12–15]. Interventions utilizing a multidisciplinary approach have been implemented with the aim of decreasing UE, yet few have proven successful on improving rates nationally.

Unplanned self-extubation by the patient (deliberate self-extubation) is the most common type of UE [3,10,12,16–18]. A multicenter trial of 426 patients from 11 medical centers indicates that 46 patients experienced UE, with 36 of these (78.2%) caused by patient self-extubation [6]. Prospective single-site studies report similar or higher estimates of patient self-extubation, ranging from 75.8% to 91.7% [3,5], while a multisite study of 10,112 patients revealed 32 of 35 UE (91.4%) were due to patient self-extubation [12]. Similarly, a 4-year analysis of 85 UEs reported 82 incidences (96.5%) were a result of deliberate patient removal [13]. Patients either physically pull out the endotracheal tube or use their tongue or coughing/gagging maneuvers to displace or intentionally remove the endotracheal tube [5]. Only 3% to 8% of UEs are caused by inadvertent removal by health care staff [3,5,12,13].

Effects on Patient and Organizational Outcomes

Regardless of the cause of the UE, there are adverse consequences for both patients and hospitals. Some patients who experience UE have higher rates of in-hospital mortality; however, this is often due to contributing factors associated with severity of injury, the need for reintubation, and underlying chronic diseases [13]. Patients who experience accidental UE have higher incidence of nosocomial pneumonia (27.6% vs. 138%, P = 0.002) [11], longer duration of mechanical ventilation, and increased length of stay (LOS) [7,13]. While some studies report UE can result in serious consequences such as respiratory distress, hypoxia [13], and even death [6,12], others report lower mortality and length of stay when UE occurs, likely due to the fact that many patients are ready for liberation from mechanical ventilation at the time of UE [5,15].

Despite the emergent nature of UE, not all patients experience immediate reintubation. Many instances of UE occur during patient weaning trials or in preparation for planned extubations [5,11], which explains why only 10% to 60% of patients require reintubation [3,5,10,11,15,19,20]. When reintubation is necessary, it results in increased number of ventilator days [10,11], and increased ICU and hospital LOS [1,11]. There is little evidence directly linking reintubation with in-hospital mortality; however, it can cause serious complications such as hypotension, hypertension, arrhythmias, and airway trauma [21]. For hospitals and health care organizations, the need for reintubation results in increased hospital costs, estimated to be $1000 per reintubation event [17,22]. This estimate does not take into account additional costs incurred with increased ICU care, longer periods of mechanical ventilation, and increased LOS. Estimates of these additional costs in pediatric patients are approximately $36,000 [23]. Costs are likely higher in adult patients, due to multiple comorbidities that often accompany the need for mechanical ventilation, as well as increased pharmacy, lab, and diagnostic charges [1].

Risk Factors for Unplanned Extubation

Medical ICU Risk Factors

MICUs traditionally have the highest rates of UE [4,8]. Data from a national prevalence study indicated that there were 23.4 episodes of UE in MICUs per 1000 ventilator days [4]. Approximately 9.5% to 15% of all ventilated patients in the MICU experience UE [4,5,8]. Patients in the MICU who require mechanical ventilation often have complex chronic illness with underlying respiratory disease, which can result in prolonged periods of ventilation and increased risk of UE. Specific risk factors investigated in UE research include patient specific factors (age, gender, diagnosis, comorbidities, agitation, level of consciousness, laboratory values), ventilatory factors (ventilator type and setting, type of tracheal tube, method of tube fixation), as well as type of sedation and use of protocols [5,6,24]. Surprisingly, few variables emerge as significant risk factors for UE among MICU patients. Risk factors associated with UE have included male gender [24], presence of chronic obstructive pulmonary disease (COPD) [24], increased level of consciousness [25], and use of weaning protocols [5]. While gender, COPD, and level of consciousness increase risk of UE, the presence of weaning protocols is shown to decrease risk of UE [5]. Although UE are reported most often in MICUs, few risk factors consistently emerge for this specific cohort, making definitive recommendations for prevention of UE difficult.

Surgical ICU Risk Factors

The prevalence of UE for mechanically ventilated patients in the SICU tend to be lower than those for MICU cohorts. Prevalence of UE in the SICU is reported at 1.41 episodes per 100 ventilator days [13], or 6.8 episodes per 1000 ventilator days [4]. Percentages of UE in the SICU range from 2% to 6% [4,8,19]. Similar to MICU patients, critically ill patients in the SICU often have specific risk factors placing them at risk for UE. Causative factors examined in research studies with this population include gender, age, sedation scale scores, need for reintubation, time from intubation to extubation, use of sedatives/analgesics, restraints, ICU nurse experience, location of staff at time of UE, and criteria for extubation [17,19]. Similar to MICU cohorts, few variables are identified as predictors of UE. Significant predictors include use of restraints, decreased sedation [17], and meeting criteria for extubation [19]. Among patients who experienced an UE, 87% were restrained at the time of the UE [17], and most had low levels of sedation (mean Ramsay sedation scale score = 2.42 in the hour preceding the UE). Approximately 64% of patients who experienced UE met criteria for planned extubation and did not require re-intubation [19], suggesting many patients were essentially ready for planned extubation.

Mixed ICU Risk Factors

The majority of research investigating risk factors for UE is conducted within medical-surgical or mixed/general ICUs. The prevalence of UE within this type of unit is reported at 1.59 episodes per 100 patient days [6], or approximately 2% to 10% [4,6,7]. Among this population, potential risk factors are similar to those included in solely MICU or SICU studies. Because of the high number of studies investigating UE in a mixed ICU setting, there are significantly more variables included in as potential risk factors. Variables include patient age, gender, admission diagnosis, injury severity using Acute Physiological and Chronic Health Evaluation (APACHE II), ICU and hospital LOS, patient level of consciousness, agitation, days of mechanical ventilation, ventilator settings, nosocomial infection, sedation, physical restraints, vital signs [7,14,26], laboratory values, medication types, and body mass index [15,26]. One study also included time of UE and ICU nurse level of experience [3]. Among all factors, several were significant predictors of UE: male gender [15], decreased sedation and increased level of consciousness [8], agitation [3,19,26], use of restraints [3,7], sedation practices (particularly use of benzodiazapines) [3,7,15,26,27], lack of strong tube fixation, absence of IV sedation, and orotracheal intubation [6]. UE were more likely to occur on the night shift and among staff that included nurses with fewer years of experience [3]. Many episodes of UE occurred during weaning [10] or among patients who could communicate and were alert [3]. One study reports 57% of patients who intentionally self-extubated explained they simply removed the tube because it was uncomfortable [3].

Strategies for Reducing Adverse Events

Agitation Management

The majority of studies cited agitation, altered level of consciousness, or inadequate sedation as risk factors for UE [3,6–8,15,17,18,25,26,28,29]. These factors directly impact restraint use, another common risk factor for UE [3,7,17]. A key recommendation for agitation management is to identify the source of agitation, which is often caused by delirium onset in the ICU [30–32]. Prevalence of delirium in the ICU ranges from 20% to 80% [33–35]. ICU patients are at high risk for delirium due to sleep deprivation, older age, restraints, abnormal lab values, medications, infection, and respiratory complications [31]. Treatment for delirium centers on prevention, early recognition, interdisciplinary and pharmacologic protocols, increased nursing presence, and use of short-acting sedation when necessary [30–32,36]. While there is no research specifically linking delirium to UE, a quality analysis of risk factors present at the time of UE using bow-tie analysis methods identified delirium as a key factor present in the majority of UE cases [36]. It is possible that agitation reported in other studies investigating risk factors for UE may actually be reflective of underlying delirium. Routine screening using validated tools, such as the Confusion Assessment Method-ICU (CAM-ICU) [37] would aid in early detection and management of delirium, and would provide a standardized method for exploring the relationship of delirium and UE in future trials.

Integration of Weaning Protocols

Protocol-directed weaning is beneficial for decreasing ventilator days, time to wean from mechanical ventilation, and ICU LOS [38]. A systematic review including 7 trials (2434 patients) comparing protocol/non-protocol for weaning from mechanical ventilation reported a 26% decrease in the mean duration of mechanical ventilation for the protocol groups (95% CI 13%–37%, P < 0.001), a 70% reduction in time to wean, (95% CI 27%–88%, P = 0.009), and a decrease in ICU LOS by 11% (95% CI 3%–19%, P = 0.01). Weaning protocols are also an important risk factor for UE [5]. Findings from a prospective cohort study specifically identify the presence of weaning protocols as an important factor for reducing UE; patients who had weaning protocols ordered and followed were least likely to experience UE (P = 0.02) [5]. A separate quality improvement initiative demonstrated an overall decrease in the number of UEs (from 5.2% to 0.9%) after implementing weaning protocols as standard of care [39]. Considering many UEs occur during weaning [10], integration of weaning protocols aids in expediting the process and ensuring timely extubation.

Increased Surveillance

Increasing surveillance and monitoring of ventilated patients is a recommendation based on risk factors presented at the time of UE. Specifically, staffing levels and shifts and the use of physical restraints are variables associated with UE that are amendable to changes in unit processes based on increased surveillance. It is reported that 40% to 76% of UEs occurred during the night shift [14,17,24,40]; many more occur during change of shift or when there is not a nurse present at the bedside [3,17]. Recent trends towards mandatory bedside reporting is a specific intervention that may positively impact UE among patients in the ICU [41]. Meta-analyses of observational studies investigating the effect of nurse staffing on hospital outcomes indicate that increasing the number of RNs is associated with decreased risk of adverse patient outcomes, including UE [42,43]. The addition of 1 additional nurse per patient day can result in a 51% decrease in UE, while a decrease in nursing workload could result in a 45% decrease in UE [42]. Data from a national prevalence study reports ICUs with fewer available resources, including staff, experienced a higher number of UEs [4].

Increasing surveillance by nursing and health care staff may also impact prevalence of physical restraint use. A significant number of patients who experience UE are physically restrained at the time of the incident, ranging from 40% to 90% of intubated patients [5–7,14,17,40]. It is well documented that UE continue to occur despite the use of restraints [5,7,28,29,44] Patients who are physically restrained often experience higher rates of unplanned extubation (42.9% vs. 16.5% , P < 0.001 in Chang et al’s study [7]), and longer ICU LOS (20.3 days vs. 15.8 days, P = 0.009) [7]. Soft wrist restraints are commonly used to prevent pulling of the endotracheal tube; however, research evidence on UE demonstrates this is not always an effective intervention. Increasing surveillance of ventilated patients, treating their agitation and screening for underlying delirium, and integration of weaning protocols are all interventions that may decrease UE and the need for routine use of physical restraints.

Ongoing Education for Patients and Health Care Staff

Initial and ongoing education about UE, risk factors, and effective interventions is beneficial for patients and health care staff. Although there are no trials investigating effects of educational interventions for patients on UE outcomes, pre-education of surgical patients regarding what to expect while intubated may aid in decreasing delirium risk, agitation, physical restraint use, and possibly UE. Verbal and written educational information during pre-admission testing is a feasible method easily integrated into pre-operative programs.

Because UEs often occur more frequently among less experienced staff, initial education about risk factors for UE is crucial to include in ICU staff orientation programs [3,7]. Educational initiatives should incorporate training on routine delirium screening and avoidance of agitation, use of protocols, and increased surveillance of patients receiving mechanical ventilation [5,15,17,39,45]. Ongoing education of staff regarding ventilatory equipment and risk factors for UE can be particularly effective in decreasing UE [46]. Initial educational efforts should be followed by routine updates for all members of the healthcare team about ongoing quality improvement efforts to monitor UE. Associated factors for UE that may be unit- or process-specific, including methods for endotracheal tube securement and intra-hospital transport, should be communicated with all individuals involved in patient care. Integration of continuous quality improvement programs can decrease UE rates by 22% to 53% [16]. Quality efforts typically focus on standardization of reporting and tracking tools, protocol implementations, and ongoing monitoring, auditing, and recording of UE.

Current Trends and Future Directions

Recent trends in critical care recommendations may mitigate potential risk factors identified in UE research. Integration of lightened sedation and daily wake up periods for intubated patients may decrease prevalence of risk factors for UE, specifically agitation, physical restraint use, and altered level of consciousness [30], while routine weaning protocols may improve ventilatory outcomes, including UE [5,38,40]. Nursing bedside report and purposeful hourly rounding are quickly emerging as mainstays of professional nursing care [41]. Inherent in these 2 initiatives are increased surveillance and vigilance by health care staff, which can result in timely extubation of those who indicate readiness, as well as decreased incidence of adverse events. Delirium remains a key factor that may be a likely cause for UE; recent trends towards early detection and proper management of delirium among ICU staff may result in improved ventilatory outcomes, including weaning, planned extubation, and the prevalence of UE.

Another important trend in critical care is the emergence of a neurocritical care specialty and routine admission of neurocritically ill patients to neuroscience ICUs [47,48]. However, there are no studies investigating prevalence of UE among these patients, who often have higher rates of agitation or restlessness due to cognitive impairment. Among general ICUs, patients with a primary respiratory diagnosis accounted for 23% of all UE in one study, while those with a neurological diagnosis accounted for the second highest percentage (12%) among the study population [15]. A separate study concluded that presence of neurological injury with a concomitant nosocomial infection increased risk of UE among patients in a mixed ICU [7]. A recent systematic review of weaning protocols highlights positive effects on ventilatory outcomes but cites lack of evidence for effectiveness of protocols among those with neurological injury [38]. Areas for future UE research should include factors specific to this patient population, as they may be at higher risk for adverse ventilatory outcomes due to the nature of the neurological injury.

Conclusion

Prevention of UE remains an elusive target, evidenced by little change in reported rates over 2 decades. Research provides data on risk factors that may be patient, unit, or process related. Structuring prevention efforts around modifiable risk factors for UE is a feasible approach amenable to ongoing monitoring for effectiveness. Integration of current trends in health care safety and quality may produce an added benefit of reducing the occurrence of UE in critical care units. Future research evaluating these trends and the prevalence of UE in subspecialty populations is warranted.

Corresponding author: Molly McNett, PhD, RN, CNRN, Attn: NBO, MetroHealth Medical Center, 2500 MetroHealth Drive; Cleveland, OH 44109, [email protected].

Financial disclosures: None.

From the MetroHealth System, Cleveland, OH.

Abstract

• Objective: To describe risk factors for unplanned extubation (UE) among critically ill adults requiring mechanical ventilation and to identify strategies to reduce the occurrence of this adverse event.
• Methods: Review of the literature.
• Results: Inadvertent removal of an endotracheal tube, or a UE, occurs in 7% to 22.5% of mechanically ventilated adult patients and is often due to deliberate patient removal. Despite the multitude of research examining risk factors and predictors of UE, rates have remained unchanged for the past 2 decades. Risk factors can be classified by intensive care unit (ICU) type, including medical ICUs, surgical ICUs, and mixed medical-surgical ICUs. The majority of risk factors for UEs across ICUs may be amenable to changes in unit processes, such as programs for agitation management, use of weaning protocols, increased surveillance of patients, and ongoing education for patients and health care staff.
• Conclusion: Prevention of UE remains an elusive target. Changes in unit processes that target identified risk factors may be an effective method to decrease prevalence of UE.

Unplanned extubation (UE) is the inadvertent removal of an endotracheal tube, either by a patient (deliberate self-extubation), or by a member of the health care team providing routine care such as repositioning, suctioning, or procedures (accidental extubation). Approximately 7% to 22.5% of mechanically ventilated patients in the intensive care unit (ICU) experience UE [1–7]. Estimates are likely higher, as current regulatory and accreditation standards do not include mandatory reporting of this event. Despite numerous studies investigating risk factors associated with UE, it remains a prevalent problem with adverse outcomes for patients and hospitals. The purpose of this review is to provide a summary of the literature on risk factors for UE, review effects on patient and organizational outcomes, and identify evidence-based strategies for reducing occurrence of UE among mechanically ventilated patients.

Prevalence of Unplanned Exubation

There is substantial heterogeneity in how UE is calculated and reported in the research literature. UE is calculated as the number of UE events per 100 or 1000 patient days, or the number of UE per total ventilator days. Rates of UE are also reported as the proportion of patients who experience UE out of all intubated patients over a set time period [8]. Despite efforts aimed at mitigating risk factors for UE, rates have remained static over the past 2 decades. Reported UE rates from 1994–2002 were 2.6% to 14% [3,6,9–11], while rates from 2004–2014 ranged from 1% to 22% [3–5,8,12–15]. Interventions utilizing a multidisciplinary approach have been implemented with the aim of decreasing UE, yet few have proven successful on improving rates nationally.

Unplanned self-extubation by the patient (deliberate self-extubation) is the most common type of UE [3,10,12,16–18]. A multicenter trial of 426 patients from 11 medical centers indicates that 46 patients experienced UE, with 36 of these (78.2%) caused by patient self-extubation [6]. Prospective single-site studies report similar or higher estimates of patient self-extubation, ranging from 75.8% to 91.7% [3,5], while a multisite study of 10,112 patients revealed 32 of 35 UE (91.4%) were due to patient self-extubation [12]. Similarly, a 4-year analysis of 85 UEs reported 82 incidences (96.5%) were a result of deliberate patient removal [13]. Patients either physically pull out the endotracheal tube or use their tongue or coughing/gagging maneuvers to displace or intentionally remove the endotracheal tube [5]. Only 3% to 8% of UEs are caused by inadvertent removal by health care staff [3,5,12,13].

Effects on Patient and Organizational Outcomes

Regardless of the cause of the UE, there are adverse consequences for both patients and hospitals. Some patients who experience UE have higher rates of in-hospital mortality; however, this is often due to contributing factors associated with severity of injury, the need for reintubation, and underlying chronic diseases [13]. Patients who experience accidental UE have higher incidence of nosocomial pneumonia (27.6% vs. 138%, P = 0.002) [11], longer duration of mechanical ventilation, and increased length of stay (LOS) [7,13]. While some studies report UE can result in serious consequences such as respiratory distress, hypoxia [13], and even death [6,12], others report lower mortality and length of stay when UE occurs, likely due to the fact that many patients are ready for liberation from mechanical ventilation at the time of UE [5,15].

Despite the emergent nature of UE, not all patients experience immediate reintubation. Many instances of UE occur during patient weaning trials or in preparation for planned extubations [5,11], which explains why only 10% to 60% of patients require reintubation [3,5,10,11,15,19,20]. When reintubation is necessary, it results in increased number of ventilator days [10,11], and increased ICU and hospital LOS [1,11]. There is little evidence directly linking reintubation with in-hospital mortality; however, it can cause serious complications such as hypotension, hypertension, arrhythmias, and airway trauma [21]. For hospitals and health care organizations, the need for reintubation results in increased hospital costs, estimated to be $1000 per reintubation event [17,22]. This estimate does not take into account additional costs incurred with increased ICU care, longer periods of mechanical ventilation, and increased LOS. Estimates of these additional costs in pediatric patients are approximately $36,000 [23]. Costs are likely higher in adult patients, due to multiple comorbidities that often accompany the need for mechanical ventilation, as well as increased pharmacy, lab, and diagnostic charges [1].

Risk Factors for Unplanned Extubation

Medical ICU Risk Factors

MICUs traditionally have the highest rates of UE [4,8]. Data from a national prevalence study indicated that there were 23.4 episodes of UE in MICUs per 1000 ventilator days [4]. Approximately 9.5% to 15% of all ventilated patients in the MICU experience UE [4,5,8]. Patients in the MICU who require mechanical ventilation often have complex chronic illness with underlying respiratory disease, which can result in prolonged periods of ventilation and increased risk of UE. Specific risk factors investigated in UE research include patient specific factors (age, gender, diagnosis, comorbidities, agitation, level of consciousness, laboratory values), ventilatory factors (ventilator type and setting, type of tracheal tube, method of tube fixation), as well as type of sedation and use of protocols [5,6,24]. Surprisingly, few variables emerge as significant risk factors for UE among MICU patients. Risk factors associated with UE have included male gender [24], presence of chronic obstructive pulmonary disease (COPD) [24], increased level of consciousness [25], and use of weaning protocols [5]. While gender, COPD, and level of consciousness increase risk of UE, the presence of weaning protocols is shown to decrease risk of UE [5]. Although UE are reported most often in MICUs, few risk factors consistently emerge for this specific cohort, making definitive recommendations for prevention of UE difficult.

Surgical ICU Risk Factors

The prevalence of UE for mechanically ventilated patients in the SICU tend to be lower than those for MICU cohorts. Prevalence of UE in the SICU is reported at 1.41 episodes per 100 ventilator days [13], or 6.8 episodes per 1000 ventilator days [4]. Percentages of UE in the SICU range from 2% to 6% [4,8,19]. Similar to MICU patients, critically ill patients in the SICU often have specific risk factors placing them at risk for UE. Causative factors examined in research studies with this population include gender, age, sedation scale scores, need for reintubation, time from intubation to extubation, use of sedatives/analgesics, restraints, ICU nurse experience, location of staff at time of UE, and criteria for extubation [17,19]. Similar to MICU cohorts, few variables are identified as predictors of UE. Significant predictors include use of restraints, decreased sedation [17], and meeting criteria for extubation [19]. Among patients who experienced an UE, 87% were restrained at the time of the UE [17], and most had low levels of sedation (mean Ramsay sedation scale score = 2.42 in the hour preceding the UE). Approximately 64% of patients who experienced UE met criteria for planned extubation and did not require re-intubation [19], suggesting many patients were essentially ready for planned extubation.

Mixed ICU Risk Factors

The majority of research investigating risk factors for UE is conducted within medical-surgical or mixed/general ICUs. The prevalence of UE within this type of unit is reported at 1.59 episodes per 100 patient days [6], or approximately 2% to 10% [4,6,7]. Among this population, potential risk factors are similar to those included in solely MICU or SICU studies. Because of the high number of studies investigating UE in a mixed ICU setting, there are significantly more variables included in as potential risk factors. Variables include patient age, gender, admission diagnosis, injury severity using Acute Physiological and Chronic Health Evaluation (APACHE II), ICU and hospital LOS, patient level of consciousness, agitation, days of mechanical ventilation, ventilator settings, nosocomial infection, sedation, physical restraints, vital signs [7,14,26], laboratory values, medication types, and body mass index [15,26]. One study also included time of UE and ICU nurse level of experience [3]. Among all factors, several were significant predictors of UE: male gender [15], decreased sedation and increased level of consciousness [8], agitation [3,19,26], use of restraints [3,7], sedation practices (particularly use of benzodiazapines) [3,7,15,26,27], lack of strong tube fixation, absence of IV sedation, and orotracheal intubation [6]. UE were more likely to occur on the night shift and among staff that included nurses with fewer years of experience [3]. Many episodes of UE occurred during weaning [10] or among patients who could communicate and were alert [3]. One study reports 57% of patients who intentionally self-extubated explained they simply removed the tube because it was uncomfortable [3].

Strategies for Reducing Adverse Events

Agitation Management

The majority of studies cited agitation, altered level of consciousness, or inadequate sedation as risk factors for UE [3,6–8,15,17,18,25,26,28,29]. These factors directly impact restraint use, another common risk factor for UE [3,7,17]. A key recommendation for agitation management is to identify the source of agitation, which is often caused by delirium onset in the ICU [30–32]. Prevalence of delirium in the ICU ranges from 20% to 80% [33–35]. ICU patients are at high risk for delirium due to sleep deprivation, older age, restraints, abnormal lab values, medications, infection, and respiratory complications [31]. Treatment for delirium centers on prevention, early recognition, interdisciplinary and pharmacologic protocols, increased nursing presence, and use of short-acting sedation when necessary [30–32,36]. While there is no research specifically linking delirium to UE, a quality analysis of risk factors present at the time of UE using bow-tie analysis methods identified delirium as a key factor present in the majority of UE cases [36]. It is possible that agitation reported in other studies investigating risk factors for UE may actually be reflective of underlying delirium. Routine screening using validated tools, such as the Confusion Assessment Method-ICU (CAM-ICU) [37] would aid in early detection and management of delirium, and would provide a standardized method for exploring the relationship of delirium and UE in future trials.

Integration of Weaning Protocols

Protocol-directed weaning is beneficial for decreasing ventilator days, time to wean from mechanical ventilation, and ICU LOS [38]. A systematic review including 7 trials (2434 patients) comparing protocol/non-protocol for weaning from mechanical ventilation reported a 26% decrease in the mean duration of mechanical ventilation for the protocol groups (95% CI 13%–37%, P < 0.001), a 70% reduction in time to wean, (95% CI 27%–88%, P = 0.009), and a decrease in ICU LOS by 11% (95% CI 3%–19%, P = 0.01). Weaning protocols are also an important risk factor for UE [5]. Findings from a prospective cohort study specifically identify the presence of weaning protocols as an important factor for reducing UE; patients who had weaning protocols ordered and followed were least likely to experience UE (P = 0.02) [5]. A separate quality improvement initiative demonstrated an overall decrease in the number of UEs (from 5.2% to 0.9%) after implementing weaning protocols as standard of care [39]. Considering many UEs occur during weaning [10], integration of weaning protocols aids in expediting the process and ensuring timely extubation.

Increased Surveillance

Increasing surveillance and monitoring of ventilated patients is a recommendation based on risk factors presented at the time of UE. Specifically, staffing levels and shifts and the use of physical restraints are variables associated with UE that are amendable to changes in unit processes based on increased surveillance. It is reported that 40% to 76% of UEs occurred during the night shift [14,17,24,40]; many more occur during change of shift or when there is not a nurse present at the bedside [3,17]. Recent trends towards mandatory bedside reporting is a specific intervention that may positively impact UE among patients in the ICU [41]. Meta-analyses of observational studies investigating the effect of nurse staffing on hospital outcomes indicate that increasing the number of RNs is associated with decreased risk of adverse patient outcomes, including UE [42,43]. The addition of 1 additional nurse per patient day can result in a 51% decrease in UE, while a decrease in nursing workload could result in a 45% decrease in UE [42]. Data from a national prevalence study reports ICUs with fewer available resources, including staff, experienced a higher number of UEs [4].

Increasing surveillance by nursing and health care staff may also impact prevalence of physical restraint use. A significant number of patients who experience UE are physically restrained at the time of the incident, ranging from 40% to 90% of intubated patients [5–7,14,17,40]. It is well documented that UE continue to occur despite the use of restraints [5,7,28,29,44] Patients who are physically restrained often experience higher rates of unplanned extubation (42.9% vs. 16.5% , P < 0.001 in Chang et al’s study [7]), and longer ICU LOS (20.3 days vs. 15.8 days, P = 0.009) [7]. Soft wrist restraints are commonly used to prevent pulling of the endotracheal tube; however, research evidence on UE demonstrates this is not always an effective intervention. Increasing surveillance of ventilated patients, treating their agitation and screening for underlying delirium, and integration of weaning protocols are all interventions that may decrease UE and the need for routine use of physical restraints.

Ongoing Education for Patients and Health Care Staff

Initial and ongoing education about UE, risk factors, and effective interventions is beneficial for patients and health care staff. Although there are no trials investigating effects of educational interventions for patients on UE outcomes, pre-education of surgical patients regarding what to expect while intubated may aid in decreasing delirium risk, agitation, physical restraint use, and possibly UE. Verbal and written educational information during pre-admission testing is a feasible method easily integrated into pre-operative programs.

Because UEs often occur more frequently among less experienced staff, initial education about risk factors for UE is crucial to include in ICU staff orientation programs [3,7]. Educational initiatives should incorporate training on routine delirium screening and avoidance of agitation, use of protocols, and increased surveillance of patients receiving mechanical ventilation [5,15,17,39,45]. Ongoing education of staff regarding ventilatory equipment and risk factors for UE can be particularly effective in decreasing UE [46]. Initial educational efforts should be followed by routine updates for all members of the healthcare team about ongoing quality improvement efforts to monitor UE. Associated factors for UE that may be unit- or process-specific, including methods for endotracheal tube securement and intra-hospital transport, should be communicated with all individuals involved in patient care. Integration of continuous quality improvement programs can decrease UE rates by 22% to 53% [16]. Quality efforts typically focus on standardization of reporting and tracking tools, protocol implementations, and ongoing monitoring, auditing, and recording of UE.

Current Trends and Future Directions

Recent trends in critical care recommendations may mitigate potential risk factors identified in UE research. Integration of lightened sedation and daily wake up periods for intubated patients may decrease prevalence of risk factors for UE, specifically agitation, physical restraint use, and altered level of consciousness [30], while routine weaning protocols may improve ventilatory outcomes, including UE [5,38,40]. Nursing bedside report and purposeful hourly rounding are quickly emerging as mainstays of professional nursing care [41]. Inherent in these 2 initiatives are increased surveillance and vigilance by health care staff, which can result in timely extubation of those who indicate readiness, as well as decreased incidence of adverse events. Delirium remains a key factor that may be a likely cause for UE; recent trends towards early detection and proper management of delirium among ICU staff may result in improved ventilatory outcomes, including weaning, planned extubation, and the prevalence of UE.

Another important trend in critical care is the emergence of a neurocritical care specialty and routine admission of neurocritically ill patients to neuroscience ICUs [47,48]. However, there are no studies investigating prevalence of UE among these patients, who often have higher rates of agitation or restlessness due to cognitive impairment. Among general ICUs, patients with a primary respiratory diagnosis accounted for 23% of all UE in one study, while those with a neurological diagnosis accounted for the second highest percentage (12%) among the study population [15]. A separate study concluded that presence of neurological injury with a concomitant nosocomial infection increased risk of UE among patients in a mixed ICU [7]. A recent systematic review of weaning protocols highlights positive effects on ventilatory outcomes but cites lack of evidence for effectiveness of protocols among those with neurological injury [38]. Areas for future UE research should include factors specific to this patient population, as they may be at higher risk for adverse ventilatory outcomes due to the nature of the neurological injury.

Conclusion

Prevention of UE remains an elusive target, evidenced by little change in reported rates over 2 decades. Research provides data on risk factors that may be patient, unit, or process related. Structuring prevention efforts around modifiable risk factors for UE is a feasible approach amenable to ongoing monitoring for effectiveness. Integration of current trends in health care safety and quality may produce an added benefit of reducing the occurrence of UE in critical care units. Future research evaluating these trends and the prevalence of UE in subspecialty populations is warranted.

Corresponding author: Molly McNett, PhD, RN, CNRN, Attn: NBO, MetroHealth Medical Center, 2500 MetroHealth Drive; Cleveland, OH 44109, [email protected].

Financial disclosures: None.