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Clinical Research
New guidelines for adult bronchiectasis
Clinically significant bronchiectasis is a combination of radiologic bronchial dilatation with clinical symptoms. Guidelines on management of adult bronchiectasis were recently published (Eur Respir J. 2017; Sep 10;50[3]).
For all adult patients with clinically significant bronchiectasis, the guidelines suggest standardized minimum testing with differential blood count, serum immunoglobulins, and testing for allergic bronchopulmonary aspergillosis with any further workup on an individual basis. Annual sputum surveillance is suggested for clinically stable adult patients; however, the evidence for this recommendation came from studies done on patients with cystic fibrosis.
Inhaled bronchodilators are suggested as the first-line treatment in symptomatic patients. Long-term antibiotics (greater than 3 months) are recommended in patients with greater than 3 exacerbations/year after optimizing airway clearance and disease-specific treatment. Pseudomonas aeruginosa infections are to be treated with inhaled antibiotics (colistin or gentamicin) (Charles SH, et al. Am J Respir Crit Care Med. 2014;189[8]975; Murray P, et al. Am J Respir Crit Care Med. 2011;183[4]:491; and nonpseudomonal infections are to be treated with macrolides (Conroy W, et al. Lancet. 2012;380[9842]:660; Altenburg J, et al. JAMA. 2013;309[12];1251), although interchangeable for intolerance. Sputum cultured early will guide therapy among poor responders. Long-term mucolytic agents are suggested in appropriate tolerating patients. Pulmonary rehabilitation for 6-8 weeks is strongly recommended in adult bronchiectasis with impaired exercise capacity. Surgical interventions for bronchiectasis are reserved for a small group of patients who have localized disease and high exacerbation rates despite maximal medical therapy. Inhaled corticosteroids are suggested not to be used in adult bronchiectasis. Guidelines recommend against the use of statins and recombinant human DNase as it increases exacerbations (Chest. 1998;113[5]:1329. The task force acknowledged the low quality of evidence for their recommendations requiring more research in the field of adult bronchiectasis.
Bharat Bajantri, MD
Fellow-in-Training Member
Airways Disorders
ICS/LABA combo therapy: black box warning removed
Publication of the Salmeterol Multicenter Asthma Research Trial (SMART) in 2006 caused panic among asthmatics and the physicians who treat them (Nelson et al. Chest. 2006;129[1]:15). The study suggested that the long-acting beta-2-agonist (LABA) salmeterol leads to an increased risk of asthma/respiratory-related deaths compared with placebo. This finding was more pronounced in the African American subpopulation. The study left many questions unanswered, including whether or not this risk is present when LABA therapy is combined with inhaled corticosteroids (ICS) (O’Byrne. Chest. 2006;129[1]:3). Subsequent meta-analyses confirmed the increased risk with LABA monotherapy but not with LABA/ICS (Salpeter et al. Ann Inter Med. 2006;144[12]: 904; Jaeschke et al. Am J Respir Crit Care Med. 2008;178[10]:1009). Still, a black box warning relating LABA to asthma-related death was applied to LABA/ICS products.
In 2011, the Food and Drug Administration (FDA) mandated large, randomized controlled trials be performed for LABA/ICS products to assess safety. These trials were recently completed, showing no difference in asthma-related deaths between LABA/ICS and ICS alone. There were 41, 297 patients across four trials, three included teenagers and adults (age ≥ 12) and one enrolled children (ages 4-11). These studies prompted the FDA to remove the black box warning from salmeterol/fluticasone, formoterol/budesonide, and formoterol/mometasone (https://wwwfdagov/downloads/Drugs/DrugSafety/UCM589997pdf).
Conclusion: Because LABA/ICS therapy is effective for asthma, most pulmonologists continue to prescribe it despite the SMART study results and FDA warning. In a practical sense, we don’t expect the FDA findings to radically change asthma care. Still, it seems we can finally put this question to rest – LABA/ICS is indeed safe for asthmatics. Most physicians will continue to avoid LABA monotherapy, and now that tiotropium is included in the 2017 GINA guidelines, it’s only matter of time before we’re debating whether LABA/long-acting muscarinic antagonist (LAMA) is safe for asthmatics.
Aaron Holley, MD, FCCP
Steering Committee Member
Navitha Ramesh, MD, MBBS
Fellow-in-Training Member
Critical Care
Standardized handoffs in the ICU: room for improvement?
Transitions in patient care are commonplace in the ICU. But handoffs are particularly susceptible to error given the complexity of the patient population. Impacts of less-than-ideal handoffs likely include adverse events, delays in medical diagnosis and treatment, redundant communications, redundant activities such as additional procedures and tests, lower provider and patient satisfaction, higher costs, longer hospital stays, more hospital admissions, and less effective training for health -care providers. Yet, there is great heterogeneity in handoff practiced, and the impact of standardized handoffs in the ICU is unclear (Cochran A. JAMA Surg. 2018 Jan 3. doi: 10.1001/jamasurg.2017.5468. [Epub ahead of print]).
In a survey of over 600 academic intensivists, 55% of the participants stated that attending handoffs in the ICU should be standardized, yet, only 13% of those participating in handoffs reported using a standardized process (Lane-Fall M. Crit Care Med. 2016;44[4]690). Clinician miscommunication contributes to an estimated 250,000 deaths in US hospitals per year (Makary M. BMJ. 2016 May 3;353:i2139. doi: 10.1136/bmj.i2139). Standardized handoffs may improve outcomes in the ICU.
In many ICUs that do use standardized sign-out templates, higher clinician satisfaction and fewer unexpected patient events have been reported (Bavare AC. J Healthc Qual. 2015;37[5]:267; Nanchal R. BMJ Qual Saf. 2017;26[12]:987). In a recent randomized controlled trial, use of a standardized handoff curriculum in the ICU resulted in a significant 3% decrease in communication errors, without any change in the duration of the handoff. There also was a clinician-reported improvement in team communication and patient safety; but no changes in ICU length of stay, duration of mechanical ventilation, or number of re-intubations were noted (JAMA Surg. 2018 Jan 3. doi: 10.1001/jamasurg.2017.5440. [Epub ahead of print]).
Unfortunately, despite interest in improving patient handoffs, there are few tools to evaluate the effectiveness of different handoff strategies. Most studies report clinician perceptions rather than patient-centered outcomes. Further research is required to examine the optimal approach to handover communication. However, based on the available evidence, a standardized approach to handoffs is likely better than a nonstandardized format.
Shruti Gadre, MD
Fellow-in-Training Member
Christopher Carroll, MD, FCCP
Vice-Chair
Home-Based Mechanical Ventilation and Neuromuscular Disease
Update on two recent FDA-approved therapies for ALS and SMA
Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are neuromuscular diseases often deteriorating to progressive respiratory failure. Two medications received recent FDA approval and are now available in clinical practice – edaravone for ALS and nusinersen for SMA. We present a balanced overview of the favorable data along with realistic challenges.
Edaravone (Radicava) is the second FDA-approved medication for management of ALS (Riluzole was approved over 20 years ago). Edaravone is a free radical scavenger that reduces oxidative stress, resulting in a protective effect on neuronal cells. It originally showed promise in acute ischemic stroke in Japan and was subsequently studied for ALS. A phase 3 randomized, double-blind placebo-controlled study performed in Japan (Lancet Neurol. 2017;16[7]:505) compared ALSFRS-R scores of a specific subset of ALS patients receiving edaravone vs placebo. This study revealed that patients with early ALS (2 years duration or less) with rapid progression (ALSFRS-R score of 7.5 in 6 months) had a 33% decrease in their degree of progression (reducing their ALSFRS-R score to 5) in the edaravone group. Of note, there was also slowing in the decline of FVC, though not clinically significant. Although the drug was rapidly approved by the FDA, there are obvious challenges that must be recognized. First, it is unclear if patients will discern such a mild degree of slowing of disease progression. In addition, the annual cost may be prohibitive, and lifelong IV administration of the medication for 10 days every month may pose logistical barriers.
Nusinersen (Spinraza) is the first FDA-approved therapeutic medication for spinal muscular atrophy (SMA). SMA is a hereditary neuromuscular disorder leading to degeneration of motor neuron cells and ultimately diffuse muscle weakness and often respiratory failure. Nusinersen is an antisense oligonucleotide that modifies splicing of the SMN-2 gene to increase production of normal, full-length SMN protein, which is deficient in SMA. The ENDEAR trial (Finkel RS, et al. N Engl J Med. 2017;377[18]:1723) was a phase 3, multicenter, double-blind study that enrolled SMA infants to receive nusinersen vs sham. Infants who received treatment had improvements in motor milestones (41% vs 0%) and less permanent-assisted ventilation or death in the nusinersen group (39% vs 68%), a 47% reduction in risk of death. The therapy is safe and tolerable, although there is reported risk of bleeding abnormalities, renal toxicity, and constipation. Administered intrathecally, there is a series of four loading doses, followed by maintenance doses every 4 months – presumably lifelong. Although FDA approved all three SMA subtypes, the eventual impact is uncertain, especially in cases of advanced muscle weakness. There are realistic challenges: the high cost ($125,000/dose), limited longitudinal evidence, technical administration, and limited access.
Pulmonologists should be aware of both medications as new therapeutic options for ALS and SMA; however, the long-term impact is yet to be determined.
Ashraf Elsayegh, MD, FCCP
Steering Committee Member
Won Y. Lee, MD
Steering Committee Member
Interstitial and Diffuse Lung Disease
Frailty as a measure of disease activity in ILD
Frailty is a systemic geriatric syndrome characterized by age-related accumulation of physiologic deficits across several systems with an attenuated response to biological stress. Considering that interstitial lung disease (ILD), particularly, idiopathic pulmonary fibrosis (IPF), is a disease of the aging population, frailty is an emerging area of clinical interest. The biological pathways driving the association of frailty with worse prognosis are complex but hinge on cellular senescence, systemic inflammation, and sarcopenia.
There is a high prevalence of frailty in adults with chronic lung diseases and is associated with worse prognosis. The current literature, though, is mostly derived from patients with COPD. Frailty measured using the 42-item patient-reported frailty index is associated with dyspnea severity in patients with fibrotic ILD (Milne et al. Respirology. 2017;22[4]:728) and systemic sclerosis-associated ILD (Guler et al. Respir Med. 2017 Aug;129:1-7. doi: 10.1016/j.rmed.2017.05.012. Epub 2017 May 25.). The SHARE-Frailty and the Edmonton Frail Scale instruments utilized to measure frailty in the University of Alabama at Birmingham IPF cohort detected a high-percentage of frail and pre-frail patients (Luckhardt et al. Am J Respir Crit Care Med. 2017;195:A7012). However, there are differences in targeted domains between the various frailty instruments, and this could affect the identification of the frailty syndrome in patients.
Frailty as a measure of disease activity and progression is not currently employed in clinical trials for ILD, primarily due to lack of standardized tools for this patient population. Future studies designed to utilize the frailty syndrome as outcome measures may further our understanding of the clinical manifestations and underlying mechanisms, as well as identify potential therapeutic interventions for patients with ILD.
Tejaswini Kulkarni MD, MPH
Fellow-in-Training Member
Clinical Research
New guidelines for adult bronchiectasis
Clinically significant bronchiectasis is a combination of radiologic bronchial dilatation with clinical symptoms. Guidelines on management of adult bronchiectasis were recently published (Eur Respir J. 2017; Sep 10;50[3]).
For all adult patients with clinically significant bronchiectasis, the guidelines suggest standardized minimum testing with differential blood count, serum immunoglobulins, and testing for allergic bronchopulmonary aspergillosis with any further workup on an individual basis. Annual sputum surveillance is suggested for clinically stable adult patients; however, the evidence for this recommendation came from studies done on patients with cystic fibrosis.
Inhaled bronchodilators are suggested as the first-line treatment in symptomatic patients. Long-term antibiotics (greater than 3 months) are recommended in patients with greater than 3 exacerbations/year after optimizing airway clearance and disease-specific treatment. Pseudomonas aeruginosa infections are to be treated with inhaled antibiotics (colistin or gentamicin) (Charles SH, et al. Am J Respir Crit Care Med. 2014;189[8]975; Murray P, et al. Am J Respir Crit Care Med. 2011;183[4]:491; and nonpseudomonal infections are to be treated with macrolides (Conroy W, et al. Lancet. 2012;380[9842]:660; Altenburg J, et al. JAMA. 2013;309[12];1251), although interchangeable for intolerance. Sputum cultured early will guide therapy among poor responders. Long-term mucolytic agents are suggested in appropriate tolerating patients. Pulmonary rehabilitation for 6-8 weeks is strongly recommended in adult bronchiectasis with impaired exercise capacity. Surgical interventions for bronchiectasis are reserved for a small group of patients who have localized disease and high exacerbation rates despite maximal medical therapy. Inhaled corticosteroids are suggested not to be used in adult bronchiectasis. Guidelines recommend against the use of statins and recombinant human DNase as it increases exacerbations (Chest. 1998;113[5]:1329. The task force acknowledged the low quality of evidence for their recommendations requiring more research in the field of adult bronchiectasis.
Bharat Bajantri, MD
Fellow-in-Training Member
Airways Disorders
ICS/LABA combo therapy: black box warning removed
Publication of the Salmeterol Multicenter Asthma Research Trial (SMART) in 2006 caused panic among asthmatics and the physicians who treat them (Nelson et al. Chest. 2006;129[1]:15). The study suggested that the long-acting beta-2-agonist (LABA) salmeterol leads to an increased risk of asthma/respiratory-related deaths compared with placebo. This finding was more pronounced in the African American subpopulation. The study left many questions unanswered, including whether or not this risk is present when LABA therapy is combined with inhaled corticosteroids (ICS) (O’Byrne. Chest. 2006;129[1]:3). Subsequent meta-analyses confirmed the increased risk with LABA monotherapy but not with LABA/ICS (Salpeter et al. Ann Inter Med. 2006;144[12]: 904; Jaeschke et al. Am J Respir Crit Care Med. 2008;178[10]:1009). Still, a black box warning relating LABA to asthma-related death was applied to LABA/ICS products.
In 2011, the Food and Drug Administration (FDA) mandated large, randomized controlled trials be performed for LABA/ICS products to assess safety. These trials were recently completed, showing no difference in asthma-related deaths between LABA/ICS and ICS alone. There were 41, 297 patients across four trials, three included teenagers and adults (age ≥ 12) and one enrolled children (ages 4-11). These studies prompted the FDA to remove the black box warning from salmeterol/fluticasone, formoterol/budesonide, and formoterol/mometasone (https://wwwfdagov/downloads/Drugs/DrugSafety/UCM589997pdf).
Conclusion: Because LABA/ICS therapy is effective for asthma, most pulmonologists continue to prescribe it despite the SMART study results and FDA warning. In a practical sense, we don’t expect the FDA findings to radically change asthma care. Still, it seems we can finally put this question to rest – LABA/ICS is indeed safe for asthmatics. Most physicians will continue to avoid LABA monotherapy, and now that tiotropium is included in the 2017 GINA guidelines, it’s only matter of time before we’re debating whether LABA/long-acting muscarinic antagonist (LAMA) is safe for asthmatics.
Aaron Holley, MD, FCCP
Steering Committee Member
Navitha Ramesh, MD, MBBS
Fellow-in-Training Member
Critical Care
Standardized handoffs in the ICU: room for improvement?
Transitions in patient care are commonplace in the ICU. But handoffs are particularly susceptible to error given the complexity of the patient population. Impacts of less-than-ideal handoffs likely include adverse events, delays in medical diagnosis and treatment, redundant communications, redundant activities such as additional procedures and tests, lower provider and patient satisfaction, higher costs, longer hospital stays, more hospital admissions, and less effective training for health -care providers. Yet, there is great heterogeneity in handoff practiced, and the impact of standardized handoffs in the ICU is unclear (Cochran A. JAMA Surg. 2018 Jan 3. doi: 10.1001/jamasurg.2017.5468. [Epub ahead of print]).
In a survey of over 600 academic intensivists, 55% of the participants stated that attending handoffs in the ICU should be standardized, yet, only 13% of those participating in handoffs reported using a standardized process (Lane-Fall M. Crit Care Med. 2016;44[4]690). Clinician miscommunication contributes to an estimated 250,000 deaths in US hospitals per year (Makary M. BMJ. 2016 May 3;353:i2139. doi: 10.1136/bmj.i2139). Standardized handoffs may improve outcomes in the ICU.
In many ICUs that do use standardized sign-out templates, higher clinician satisfaction and fewer unexpected patient events have been reported (Bavare AC. J Healthc Qual. 2015;37[5]:267; Nanchal R. BMJ Qual Saf. 2017;26[12]:987). In a recent randomized controlled trial, use of a standardized handoff curriculum in the ICU resulted in a significant 3% decrease in communication errors, without any change in the duration of the handoff. There also was a clinician-reported improvement in team communication and patient safety; but no changes in ICU length of stay, duration of mechanical ventilation, or number of re-intubations were noted (JAMA Surg. 2018 Jan 3. doi: 10.1001/jamasurg.2017.5440. [Epub ahead of print]).
Unfortunately, despite interest in improving patient handoffs, there are few tools to evaluate the effectiveness of different handoff strategies. Most studies report clinician perceptions rather than patient-centered outcomes. Further research is required to examine the optimal approach to handover communication. However, based on the available evidence, a standardized approach to handoffs is likely better than a nonstandardized format.
Shruti Gadre, MD
Fellow-in-Training Member
Christopher Carroll, MD, FCCP
Vice-Chair
Home-Based Mechanical Ventilation and Neuromuscular Disease
Update on two recent FDA-approved therapies for ALS and SMA
Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are neuromuscular diseases often deteriorating to progressive respiratory failure. Two medications received recent FDA approval and are now available in clinical practice – edaravone for ALS and nusinersen for SMA. We present a balanced overview of the favorable data along with realistic challenges.
Edaravone (Radicava) is the second FDA-approved medication for management of ALS (Riluzole was approved over 20 years ago). Edaravone is a free radical scavenger that reduces oxidative stress, resulting in a protective effect on neuronal cells. It originally showed promise in acute ischemic stroke in Japan and was subsequently studied for ALS. A phase 3 randomized, double-blind placebo-controlled study performed in Japan (Lancet Neurol. 2017;16[7]:505) compared ALSFRS-R scores of a specific subset of ALS patients receiving edaravone vs placebo. This study revealed that patients with early ALS (2 years duration or less) with rapid progression (ALSFRS-R score of 7.5 in 6 months) had a 33% decrease in their degree of progression (reducing their ALSFRS-R score to 5) in the edaravone group. Of note, there was also slowing in the decline of FVC, though not clinically significant. Although the drug was rapidly approved by the FDA, there are obvious challenges that must be recognized. First, it is unclear if patients will discern such a mild degree of slowing of disease progression. In addition, the annual cost may be prohibitive, and lifelong IV administration of the medication for 10 days every month may pose logistical barriers.
Nusinersen (Spinraza) is the first FDA-approved therapeutic medication for spinal muscular atrophy (SMA). SMA is a hereditary neuromuscular disorder leading to degeneration of motor neuron cells and ultimately diffuse muscle weakness and often respiratory failure. Nusinersen is an antisense oligonucleotide that modifies splicing of the SMN-2 gene to increase production of normal, full-length SMN protein, which is deficient in SMA. The ENDEAR trial (Finkel RS, et al. N Engl J Med. 2017;377[18]:1723) was a phase 3, multicenter, double-blind study that enrolled SMA infants to receive nusinersen vs sham. Infants who received treatment had improvements in motor milestones (41% vs 0%) and less permanent-assisted ventilation or death in the nusinersen group (39% vs 68%), a 47% reduction in risk of death. The therapy is safe and tolerable, although there is reported risk of bleeding abnormalities, renal toxicity, and constipation. Administered intrathecally, there is a series of four loading doses, followed by maintenance doses every 4 months – presumably lifelong. Although FDA approved all three SMA subtypes, the eventual impact is uncertain, especially in cases of advanced muscle weakness. There are realistic challenges: the high cost ($125,000/dose), limited longitudinal evidence, technical administration, and limited access.
Pulmonologists should be aware of both medications as new therapeutic options for ALS and SMA; however, the long-term impact is yet to be determined.
Ashraf Elsayegh, MD, FCCP
Steering Committee Member
Won Y. Lee, MD
Steering Committee Member
Interstitial and Diffuse Lung Disease
Frailty as a measure of disease activity in ILD
Frailty is a systemic geriatric syndrome characterized by age-related accumulation of physiologic deficits across several systems with an attenuated response to biological stress. Considering that interstitial lung disease (ILD), particularly, idiopathic pulmonary fibrosis (IPF), is a disease of the aging population, frailty is an emerging area of clinical interest. The biological pathways driving the association of frailty with worse prognosis are complex but hinge on cellular senescence, systemic inflammation, and sarcopenia.
There is a high prevalence of frailty in adults with chronic lung diseases and is associated with worse prognosis. The current literature, though, is mostly derived from patients with COPD. Frailty measured using the 42-item patient-reported frailty index is associated with dyspnea severity in patients with fibrotic ILD (Milne et al. Respirology. 2017;22[4]:728) and systemic sclerosis-associated ILD (Guler et al. Respir Med. 2017 Aug;129:1-7. doi: 10.1016/j.rmed.2017.05.012. Epub 2017 May 25.). The SHARE-Frailty and the Edmonton Frail Scale instruments utilized to measure frailty in the University of Alabama at Birmingham IPF cohort detected a high-percentage of frail and pre-frail patients (Luckhardt et al. Am J Respir Crit Care Med. 2017;195:A7012). However, there are differences in targeted domains between the various frailty instruments, and this could affect the identification of the frailty syndrome in patients.
Frailty as a measure of disease activity and progression is not currently employed in clinical trials for ILD, primarily due to lack of standardized tools for this patient population. Future studies designed to utilize the frailty syndrome as outcome measures may further our understanding of the clinical manifestations and underlying mechanisms, as well as identify potential therapeutic interventions for patients with ILD.
Tejaswini Kulkarni MD, MPH
Fellow-in-Training Member
Clinical Research
New guidelines for adult bronchiectasis
Clinically significant bronchiectasis is a combination of radiologic bronchial dilatation with clinical symptoms. Guidelines on management of adult bronchiectasis were recently published (Eur Respir J. 2017; Sep 10;50[3]).
For all adult patients with clinically significant bronchiectasis, the guidelines suggest standardized minimum testing with differential blood count, serum immunoglobulins, and testing for allergic bronchopulmonary aspergillosis with any further workup on an individual basis. Annual sputum surveillance is suggested for clinically stable adult patients; however, the evidence for this recommendation came from studies done on patients with cystic fibrosis.
Inhaled bronchodilators are suggested as the first-line treatment in symptomatic patients. Long-term antibiotics (greater than 3 months) are recommended in patients with greater than 3 exacerbations/year after optimizing airway clearance and disease-specific treatment. Pseudomonas aeruginosa infections are to be treated with inhaled antibiotics (colistin or gentamicin) (Charles SH, et al. Am J Respir Crit Care Med. 2014;189[8]975; Murray P, et al. Am J Respir Crit Care Med. 2011;183[4]:491; and nonpseudomonal infections are to be treated with macrolides (Conroy W, et al. Lancet. 2012;380[9842]:660; Altenburg J, et al. JAMA. 2013;309[12];1251), although interchangeable for intolerance. Sputum cultured early will guide therapy among poor responders. Long-term mucolytic agents are suggested in appropriate tolerating patients. Pulmonary rehabilitation for 6-8 weeks is strongly recommended in adult bronchiectasis with impaired exercise capacity. Surgical interventions for bronchiectasis are reserved for a small group of patients who have localized disease and high exacerbation rates despite maximal medical therapy. Inhaled corticosteroids are suggested not to be used in adult bronchiectasis. Guidelines recommend against the use of statins and recombinant human DNase as it increases exacerbations (Chest. 1998;113[5]:1329. The task force acknowledged the low quality of evidence for their recommendations requiring more research in the field of adult bronchiectasis.
Bharat Bajantri, MD
Fellow-in-Training Member
Airways Disorders
ICS/LABA combo therapy: black box warning removed
Publication of the Salmeterol Multicenter Asthma Research Trial (SMART) in 2006 caused panic among asthmatics and the physicians who treat them (Nelson et al. Chest. 2006;129[1]:15). The study suggested that the long-acting beta-2-agonist (LABA) salmeterol leads to an increased risk of asthma/respiratory-related deaths compared with placebo. This finding was more pronounced in the African American subpopulation. The study left many questions unanswered, including whether or not this risk is present when LABA therapy is combined with inhaled corticosteroids (ICS) (O’Byrne. Chest. 2006;129[1]:3). Subsequent meta-analyses confirmed the increased risk with LABA monotherapy but not with LABA/ICS (Salpeter et al. Ann Inter Med. 2006;144[12]: 904; Jaeschke et al. Am J Respir Crit Care Med. 2008;178[10]:1009). Still, a black box warning relating LABA to asthma-related death was applied to LABA/ICS products.
In 2011, the Food and Drug Administration (FDA) mandated large, randomized controlled trials be performed for LABA/ICS products to assess safety. These trials were recently completed, showing no difference in asthma-related deaths between LABA/ICS and ICS alone. There were 41, 297 patients across four trials, three included teenagers and adults (age ≥ 12) and one enrolled children (ages 4-11). These studies prompted the FDA to remove the black box warning from salmeterol/fluticasone, formoterol/budesonide, and formoterol/mometasone (https://wwwfdagov/downloads/Drugs/DrugSafety/UCM589997pdf).
Conclusion: Because LABA/ICS therapy is effective for asthma, most pulmonologists continue to prescribe it despite the SMART study results and FDA warning. In a practical sense, we don’t expect the FDA findings to radically change asthma care. Still, it seems we can finally put this question to rest – LABA/ICS is indeed safe for asthmatics. Most physicians will continue to avoid LABA monotherapy, and now that tiotropium is included in the 2017 GINA guidelines, it’s only matter of time before we’re debating whether LABA/long-acting muscarinic antagonist (LAMA) is safe for asthmatics.
Aaron Holley, MD, FCCP
Steering Committee Member
Navitha Ramesh, MD, MBBS
Fellow-in-Training Member
Critical Care
Standardized handoffs in the ICU: room for improvement?
Transitions in patient care are commonplace in the ICU. But handoffs are particularly susceptible to error given the complexity of the patient population. Impacts of less-than-ideal handoffs likely include adverse events, delays in medical diagnosis and treatment, redundant communications, redundant activities such as additional procedures and tests, lower provider and patient satisfaction, higher costs, longer hospital stays, more hospital admissions, and less effective training for health -care providers. Yet, there is great heterogeneity in handoff practiced, and the impact of standardized handoffs in the ICU is unclear (Cochran A. JAMA Surg. 2018 Jan 3. doi: 10.1001/jamasurg.2017.5468. [Epub ahead of print]).
In a survey of over 600 academic intensivists, 55% of the participants stated that attending handoffs in the ICU should be standardized, yet, only 13% of those participating in handoffs reported using a standardized process (Lane-Fall M. Crit Care Med. 2016;44[4]690). Clinician miscommunication contributes to an estimated 250,000 deaths in US hospitals per year (Makary M. BMJ. 2016 May 3;353:i2139. doi: 10.1136/bmj.i2139). Standardized handoffs may improve outcomes in the ICU.
In many ICUs that do use standardized sign-out templates, higher clinician satisfaction and fewer unexpected patient events have been reported (Bavare AC. J Healthc Qual. 2015;37[5]:267; Nanchal R. BMJ Qual Saf. 2017;26[12]:987). In a recent randomized controlled trial, use of a standardized handoff curriculum in the ICU resulted in a significant 3% decrease in communication errors, without any change in the duration of the handoff. There also was a clinician-reported improvement in team communication and patient safety; but no changes in ICU length of stay, duration of mechanical ventilation, or number of re-intubations were noted (JAMA Surg. 2018 Jan 3. doi: 10.1001/jamasurg.2017.5440. [Epub ahead of print]).
Unfortunately, despite interest in improving patient handoffs, there are few tools to evaluate the effectiveness of different handoff strategies. Most studies report clinician perceptions rather than patient-centered outcomes. Further research is required to examine the optimal approach to handover communication. However, based on the available evidence, a standardized approach to handoffs is likely better than a nonstandardized format.
Shruti Gadre, MD
Fellow-in-Training Member
Christopher Carroll, MD, FCCP
Vice-Chair
Home-Based Mechanical Ventilation and Neuromuscular Disease
Update on two recent FDA-approved therapies for ALS and SMA
Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are neuromuscular diseases often deteriorating to progressive respiratory failure. Two medications received recent FDA approval and are now available in clinical practice – edaravone for ALS and nusinersen for SMA. We present a balanced overview of the favorable data along with realistic challenges.
Edaravone (Radicava) is the second FDA-approved medication for management of ALS (Riluzole was approved over 20 years ago). Edaravone is a free radical scavenger that reduces oxidative stress, resulting in a protective effect on neuronal cells. It originally showed promise in acute ischemic stroke in Japan and was subsequently studied for ALS. A phase 3 randomized, double-blind placebo-controlled study performed in Japan (Lancet Neurol. 2017;16[7]:505) compared ALSFRS-R scores of a specific subset of ALS patients receiving edaravone vs placebo. This study revealed that patients with early ALS (2 years duration or less) with rapid progression (ALSFRS-R score of 7.5 in 6 months) had a 33% decrease in their degree of progression (reducing their ALSFRS-R score to 5) in the edaravone group. Of note, there was also slowing in the decline of FVC, though not clinically significant. Although the drug was rapidly approved by the FDA, there are obvious challenges that must be recognized. First, it is unclear if patients will discern such a mild degree of slowing of disease progression. In addition, the annual cost may be prohibitive, and lifelong IV administration of the medication for 10 days every month may pose logistical barriers.
Nusinersen (Spinraza) is the first FDA-approved therapeutic medication for spinal muscular atrophy (SMA). SMA is a hereditary neuromuscular disorder leading to degeneration of motor neuron cells and ultimately diffuse muscle weakness and often respiratory failure. Nusinersen is an antisense oligonucleotide that modifies splicing of the SMN-2 gene to increase production of normal, full-length SMN protein, which is deficient in SMA. The ENDEAR trial (Finkel RS, et al. N Engl J Med. 2017;377[18]:1723) was a phase 3, multicenter, double-blind study that enrolled SMA infants to receive nusinersen vs sham. Infants who received treatment had improvements in motor milestones (41% vs 0%) and less permanent-assisted ventilation or death in the nusinersen group (39% vs 68%), a 47% reduction in risk of death. The therapy is safe and tolerable, although there is reported risk of bleeding abnormalities, renal toxicity, and constipation. Administered intrathecally, there is a series of four loading doses, followed by maintenance doses every 4 months – presumably lifelong. Although FDA approved all three SMA subtypes, the eventual impact is uncertain, especially in cases of advanced muscle weakness. There are realistic challenges: the high cost ($125,000/dose), limited longitudinal evidence, technical administration, and limited access.
Pulmonologists should be aware of both medications as new therapeutic options for ALS and SMA; however, the long-term impact is yet to be determined.
Ashraf Elsayegh, MD, FCCP
Steering Committee Member
Won Y. Lee, MD
Steering Committee Member
Interstitial and Diffuse Lung Disease
Frailty as a measure of disease activity in ILD
Frailty is a systemic geriatric syndrome characterized by age-related accumulation of physiologic deficits across several systems with an attenuated response to biological stress. Considering that interstitial lung disease (ILD), particularly, idiopathic pulmonary fibrosis (IPF), is a disease of the aging population, frailty is an emerging area of clinical interest. The biological pathways driving the association of frailty with worse prognosis are complex but hinge on cellular senescence, systemic inflammation, and sarcopenia.
There is a high prevalence of frailty in adults with chronic lung diseases and is associated with worse prognosis. The current literature, though, is mostly derived from patients with COPD. Frailty measured using the 42-item patient-reported frailty index is associated with dyspnea severity in patients with fibrotic ILD (Milne et al. Respirology. 2017;22[4]:728) and systemic sclerosis-associated ILD (Guler et al. Respir Med. 2017 Aug;129:1-7. doi: 10.1016/j.rmed.2017.05.012. Epub 2017 May 25.). The SHARE-Frailty and the Edmonton Frail Scale instruments utilized to measure frailty in the University of Alabama at Birmingham IPF cohort detected a high-percentage of frail and pre-frail patients (Luckhardt et al. Am J Respir Crit Care Med. 2017;195:A7012). However, there are differences in targeted domains between the various frailty instruments, and this could affect the identification of the frailty syndrome in patients.
Frailty as a measure of disease activity and progression is not currently employed in clinical trials for ILD, primarily due to lack of standardized tools for this patient population. Future studies designed to utilize the frailty syndrome as outcome measures may further our understanding of the clinical manifestations and underlying mechanisms, as well as identify potential therapeutic interventions for patients with ILD.
Tejaswini Kulkarni MD, MPH
Fellow-in-Training Member