A new study has determined modifiable and nonmodifiable factors that can help identify patients with axial spondyloarthritis who are both likely and unlikely to respond to anti–tumor necrosis factor (TNF)–alpha therapy.

Courtesy Dr. Gary J. Macfarlane

“[This study] emphasizes that examination of predictors of nonresponse to pharmacologic therapy in inflammatory arthritis must consider the importance of socioeconomic factors,” wrote Gary J. Macfarlane, MBChB, PhD, of the University of Aberdeen (Scotland) and coauthors. The study was published in Rheumatology.

To identify common factors related to anti–TNF-alpha therapy response, the researchers launched a prospective cohort study of 335 patients with axial spondyloarthritis from the British Society for Rheumatology Biologics Register in Axial Spondyloarthritis (BSRBR-AS) who were naive to biologic therapy. Responses to therapy were assessed through various means, including meeting Assessment of Spondyloarthritis International Society (ASAS) improvement criteria, exhibiting clinically important improvement (1.1 points or more) in Ankylosing Spondylitis Disease Activity Score (ASDAS), or going from a high or very high ASDAS disease state (score of 2.1 or higher) to a moderate or inactive state (score less than 2.1).

All patients also filled out questionnaires at each follow-up on socioeconomic factors, lifestyle factors, and quality of life. Of the 335 participants, 69% were male. They had a median age of 47 years, and about half were employed full time.

At first follow-up – which occurred at a median of 14 weeks – 175 participants (52%) met ASAS20 response criteria and 111 (33%) met ASAS40 response criteria. Of the 261 participants eligible for ASDAS evaluation, 122 (47%) met the criteria for a clinically important ASDAS reduction. Of the 249 participants who had a high or very high disease state at baseline, 87 (35%) were classified as having moderate or inactive disease at follow-up.

Factors that predicted a lack of response across measures included adverse socioeconomic factors, fewer years of education, and not working full time. Clinical and patient-reported factors also associated with a lack of response included comorbidities and poor mental health. The ASDAS models proved best at predicting those unlikely to meet response criteria, with a negative predictive value of 77%.

The study was supported by the British Society for Rheumatology, which receives funding for the BSRBR-AS from Pfizer, AbbVie, and UCB. The authors reported having no conflicts of interest.

SOURCE: Macfarlane GJ et al. Rheumatology. 2020 Jan 28. doi: 10.1093/rheumatology/kez657.

A new study has determined modifiable and nonmodifiable factors that can help identify patients with axial spondyloarthritis who are both likely and unlikely to respond to anti–tumor necrosis factor (TNF)–alpha therapy.

Courtesy Dr. Gary J. Macfarlane

“[This study] emphasizes that examination of predictors of nonresponse to pharmacologic therapy in inflammatory arthritis must consider the importance of socioeconomic factors,” wrote Gary J. Macfarlane, MBChB, PhD, of the University of Aberdeen (Scotland) and coauthors. The study was published in Rheumatology.

To identify common factors related to anti–TNF-alpha therapy response, the researchers launched a prospective cohort study of 335 patients with axial spondyloarthritis from the British Society for Rheumatology Biologics Register in Axial Spondyloarthritis (BSRBR-AS) who were naive to biologic therapy. Responses to therapy were assessed through various means, including meeting Assessment of Spondyloarthritis International Society (ASAS) improvement criteria, exhibiting clinically important improvement (1.1 points or more) in Ankylosing Spondylitis Disease Activity Score (ASDAS), or going from a high or very high ASDAS disease state (score of 2.1 or higher) to a moderate or inactive state (score less than 2.1).

All patients also filled out questionnaires at each follow-up on socioeconomic factors, lifestyle factors, and quality of life. Of the 335 participants, 69% were male. They had a median age of 47 years, and about half were employed full time.

At first follow-up – which occurred at a median of 14 weeks – 175 participants (52%) met ASAS20 response criteria and 111 (33%) met ASAS40 response criteria. Of the 261 participants eligible for ASDAS evaluation, 122 (47%) met the criteria for a clinically important ASDAS reduction. Of the 249 participants who had a high or very high disease state at baseline, 87 (35%) were classified as having moderate or inactive disease at follow-up.

Factors that predicted a lack of response across measures included adverse socioeconomic factors, fewer years of education, and not working full time. Clinical and patient-reported factors also associated with a lack of response included comorbidities and poor mental health. The ASDAS models proved best at predicting those unlikely to meet response criteria, with a negative predictive value of 77%.

The study was supported by the British Society for Rheumatology, which receives funding for the BSRBR-AS from Pfizer, AbbVie, and UCB. The authors reported having no conflicts of interest.

SOURCE: Macfarlane GJ et al. Rheumatology. 2020 Jan 28. doi: 10.1093/rheumatology/kez657.

A new study has determined modifiable and nonmodifiable factors that can help identify patients with axial spondyloarthritis who are both likely and unlikely to respond to anti–tumor necrosis factor (TNF)–alpha therapy.

Courtesy Dr. Gary J. Macfarlane

“[This study] emphasizes that examination of predictors of nonresponse to pharmacologic therapy in inflammatory arthritis must consider the importance of socioeconomic factors,” wrote Gary J. Macfarlane, MBChB, PhD, of the University of Aberdeen (Scotland) and coauthors. The study was published in Rheumatology.

To identify common factors related to anti–TNF-alpha therapy response, the researchers launched a prospective cohort study of 335 patients with axial spondyloarthritis from the British Society for Rheumatology Biologics Register in Axial Spondyloarthritis (BSRBR-AS) who were naive to biologic therapy. Responses to therapy were assessed through various means, including meeting Assessment of Spondyloarthritis International Society (ASAS) improvement criteria, exhibiting clinically important improvement (1.1 points or more) in Ankylosing Spondylitis Disease Activity Score (ASDAS), or going from a high or very high ASDAS disease state (score of 2.1 or higher) to a moderate or inactive state (score less than 2.1).

All patients also filled out questionnaires at each follow-up on socioeconomic factors, lifestyle factors, and quality of life. Of the 335 participants, 69% were male. They had a median age of 47 years, and about half were employed full time.

At first follow-up – which occurred at a median of 14 weeks – 175 participants (52%) met ASAS20 response criteria and 111 (33%) met ASAS40 response criteria. Of the 261 participants eligible for ASDAS evaluation, 122 (47%) met the criteria for a clinically important ASDAS reduction. Of the 249 participants who had a high or very high disease state at baseline, 87 (35%) were classified as having moderate or inactive disease at follow-up.

Factors that predicted a lack of response across measures included adverse socioeconomic factors, fewer years of education, and not working full time. Clinical and patient-reported factors also associated with a lack of response included comorbidities and poor mental health. The ASDAS models proved best at predicting those unlikely to meet response criteria, with a negative predictive value of 77%.

The study was supported by the British Society for Rheumatology, which receives funding for the BSRBR-AS from Pfizer, AbbVie, and UCB. The authors reported having no conflicts of interest.

SOURCE: Macfarlane GJ et al. Rheumatology. 2020 Jan 28. doi: 10.1093/rheumatology/kez657.

Clinical significance

Continuous positive airway pressure remains the gold standard and first-line treatment for moderate to severe OSA. When CPAP and other medical therapies fail or are poorly adopted, surgical solutions - either standalone or in unison - can be directed to target precision therapy.

The newest of these techniques is neuromodulation of the lingual musculature, particularly by way of selective stimulation of the hypoglossal nerve, which first demonstrated success in human clinical trials in 1996.¹ Upper airway stimulation (UAS) was formally FDA-approved in 2014 (Inspire Medical Systems, Inc). UAS is designed to eliminate clinically significant OSA through stimulation of the anteriorly directed branches of the hypoglossal nerve, increasing the posterior airway space in a multilevel fashion.² Since this time, over 7,500 patients have been treated with Inspire in nine countries (United States, Germany, The Netherlands, Switzerland, Belgium, Spain, France, Italy, and Finland). Prospective, international multicenter trials have demonstrated 68% to 96% clinical efficacy in well selected individuals. This is defined as a ≥ 50% reduction in the apnea hypopnea index (AHI) to an overall AHI of ≤ 20/hour.^3,4 Additionally, post-UAS analysis demonstrates subjective reduction in daytime sleepiness as reported by Epworth sleepiness scores, with improvements in sleep-related quality of life. Further, UAS reduces socially disruptive snoring with 85% of bedpartners reporting soft to no snoring at 48-month follow-up.⁵ The procedure has also demonstrated long-term cost benefit in the US health-care system.⁶
 

Background and pathophysiology

Oliven and colleagues⁷ first observed the critical finding that selective intra-muscular stimulation of the genioglossus muscle lowered airway critical closing pressure (PCrit), thereby stabilizing the pharyngeal airway. Conversely, activation of the “retrusor” musculature, namely the hyoglossus and styloglossus muscles, increased Pcrit, increasing collapsibility of the pharyngeal airway.

Therapeutic implantation requires three incisions directed to the neck, chest, and right rib space (between the 4th to 6th intercostal spaces), with an operative time of 90 minutes or less in experienced hands. The majority of patients are discharged on the day of the procedure. Morbidity remains low with minimal pain reported during recovery. The most common complication is that of temporary tongue weakness, which typically resolves within 2 to 3 weeks. While very infrequent, patients should be counseled on the risk of postoperative hematoma, which can precipitate infection and subsequent explant of the device. Average recovery time spans between 3 and 7 days with activation of the device 4 weeks after surgical implantation to allow for appropriate tissue healing and reduce the risk of dislodgement of the implanted components. In contrast to other surgical treatment options, UAS is also reversible with no underlying alteration to existing pharyngeal anatomy apart from external incisions created during the procedure.
 

Stimulation to titration

As the need for a multidisciplinary approach to salvage of patients failing first-line therapy for OSA continues to grow, UAS with its multilevel impact continues to be of key interest. In similar fashion to established medical therapies such as PAP and oral appliance therapy (OAT), close observation between sleep medicine specialists and the implanting surgeon during the adaptation period with attention paid to titration parameters such as stimulation duration, pulse width, amplitude, and polarity, allow optimization of response outcome.

The stimulation electrode, which is designed in the form of a cuff to envelope the anterior (protrusor) branches of the hypoglossal nerve receives electrical stimulation from the implanted pulse generator, implanted above the pectoralis muscle of the chest wall. This design allows for collaborative awake and overnight titration of the device as directed by a sleep medicine physician. Attention is paid not only to the voltage “strength” administered with each pulse but also the degree of synchronization between respiration and stimulation, as well as pattern of pulse administration. Our experience remains that true success and adaptation to therapy requires not just meticulous surgical technique but a diligent approach to postoperative therapeutic titration to achieve a comfortable, yet effective, voltage for maintaining airway patency. Thus, akin to initiation of CPAP, UAS requires regular follow-up and device fine-tuning with patient comfort taken into consideration to achieve optimal results, and patient expectation should be aligned with this process.
 

Current indications

Success in UAS relies heavily on appropriate presurgical evaluation and clinical phenotyping. The following surgical indications have been demonstrated in the Stimulation Therapy for Apnea Reduction (STAR) trial and subsequent 3-year clinical follow-up: AHI between 15 and 80 events/hour (with ≤ 25% central apneas) and a BMI ≤ 32.⁸

As OSA often results from multi-level airway collapse, UAS targets an increase not only in the diameter of the retropalatal/oropharyngeal airway space but also the antero-posterior hypopharyngeal airway. Original criteria for implantation excluded patients with a pattern of complete circumferential collapse (CCC) noted on dynamic airway evaluation during pre-implant drug-induced sleep endoscopy (DISE). DISE aims to precisely target dynamic airway collapse patterns during simulated (propofol or midazolom induced) sleep.
 

Future directions

The effects of UAS are dependent on upper-airway cross-sectional area, particularly diameter. In patients who demonstrate CCC, the anteroposterior direction of activation derived from the UAS stimulus is unable to overcome CCC. In a recent prospective study, our group demonstrated that CCC can be converted to an airway collapse pattern compatible with UAS implantation, using a modified palatopharyngoplasty prior to UAS implantation. By stabilizing the lateral walls of the oropharyngeal airway with pre-implant palatal surgery, UAS is able to successfully direct widening of the airway cross-sectional area in an antero-posterior fashion. This exciting finding potentially allows for expansion of current indications, thus opening treatment to a wider patient population.⁹ Still, UAS remains highly studied in a relatively uniform patient population with data in more diverse subsets requiring further directed attention to expand and better define optimal patient populations for treatment.

From the perspective of improving patient adaptation and tolerance in UAS, a well-established concept in the CPAP literature can be applied, as explained by the Starling resistor model. The starling resistor is comprised of two rigid tubes connected by a collapsible segment in between. In parallel, the pharynx is a collapsible muscular tube connected on either end by the nose/nasal cavity and the trachea – both of which are bony/cartilaginous, noncollapsible structures. As has been shown in the use of CPAP, the same pressure required to maintain stability of the collapsible muscular pharynx via nasal breathing may lead to pharyngeal collapse when applied orally.¹⁰ This concept has also been directed towards UAS with our clinical experience demonstrating that oro or oronasal breathers tend to require a higher amplitude to maintain airway patency versus nasal breathers. This is an important area for future-directed study as medically/surgically improving nasal breathing in UAS subjects may subsequently lower amplitude requirements and improve patient tolerance.

Future direction to allow for improvement in the technology for application in a broader populational segment, external or alternative device powering mechanisms, along with MRI Compatibility and reducing the number of required external incisions will continue to broaden the patient selection criteria. As we move from a “stimulation” to a precision-tailored “stimulation and titration” approach, the mid to long term data supporting UAS remains very promising with 5-year follow up demonstrating sustained polysomnographic and subjective reported outcomes in well selected patients.
 

Dr. Awad is Assistant Professor – Department of Otolaryngology/Head & Neck Surgery, and Chief – Division of Sleep Surgery; Northwestern University, Chicago, Illinois. Dr. Capasso is Associate Professor – Department of Otolaryngology/Head & Neck Surgery, and Chief – Division of Sleep Surgery; Stanford Hospital and Clinics, Stanford, California.

References

1. Schwartz AR et al. Electrical stimulation of the lingual musculature in obstructive sleep apnea. J Appl Physiol. 1996;81(2):643-52. doi: 10.1152/jappl.1996.81.2.643.

2. Ong AA et al. Efficacy of upper airway stimulation on collapse patterns observed during drug-induced sedation endoscopy. Otolaryngol Head Neck Surg. 2016;154(5):970-7. doi: 10.1177/0194599816636835.

3. Woodson BT et al. Three-year outcomes of cranial nerve stimulation for obstructive sleep apnea: The STAR trial. Otolaryngol Head Neck Surg. 2016;154(1):181-8. doi: 10.1177/0194599815616618.

4. Heiser C et al. Outcomes of upper airway stimulation for obstructive sleep apnea in a multicenter german postmarket study. Otolaryngol Head Neck Surg. 2017;156(2):378-84. doi: 10.1177/0194599816683378.

5. Gillespie MB et al. Upper airway stimulation for obstructive sleep apnea: Patient-reported outcomes after 48 months of follow-up. Otolaryngol Head Neck Surg. 2017;156(4):765-71. doi: 10.1177/0194599817691491.

6. Pietzsch JB et al. Long-term cost-effectiveness of upper airway stimulation for the treatment of obstructive sleep apnea: A model-based projection based on the star trial. Sleep. 2015;38(5):735-44. doi: 10.5665/sleep.4666.

7. Oliven A et al. Improved upper airway patency elicited by electrical stimulation of the hypoglossus nerves. Respiration. 1996;63(4):213-16. doi: 10.1159/000196547.

8. Strollo PJ et al. Upper-airway stimulation for obstructive sleep apnea. N Engl J Med. 2014;370(2):139-49. doi: 10.1056/NEJMoa1308659.

9. Liu YC et al. Palatopharyngoplasty resolves concentric collapse in patients ineligible for upper airway stimulation. Laryngoscope. Forthcoming.

10. De Andrade RGS et al. Impact of the type of mask on the effectiveness of and adherence to continuous positive airway pressure treatment for obstructive sleep apnea. J Bras Pneumol. 2014;40(6):658-68. doi: 10.1590/S1806-37132014000600010

Clinical significance

Continuous positive airway pressure remains the gold standard and first-line treatment for moderate to severe OSA. When CPAP and other medical therapies fail or are poorly adopted, surgical solutions - either standalone or in unison - can be directed to target precision therapy.

The newest of these techniques is neuromodulation of the lingual musculature, particularly by way of selective stimulation of the hypoglossal nerve, which first demonstrated success in human clinical trials in 1996.¹ Upper airway stimulation (UAS) was formally FDA-approved in 2014 (Inspire Medical Systems, Inc). UAS is designed to eliminate clinically significant OSA through stimulation of the anteriorly directed branches of the hypoglossal nerve, increasing the posterior airway space in a multilevel fashion.² Since this time, over 7,500 patients have been treated with Inspire in nine countries (United States, Germany, The Netherlands, Switzerland, Belgium, Spain, France, Italy, and Finland). Prospective, international multicenter trials have demonstrated 68% to 96% clinical efficacy in well selected individuals. This is defined as a ≥ 50% reduction in the apnea hypopnea index (AHI) to an overall AHI of ≤ 20/hour.^3,4 Additionally, post-UAS analysis demonstrates subjective reduction in daytime sleepiness as reported by Epworth sleepiness scores, with improvements in sleep-related quality of life. Further, UAS reduces socially disruptive snoring with 85% of bedpartners reporting soft to no snoring at 48-month follow-up.⁵ The procedure has also demonstrated long-term cost benefit in the US health-care system.⁶
 

Background and pathophysiology

Oliven and colleagues⁷ first observed the critical finding that selective intra-muscular stimulation of the genioglossus muscle lowered airway critical closing pressure (PCrit), thereby stabilizing the pharyngeal airway. Conversely, activation of the “retrusor” musculature, namely the hyoglossus and styloglossus muscles, increased Pcrit, increasing collapsibility of the pharyngeal airway.

Therapeutic implantation requires three incisions directed to the neck, chest, and right rib space (between the 4th to 6th intercostal spaces), with an operative time of 90 minutes or less in experienced hands. The majority of patients are discharged on the day of the procedure. Morbidity remains low with minimal pain reported during recovery. The most common complication is that of temporary tongue weakness, which typically resolves within 2 to 3 weeks. While very infrequent, patients should be counseled on the risk of postoperative hematoma, which can precipitate infection and subsequent explant of the device. Average recovery time spans between 3 and 7 days with activation of the device 4 weeks after surgical implantation to allow for appropriate tissue healing and reduce the risk of dislodgement of the implanted components. In contrast to other surgical treatment options, UAS is also reversible with no underlying alteration to existing pharyngeal anatomy apart from external incisions created during the procedure.
 

Stimulation to titration

As the need for a multidisciplinary approach to salvage of patients failing first-line therapy for OSA continues to grow, UAS with its multilevel impact continues to be of key interest. In similar fashion to established medical therapies such as PAP and oral appliance therapy (OAT), close observation between sleep medicine specialists and the implanting surgeon during the adaptation period with attention paid to titration parameters such as stimulation duration, pulse width, amplitude, and polarity, allow optimization of response outcome.

The stimulation electrode, which is designed in the form of a cuff to envelope the anterior (protrusor) branches of the hypoglossal nerve receives electrical stimulation from the implanted pulse generator, implanted above the pectoralis muscle of the chest wall. This design allows for collaborative awake and overnight titration of the device as directed by a sleep medicine physician. Attention is paid not only to the voltage “strength” administered with each pulse but also the degree of synchronization between respiration and stimulation, as well as pattern of pulse administration. Our experience remains that true success and adaptation to therapy requires not just meticulous surgical technique but a diligent approach to postoperative therapeutic titration to achieve a comfortable, yet effective, voltage for maintaining airway patency. Thus, akin to initiation of CPAP, UAS requires regular follow-up and device fine-tuning with patient comfort taken into consideration to achieve optimal results, and patient expectation should be aligned with this process.
 

Current indications

Success in UAS relies heavily on appropriate presurgical evaluation and clinical phenotyping. The following surgical indications have been demonstrated in the Stimulation Therapy for Apnea Reduction (STAR) trial and subsequent 3-year clinical follow-up: AHI between 15 and 80 events/hour (with ≤ 25% central apneas) and a BMI ≤ 32.⁸

As OSA often results from multi-level airway collapse, UAS targets an increase not only in the diameter of the retropalatal/oropharyngeal airway space but also the antero-posterior hypopharyngeal airway. Original criteria for implantation excluded patients with a pattern of complete circumferential collapse (CCC) noted on dynamic airway evaluation during pre-implant drug-induced sleep endoscopy (DISE). DISE aims to precisely target dynamic airway collapse patterns during simulated (propofol or midazolom induced) sleep.
 

Future directions

The effects of UAS are dependent on upper-airway cross-sectional area, particularly diameter. In patients who demonstrate CCC, the anteroposterior direction of activation derived from the UAS stimulus is unable to overcome CCC. In a recent prospective study, our group demonstrated that CCC can be converted to an airway collapse pattern compatible with UAS implantation, using a modified palatopharyngoplasty prior to UAS implantation. By stabilizing the lateral walls of the oropharyngeal airway with pre-implant palatal surgery, UAS is able to successfully direct widening of the airway cross-sectional area in an antero-posterior fashion. This exciting finding potentially allows for expansion of current indications, thus opening treatment to a wider patient population.⁹ Still, UAS remains highly studied in a relatively uniform patient population with data in more diverse subsets requiring further directed attention to expand and better define optimal patient populations for treatment.

From the perspective of improving patient adaptation and tolerance in UAS, a well-established concept in the CPAP literature can be applied, as explained by the Starling resistor model. The starling resistor is comprised of two rigid tubes connected by a collapsible segment in between. In parallel, the pharynx is a collapsible muscular tube connected on either end by the nose/nasal cavity and the trachea – both of which are bony/cartilaginous, noncollapsible structures. As has been shown in the use of CPAP, the same pressure required to maintain stability of the collapsible muscular pharynx via nasal breathing may lead to pharyngeal collapse when applied orally.¹⁰ This concept has also been directed towards UAS with our clinical experience demonstrating that oro or oronasal breathers tend to require a higher amplitude to maintain airway patency versus nasal breathers. This is an important area for future-directed study as medically/surgically improving nasal breathing in UAS subjects may subsequently lower amplitude requirements and improve patient tolerance.

Future direction to allow for improvement in the technology for application in a broader populational segment, external or alternative device powering mechanisms, along with MRI Compatibility and reducing the number of required external incisions will continue to broaden the patient selection criteria. As we move from a “stimulation” to a precision-tailored “stimulation and titration” approach, the mid to long term data supporting UAS remains very promising with 5-year follow up demonstrating sustained polysomnographic and subjective reported outcomes in well selected patients.
 

Dr. Awad is Assistant Professor – Department of Otolaryngology/Head & Neck Surgery, and Chief – Division of Sleep Surgery; Northwestern University, Chicago, Illinois. Dr. Capasso is Associate Professor – Department of Otolaryngology/Head & Neck Surgery, and Chief – Division of Sleep Surgery; Stanford Hospital and Clinics, Stanford, California.

References

1. Schwartz AR et al. Electrical stimulation of the lingual musculature in obstructive sleep apnea. J Appl Physiol. 1996;81(2):643-52. doi: 10.1152/jappl.1996.81.2.643.

2. Ong AA et al. Efficacy of upper airway stimulation on collapse patterns observed during drug-induced sedation endoscopy. Otolaryngol Head Neck Surg. 2016;154(5):970-7. doi: 10.1177/0194599816636835.

3. Woodson BT et al. Three-year outcomes of cranial nerve stimulation for obstructive sleep apnea: The STAR trial. Otolaryngol Head Neck Surg. 2016;154(1):181-8. doi: 10.1177/0194599815616618.

4. Heiser C et al. Outcomes of upper airway stimulation for obstructive sleep apnea in a multicenter german postmarket study. Otolaryngol Head Neck Surg. 2017;156(2):378-84. doi: 10.1177/0194599816683378.

5. Gillespie MB et al. Upper airway stimulation for obstructive sleep apnea: Patient-reported outcomes after 48 months of follow-up. Otolaryngol Head Neck Surg. 2017;156(4):765-71. doi: 10.1177/0194599817691491.

6. Pietzsch JB et al. Long-term cost-effectiveness of upper airway stimulation for the treatment of obstructive sleep apnea: A model-based projection based on the star trial. Sleep. 2015;38(5):735-44. doi: 10.5665/sleep.4666.

7. Oliven A et al. Improved upper airway patency elicited by electrical stimulation of the hypoglossus nerves. Respiration. 1996;63(4):213-16. doi: 10.1159/000196547.

8. Strollo PJ et al. Upper-airway stimulation for obstructive sleep apnea. N Engl J Med. 2014;370(2):139-49. doi: 10.1056/NEJMoa1308659.

9. Liu YC et al. Palatopharyngoplasty resolves concentric collapse in patients ineligible for upper airway stimulation. Laryngoscope. Forthcoming.

10. De Andrade RGS et al. Impact of the type of mask on the effectiveness of and adherence to continuous positive airway pressure treatment for obstructive sleep apnea. J Bras Pneumol. 2014;40(6):658-68. doi: 10.1590/S1806-37132014000600010

Clinical significance

Continuous positive airway pressure remains the gold standard and first-line treatment for moderate to severe OSA. When CPAP and other medical therapies fail or are poorly adopted, surgical solutions - either standalone or in unison - can be directed to target precision therapy.

The newest of these techniques is neuromodulation of the lingual musculature, particularly by way of selective stimulation of the hypoglossal nerve, which first demonstrated success in human clinical trials in 1996.¹ Upper airway stimulation (UAS) was formally FDA-approved in 2014 (Inspire Medical Systems, Inc). UAS is designed to eliminate clinically significant OSA through stimulation of the anteriorly directed branches of the hypoglossal nerve, increasing the posterior airway space in a multilevel fashion.² Since this time, over 7,500 patients have been treated with Inspire in nine countries (United States, Germany, The Netherlands, Switzerland, Belgium, Spain, France, Italy, and Finland). Prospective, international multicenter trials have demonstrated 68% to 96% clinical efficacy in well selected individuals. This is defined as a ≥ 50% reduction in the apnea hypopnea index (AHI) to an overall AHI of ≤ 20/hour.^3,4 Additionally, post-UAS analysis demonstrates subjective reduction in daytime sleepiness as reported by Epworth sleepiness scores, with improvements in sleep-related quality of life. Further, UAS reduces socially disruptive snoring with 85% of bedpartners reporting soft to no snoring at 48-month follow-up.⁵ The procedure has also demonstrated long-term cost benefit in the US health-care system.⁶
 

Background and pathophysiology

Oliven and colleagues⁷ first observed the critical finding that selective intra-muscular stimulation of the genioglossus muscle lowered airway critical closing pressure (PCrit), thereby stabilizing the pharyngeal airway. Conversely, activation of the “retrusor” musculature, namely the hyoglossus and styloglossus muscles, increased Pcrit, increasing collapsibility of the pharyngeal airway.

Therapeutic implantation requires three incisions directed to the neck, chest, and right rib space (between the 4th to 6th intercostal spaces), with an operative time of 90 minutes or less in experienced hands. The majority of patients are discharged on the day of the procedure. Morbidity remains low with minimal pain reported during recovery. The most common complication is that of temporary tongue weakness, which typically resolves within 2 to 3 weeks. While very infrequent, patients should be counseled on the risk of postoperative hematoma, which can precipitate infection and subsequent explant of the device. Average recovery time spans between 3 and 7 days with activation of the device 4 weeks after surgical implantation to allow for appropriate tissue healing and reduce the risk of dislodgement of the implanted components. In contrast to other surgical treatment options, UAS is also reversible with no underlying alteration to existing pharyngeal anatomy apart from external incisions created during the procedure.
 

Stimulation to titration

As the need for a multidisciplinary approach to salvage of patients failing first-line therapy for OSA continues to grow, UAS with its multilevel impact continues to be of key interest. In similar fashion to established medical therapies such as PAP and oral appliance therapy (OAT), close observation between sleep medicine specialists and the implanting surgeon during the adaptation period with attention paid to titration parameters such as stimulation duration, pulse width, amplitude, and polarity, allow optimization of response outcome.

The stimulation electrode, which is designed in the form of a cuff to envelope the anterior (protrusor) branches of the hypoglossal nerve receives electrical stimulation from the implanted pulse generator, implanted above the pectoralis muscle of the chest wall. This design allows for collaborative awake and overnight titration of the device as directed by a sleep medicine physician. Attention is paid not only to the voltage “strength” administered with each pulse but also the degree of synchronization between respiration and stimulation, as well as pattern of pulse administration. Our experience remains that true success and adaptation to therapy requires not just meticulous surgical technique but a diligent approach to postoperative therapeutic titration to achieve a comfortable, yet effective, voltage for maintaining airway patency. Thus, akin to initiation of CPAP, UAS requires regular follow-up and device fine-tuning with patient comfort taken into consideration to achieve optimal results, and patient expectation should be aligned with this process.
 

Current indications

Success in UAS relies heavily on appropriate presurgical evaluation and clinical phenotyping. The following surgical indications have been demonstrated in the Stimulation Therapy for Apnea Reduction (STAR) trial and subsequent 3-year clinical follow-up: AHI between 15 and 80 events/hour (with ≤ 25% central apneas) and a BMI ≤ 32.⁸

As OSA often results from multi-level airway collapse, UAS targets an increase not only in the diameter of the retropalatal/oropharyngeal airway space but also the antero-posterior hypopharyngeal airway. Original criteria for implantation excluded patients with a pattern of complete circumferential collapse (CCC) noted on dynamic airway evaluation during pre-implant drug-induced sleep endoscopy (DISE). DISE aims to precisely target dynamic airway collapse patterns during simulated (propofol or midazolom induced) sleep.
 

Future directions

The effects of UAS are dependent on upper-airway cross-sectional area, particularly diameter. In patients who demonstrate CCC, the anteroposterior direction of activation derived from the UAS stimulus is unable to overcome CCC. In a recent prospective study, our group demonstrated that CCC can be converted to an airway collapse pattern compatible with UAS implantation, using a modified palatopharyngoplasty prior to UAS implantation. By stabilizing the lateral walls of the oropharyngeal airway with pre-implant palatal surgery, UAS is able to successfully direct widening of the airway cross-sectional area in an antero-posterior fashion. This exciting finding potentially allows for expansion of current indications, thus opening treatment to a wider patient population.⁹ Still, UAS remains highly studied in a relatively uniform patient population with data in more diverse subsets requiring further directed attention to expand and better define optimal patient populations for treatment.

From the perspective of improving patient adaptation and tolerance in UAS, a well-established concept in the CPAP literature can be applied, as explained by the Starling resistor model. The starling resistor is comprised of two rigid tubes connected by a collapsible segment in between. In parallel, the pharynx is a collapsible muscular tube connected on either end by the nose/nasal cavity and the trachea – both of which are bony/cartilaginous, noncollapsible structures. As has been shown in the use of CPAP, the same pressure required to maintain stability of the collapsible muscular pharynx via nasal breathing may lead to pharyngeal collapse when applied orally.¹⁰ This concept has also been directed towards UAS with our clinical experience demonstrating that oro or oronasal breathers tend to require a higher amplitude to maintain airway patency versus nasal breathers. This is an important area for future-directed study as medically/surgically improving nasal breathing in UAS subjects may subsequently lower amplitude requirements and improve patient tolerance.

Future direction to allow for improvement in the technology for application in a broader populational segment, external or alternative device powering mechanisms, along with MRI Compatibility and reducing the number of required external incisions will continue to broaden the patient selection criteria. As we move from a “stimulation” to a precision-tailored “stimulation and titration” approach, the mid to long term data supporting UAS remains very promising with 5-year follow up demonstrating sustained polysomnographic and subjective reported outcomes in well selected patients.
 

Dr. Awad is Assistant Professor – Department of Otolaryngology/Head & Neck Surgery, and Chief – Division of Sleep Surgery; Northwestern University, Chicago, Illinois. Dr. Capasso is Associate Professor – Department of Otolaryngology/Head & Neck Surgery, and Chief – Division of Sleep Surgery; Stanford Hospital and Clinics, Stanford, California.

References

1. Schwartz AR et al. Electrical stimulation of the lingual musculature in obstructive sleep apnea. J Appl Physiol. 1996;81(2):643-52. doi: 10.1152/jappl.1996.81.2.643.

2. Ong AA et al. Efficacy of upper airway stimulation on collapse patterns observed during drug-induced sedation endoscopy. Otolaryngol Head Neck Surg. 2016;154(5):970-7. doi: 10.1177/0194599816636835.

3. Woodson BT et al. Three-year outcomes of cranial nerve stimulation for obstructive sleep apnea: The STAR trial. Otolaryngol Head Neck Surg. 2016;154(1):181-8. doi: 10.1177/0194599815616618.

4. Heiser C et al. Outcomes of upper airway stimulation for obstructive sleep apnea in a multicenter german postmarket study. Otolaryngol Head Neck Surg. 2017;156(2):378-84. doi: 10.1177/0194599816683378.

5. Gillespie MB et al. Upper airway stimulation for obstructive sleep apnea: Patient-reported outcomes after 48 months of follow-up. Otolaryngol Head Neck Surg. 2017;156(4):765-71. doi: 10.1177/0194599817691491.

6. Pietzsch JB et al. Long-term cost-effectiveness of upper airway stimulation for the treatment of obstructive sleep apnea: A model-based projection based on the star trial. Sleep. 2015;38(5):735-44. doi: 10.5665/sleep.4666.

7. Oliven A et al. Improved upper airway patency elicited by electrical stimulation of the hypoglossus nerves. Respiration. 1996;63(4):213-16. doi: 10.1159/000196547.

8. Strollo PJ et al. Upper-airway stimulation for obstructive sleep apnea. N Engl J Med. 2014;370(2):139-49. doi: 10.1056/NEJMoa1308659.

9. Liu YC et al. Palatopharyngoplasty resolves concentric collapse in patients ineligible for upper airway stimulation. Laryngoscope. Forthcoming.

10. De Andrade RGS et al. Impact of the type of mask on the effectiveness of and adherence to continuous positive airway pressure treatment for obstructive sleep apnea. J Bras Pneumol. 2014;40(6):658-68. doi: 10.1590/S1806-37132014000600010

Chronic obstructive pulmonary disease (COPD), projected to be the third leading cause of death by 2020, accounts for 6% of deaths globally.³ Hospitalization for COPD exacerbations is common and impacts patients’ disease trajectory, and mortality, with fewer than half of patients hospitalized for exacerbation surviving 5 years.⁴ Hospitalization provides an opportunity to optimize care. Due to recent practice-changing evidence, the National Institute for Health and Care Excellence (NICE) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) published updated guidelines.

These are selected recommendations relevant to adult hospitalists. The GOLD guidelines grade recommendations by evidence strength from category A (randomized control trial data) to category D (expert consensus). The NICE guidelines relay strength of evidence through terminology referring to the presence or absence of a strong recommendation. Recommendations without evidence level specified are NS.

Diagnosis and Classification of COPD Severity

Recommendation 1. In patients with risk factors for and symptoms of COPD, spirometry is required to confirm the diagnosis, defined as a postbronchodilator FEV₁/FVC ratio of <0.7 (NS, NICE, GOLD). The Global Lung Function Initiative (GLI) 2012 reference ranges⁵ are recommended (NS, NICE). Recommendation 2. Severity of airflow obstruction should be assessed according to reduction in the postbronchodilator FEV₁ as: Stage I, Mild: FEV₁ ≥80%; Stage II, Moderate: FEV₁ = 50-79%; Stage III, Severe FEV₁ = 30%-49%; Stage IV, FEV₁<30% (NS, NICE, GOLD). Recommendation 3. Reversibility testing (aka bronchodilator response) does not indicate long-term response to therapy (NS, NICE, GOLD). Recommendation 4. The combined COPD assessment to classify patient symptoms and disease severity in one of four groups (A, B, C, or D) based on exacerbation history and daily symptom control (NS, GOLD). Use the Medical Research Council dyspnea scale to classify symptoms (strong, NICE).

Pharmacologic COPD Management

Recommendation 5. Short-acting inhaled bronchodilators such as short-acting beta2 agonists (SABAs) or short-acting muscarinic antagonists (SAMAs) improve FEV₁ and symptoms. Combining SABA/SAMA is superior to monotherapy (A, GOLD). Recommendation 6. Long-acting bronchodilators, such as long-acting antimuscarinics (LAMAs) or long-acting beta2 agonists (LABAs), improve lung function and dyspnea and reduce exacerbations. Combination therapy (LABA/LAMA) is superior to using a single agent (LABA or LAMA) for improving FEV₁ and reducing exacerbations (A, GOLD). Recommendation 7. Triple therapy of inhaled corticosteroid ICS/LAMA/LABA is more effective than the individual components in reducing exacerbations in the case of moderate to severe COPD (A, GOLD). Recommendation 8. Treatment with an ICS increases pneumonia risk (A, GOLD). Discuss these side effects (Strong, NICE). Recommendation 9. Use SABAs and SAMAs as initial treatment for patients with COPD (Strong, NICE). LABAs and LAMAs are preferred over short-acting agents except for patients with mild symptoms (A, GOLD). Recommendation 10. For symptomatic patients on long-acting monotherapy, escalate to combination LABA/LAMA, or if asthmatic features or elevated eosinophils (≥300 cells/µL) are present, combination LABA/ICS (A, GOLD; Strong, NICE). Recommendation 11. Assess and correct patient inhaler technique (NS, GOLD; Strong, NICE).

Nonpharmacologic COPD Management

Oxygen. Recommendation 12. Long-term oxygen supplementation increases survival in patients with resting arterial hypoxemia (PaO₂<55 mm Hg) or hypoxemia (PaO₂<60 mm Hg) with cor pulmonale (A, GOLD). Recommendation 13. In patients with moderate resting (89%-93%) or exercise-induced arterial desaturation (80%-90%), long-term oxygen does not improve outcomes (A, GOLD).⁶ Recommendation 14. Consider long-term oxygan after a risk assessment of fall and burn risk. Do not offer oxygen to those who continue to smoke (Strong, NICE).

Tobacco Cessation. Recommendation 15. Offer smoking cessation to COPD patients (A, GOLD; Strong, NICE). Recommendation 16. Counseling intensity has a dose-response relationship with effective cessation. Pharmacotherapies complementing behavioral therapies are most successful (A, GOLD).

Pulmonary Rehabilitation. Recommendation 17. Provide rehabilitation to patients with high exacerbation risk and relevant symptoms (A, GOLD). Offer pulmonary rehabilitation to patients with recent hospitalizations and/or severe dyspnea (Strong, NICE).

Immunizations. Recommendation 18. Influenza and pneumococcal vaccinations (PPSV23 as well as PCV13 when age ≥ 65 years) are recommended for patients with COPD (NS, GOLD; Strong, NICE).

Palliative Care. Recommendation 19. For patients with end-stage COPD or poorly controlled symptoms, provide access to palliative care (NS, GOLD; Strong, NICE).

Management of COPD Exacerbations and Patients at high risk for Exacerbations

Recommendation 20. Use SABAs with or without SAMAs as initial bronchodilators to treat acute exacerbations (C, GOLD). Recommendation 21. Systemic corticosteroids for exacerbations improve lung function, oxygenation, and recovery time. Recommend 5 to 7 days of therapy (A, GOLD; Strong, NICE). Recommendation 22. Antibiotics shorten recovery time and reduce treatment failure and rehospitalization. Treatment should be 5 to 7 days (B, GOLD). Consider antibiotics while balancing the severity of symptoms and hospitalization need (Conditional, NICE). Recommendation 23. Noninvasive mechanical ventilation is the preferred mode of ventilation for COPD patients with acute respiratory failure without acute contraindications (A, GOLD). Recommendation 24. Avoid long-term oral corticosteroids therapy (A, GOLD). Recommendation 25. Consider roflumilast for patients with exacerbations despite LABA/ICS or LABA/LAMA/ICS, and seek respiratory medicine consultation (B, GOLD; Strong, NICE). For former smokers with exacerbations despite appropriate therapy, consider azithromycin (B, GOLD; Strong, NICE).

GOLD is an International committee of experts who compile the report based on scientific literature review. NICE is an independent organization funded by Department of Health and Social Care in the United Kingdom responsible for evidence-based guidance on healthcare determined by an expert committee through scientific review and a transparent process that details committee formation and framework (GRADE) used and stakeholder input. While both guidelines review current publications, practice-influencing clinical trials of recent publication may be missed.

On the GOLD Science committee, 17/20 members have pharmaceutical relationships, with no mitigation plan provided. The NICE guidelines detail a panel with few industry ties and a mitigation plan for potential conflicts of interest.

These recommendations comprehensively cover outpatient and inpatient COPD management. The GOLD and NICE guidelines are similar with the exception of recommendations surrounding use of oxygen. The NICE guidelines, based on the adverse events documented in the recent Long-Term Oxygen Treatment Trial,⁶ recommend against oxygen use by patients who smoke because of the risk of fire-related injuries;⁷ GOLD guidelines do not differentiate oxygen recommendation by patient population.

Differences in the strength of NICE and GOLD recommendations highlight areas for further study. Investigations determining distinct COPD phenotypes will likely influence future guidelines. More discriminative multidimensional prognostication tools are needed to improve precision surrounding prognosis.

Chronic obstructive pulmonary disease (COPD), projected to be the third leading cause of death by 2020, accounts for 6% of deaths globally.³ Hospitalization for COPD exacerbations is common and impacts patients’ disease trajectory, and mortality, with fewer than half of patients hospitalized for exacerbation surviving 5 years.⁴ Hospitalization provides an opportunity to optimize care. Due to recent practice-changing evidence, the National Institute for Health and Care Excellence (NICE) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) published updated guidelines.

These are selected recommendations relevant to adult hospitalists. The GOLD guidelines grade recommendations by evidence strength from category A (randomized control trial data) to category D (expert consensus). The NICE guidelines relay strength of evidence through terminology referring to the presence or absence of a strong recommendation. Recommendations without evidence level specified are NS.

Diagnosis and Classification of COPD Severity

Recommendation 1. In patients with risk factors for and symptoms of COPD, spirometry is required to confirm the diagnosis, defined as a postbronchodilator FEV₁/FVC ratio of <0.7 (NS, NICE, GOLD). The Global Lung Function Initiative (GLI) 2012 reference ranges⁵ are recommended (NS, NICE). Recommendation 2. Severity of airflow obstruction should be assessed according to reduction in the postbronchodilator FEV₁ as: Stage I, Mild: FEV₁ ≥80%; Stage II, Moderate: FEV₁ = 50-79%; Stage III, Severe FEV₁ = 30%-49%; Stage IV, FEV₁<30% (NS, NICE, GOLD). Recommendation 3. Reversibility testing (aka bronchodilator response) does not indicate long-term response to therapy (NS, NICE, GOLD). Recommendation 4. The combined COPD assessment to classify patient symptoms and disease severity in one of four groups (A, B, C, or D) based on exacerbation history and daily symptom control (NS, GOLD). Use the Medical Research Council dyspnea scale to classify symptoms (strong, NICE).

Pharmacologic COPD Management

Recommendation 5. Short-acting inhaled bronchodilators such as short-acting beta2 agonists (SABAs) or short-acting muscarinic antagonists (SAMAs) improve FEV₁ and symptoms. Combining SABA/SAMA is superior to monotherapy (A, GOLD). Recommendation 6. Long-acting bronchodilators, such as long-acting antimuscarinics (LAMAs) or long-acting beta2 agonists (LABAs), improve lung function and dyspnea and reduce exacerbations. Combination therapy (LABA/LAMA) is superior to using a single agent (LABA or LAMA) for improving FEV₁ and reducing exacerbations (A, GOLD). Recommendation 7. Triple therapy of inhaled corticosteroid ICS/LAMA/LABA is more effective than the individual components in reducing exacerbations in the case of moderate to severe COPD (A, GOLD). Recommendation 8. Treatment with an ICS increases pneumonia risk (A, GOLD). Discuss these side effects (Strong, NICE). Recommendation 9. Use SABAs and SAMAs as initial treatment for patients with COPD (Strong, NICE). LABAs and LAMAs are preferred over short-acting agents except for patients with mild symptoms (A, GOLD). Recommendation 10. For symptomatic patients on long-acting monotherapy, escalate to combination LABA/LAMA, or if asthmatic features or elevated eosinophils (≥300 cells/µL) are present, combination LABA/ICS (A, GOLD; Strong, NICE). Recommendation 11. Assess and correct patient inhaler technique (NS, GOLD; Strong, NICE).

Nonpharmacologic COPD Management

Oxygen. Recommendation 12. Long-term oxygen supplementation increases survival in patients with resting arterial hypoxemia (PaO₂<55 mm Hg) or hypoxemia (PaO₂<60 mm Hg) with cor pulmonale (A, GOLD). Recommendation 13. In patients with moderate resting (89%-93%) or exercise-induced arterial desaturation (80%-90%), long-term oxygen does not improve outcomes (A, GOLD).⁶ Recommendation 14. Consider long-term oxygan after a risk assessment of fall and burn risk. Do not offer oxygen to those who continue to smoke (Strong, NICE).

Tobacco Cessation. Recommendation 15. Offer smoking cessation to COPD patients (A, GOLD; Strong, NICE). Recommendation 16. Counseling intensity has a dose-response relationship with effective cessation. Pharmacotherapies complementing behavioral therapies are most successful (A, GOLD).

Pulmonary Rehabilitation. Recommendation 17. Provide rehabilitation to patients with high exacerbation risk and relevant symptoms (A, GOLD). Offer pulmonary rehabilitation to patients with recent hospitalizations and/or severe dyspnea (Strong, NICE).

Immunizations. Recommendation 18. Influenza and pneumococcal vaccinations (PPSV23 as well as PCV13 when age ≥ 65 years) are recommended for patients with COPD (NS, GOLD; Strong, NICE).

Palliative Care. Recommendation 19. For patients with end-stage COPD or poorly controlled symptoms, provide access to palliative care (NS, GOLD; Strong, NICE).

Management of COPD Exacerbations and Patients at high risk for Exacerbations

Recommendation 20. Use SABAs with or without SAMAs as initial bronchodilators to treat acute exacerbations (C, GOLD). Recommendation 21. Systemic corticosteroids for exacerbations improve lung function, oxygenation, and recovery time. Recommend 5 to 7 days of therapy (A, GOLD; Strong, NICE). Recommendation 22. Antibiotics shorten recovery time and reduce treatment failure and rehospitalization. Treatment should be 5 to 7 days (B, GOLD). Consider antibiotics while balancing the severity of symptoms and hospitalization need (Conditional, NICE). Recommendation 23. Noninvasive mechanical ventilation is the preferred mode of ventilation for COPD patients with acute respiratory failure without acute contraindications (A, GOLD). Recommendation 24. Avoid long-term oral corticosteroids therapy (A, GOLD). Recommendation 25. Consider roflumilast for patients with exacerbations despite LABA/ICS or LABA/LAMA/ICS, and seek respiratory medicine consultation (B, GOLD; Strong, NICE). For former smokers with exacerbations despite appropriate therapy, consider azithromycin (B, GOLD; Strong, NICE).

GOLD is an International committee of experts who compile the report based on scientific literature review. NICE is an independent organization funded by Department of Health and Social Care in the United Kingdom responsible for evidence-based guidance on healthcare determined by an expert committee through scientific review and a transparent process that details committee formation and framework (GRADE) used and stakeholder input. While both guidelines review current publications, practice-influencing clinical trials of recent publication may be missed.

On the GOLD Science committee, 17/20 members have pharmaceutical relationships, with no mitigation plan provided. The NICE guidelines detail a panel with few industry ties and a mitigation plan for potential conflicts of interest.

These recommendations comprehensively cover outpatient and inpatient COPD management. The GOLD and NICE guidelines are similar with the exception of recommendations surrounding use of oxygen. The NICE guidelines, based on the adverse events documented in the recent Long-Term Oxygen Treatment Trial,⁶ recommend against oxygen use by patients who smoke because of the risk of fire-related injuries;⁷ GOLD guidelines do not differentiate oxygen recommendation by patient population.

Differences in the strength of NICE and GOLD recommendations highlight areas for further study. Investigations determining distinct COPD phenotypes will likely influence future guidelines. More discriminative multidimensional prognostication tools are needed to improve precision surrounding prognosis.

Chronic obstructive pulmonary disease (COPD), projected to be the third leading cause of death by 2020, accounts for 6% of deaths globally.³ Hospitalization for COPD exacerbations is common and impacts patients’ disease trajectory, and mortality, with fewer than half of patients hospitalized for exacerbation surviving 5 years.⁴ Hospitalization provides an opportunity to optimize care. Due to recent practice-changing evidence, the National Institute for Health and Care Excellence (NICE) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) published updated guidelines.

These are selected recommendations relevant to adult hospitalists. The GOLD guidelines grade recommendations by evidence strength from category A (randomized control trial data) to category D (expert consensus). The NICE guidelines relay strength of evidence through terminology referring to the presence or absence of a strong recommendation. Recommendations without evidence level specified are NS.

Diagnosis and Classification of COPD Severity

Recommendation 1. In patients with risk factors for and symptoms of COPD, spirometry is required to confirm the diagnosis, defined as a postbronchodilator FEV₁/FVC ratio of <0.7 (NS, NICE, GOLD). The Global Lung Function Initiative (GLI) 2012 reference ranges⁵ are recommended (NS, NICE). Recommendation 2. Severity of airflow obstruction should be assessed according to reduction in the postbronchodilator FEV₁ as: Stage I, Mild: FEV₁ ≥80%; Stage II, Moderate: FEV₁ = 50-79%; Stage III, Severe FEV₁ = 30%-49%; Stage IV, FEV₁<30% (NS, NICE, GOLD). Recommendation 3. Reversibility testing (aka bronchodilator response) does not indicate long-term response to therapy (NS, NICE, GOLD). Recommendation 4. The combined COPD assessment to classify patient symptoms and disease severity in one of four groups (A, B, C, or D) based on exacerbation history and daily symptom control (NS, GOLD). Use the Medical Research Council dyspnea scale to classify symptoms (strong, NICE).

Pharmacologic COPD Management

Recommendation 5. Short-acting inhaled bronchodilators such as short-acting beta2 agonists (SABAs) or short-acting muscarinic antagonists (SAMAs) improve FEV₁ and symptoms. Combining SABA/SAMA is superior to monotherapy (A, GOLD). Recommendation 6. Long-acting bronchodilators, such as long-acting antimuscarinics (LAMAs) or long-acting beta2 agonists (LABAs), improve lung function and dyspnea and reduce exacerbations. Combination therapy (LABA/LAMA) is superior to using a single agent (LABA or LAMA) for improving FEV₁ and reducing exacerbations (A, GOLD). Recommendation 7. Triple therapy of inhaled corticosteroid ICS/LAMA/LABA is more effective than the individual components in reducing exacerbations in the case of moderate to severe COPD (A, GOLD). Recommendation 8. Treatment with an ICS increases pneumonia risk (A, GOLD). Discuss these side effects (Strong, NICE). Recommendation 9. Use SABAs and SAMAs as initial treatment for patients with COPD (Strong, NICE). LABAs and LAMAs are preferred over short-acting agents except for patients with mild symptoms (A, GOLD). Recommendation 10. For symptomatic patients on long-acting monotherapy, escalate to combination LABA/LAMA, or if asthmatic features or elevated eosinophils (≥300 cells/µL) are present, combination LABA/ICS (A, GOLD; Strong, NICE). Recommendation 11. Assess and correct patient inhaler technique (NS, GOLD; Strong, NICE).

Nonpharmacologic COPD Management

Oxygen. Recommendation 12. Long-term oxygen supplementation increases survival in patients with resting arterial hypoxemia (PaO₂<55 mm Hg) or hypoxemia (PaO₂<60 mm Hg) with cor pulmonale (A, GOLD). Recommendation 13. In patients with moderate resting (89%-93%) or exercise-induced arterial desaturation (80%-90%), long-term oxygen does not improve outcomes (A, GOLD).⁶ Recommendation 14. Consider long-term oxygan after a risk assessment of fall and burn risk. Do not offer oxygen to those who continue to smoke (Strong, NICE).

Tobacco Cessation. Recommendation 15. Offer smoking cessation to COPD patients (A, GOLD; Strong, NICE). Recommendation 16. Counseling intensity has a dose-response relationship with effective cessation. Pharmacotherapies complementing behavioral therapies are most successful (A, GOLD).

Pulmonary Rehabilitation. Recommendation 17. Provide rehabilitation to patients with high exacerbation risk and relevant symptoms (A, GOLD). Offer pulmonary rehabilitation to patients with recent hospitalizations and/or severe dyspnea (Strong, NICE).

Immunizations. Recommendation 18. Influenza and pneumococcal vaccinations (PPSV23 as well as PCV13 when age ≥ 65 years) are recommended for patients with COPD (NS, GOLD; Strong, NICE).

Palliative Care. Recommendation 19. For patients with end-stage COPD or poorly controlled symptoms, provide access to palliative care (NS, GOLD; Strong, NICE).

Management of COPD Exacerbations and Patients at high risk for Exacerbations

Recommendation 20. Use SABAs with or without SAMAs as initial bronchodilators to treat acute exacerbations (C, GOLD). Recommendation 21. Systemic corticosteroids for exacerbations improve lung function, oxygenation, and recovery time. Recommend 5 to 7 days of therapy (A, GOLD; Strong, NICE). Recommendation 22. Antibiotics shorten recovery time and reduce treatment failure and rehospitalization. Treatment should be 5 to 7 days (B, GOLD). Consider antibiotics while balancing the severity of symptoms and hospitalization need (Conditional, NICE). Recommendation 23. Noninvasive mechanical ventilation is the preferred mode of ventilation for COPD patients with acute respiratory failure without acute contraindications (A, GOLD). Recommendation 24. Avoid long-term oral corticosteroids therapy (A, GOLD). Recommendation 25. Consider roflumilast for patients with exacerbations despite LABA/ICS or LABA/LAMA/ICS, and seek respiratory medicine consultation (B, GOLD; Strong, NICE). For former smokers with exacerbations despite appropriate therapy, consider azithromycin (B, GOLD; Strong, NICE).

GOLD is an International committee of experts who compile the report based on scientific literature review. NICE is an independent organization funded by Department of Health and Social Care in the United Kingdom responsible for evidence-based guidance on healthcare determined by an expert committee through scientific review and a transparent process that details committee formation and framework (GRADE) used and stakeholder input. While both guidelines review current publications, practice-influencing clinical trials of recent publication may be missed.

On the GOLD Science committee, 17/20 members have pharmaceutical relationships, with no mitigation plan provided. The NICE guidelines detail a panel with few industry ties and a mitigation plan for potential conflicts of interest.

These recommendations comprehensively cover outpatient and inpatient COPD management. The GOLD and NICE guidelines are similar with the exception of recommendations surrounding use of oxygen. The NICE guidelines, based on the adverse events documented in the recent Long-Term Oxygen Treatment Trial,⁶ recommend against oxygen use by patients who smoke because of the risk of fire-related injuries;⁷ GOLD guidelines do not differentiate oxygen recommendation by patient population.

Differences in the strength of NICE and GOLD recommendations highlight areas for further study. Investigations determining distinct COPD phenotypes will likely influence future guidelines. More discriminative multidimensional prognostication tools are needed to improve precision surrounding prognosis.

The recent closure of Hahnemann University Hospital, a 500-bed teaching hospital in downtown Philadelphia, Pennsylvania, offers a case study of a new form of for-profit business involvement in academic medicine —private equity investment. Though the closure of this 171-year-old institution is the result of multiple factors affecting the hospital’s financial health over decades and may not have been avoidable, the hospital’s final years in the hands of a private equity firm led to a closure process that was chaotic, uncoordinated, and fundamentally not aligned with the needs of the patients and trainees that make up the core constituents of a teaching hospital. This hospital’s story involves a concerning trend that underscores the dissonance in mission of private equity and academic medicine. In an era of competition and market consolidation, other teaching hospitals may be forced to close under similar circumstances in the future, making it vital that the medical and academic communities be aware of these discordant missions to guide policy-making efforts and ensure that the needs of patients and trainees take priority in transition planning rather than the needs of investors.

Tracing the hospital’s history, much of its financial troubles began over 20 years ago. In 1993, the Allegheny Health, Education, and Research Foundation (AHERF), a nonprofit Pittsburgh-based hospital and physician practice organization, acquired Hahnemann Medical College. Forming the MCP-Hahnemann Medical School, AHERF merged the institution with another acquisition, Medical College of Pennsylvania (MCP),¹ formerly known as the Woman’s Medical College of Pennsylvania, one of the first American medical schools devoted to exclusively training female physicians.^1,2 This was part of AHERF’s aggressive growth strategy at the time and resulted in the acquisition of 14 hospitals and more than 300 Philadelphia-area primary care physician practices by 1998. This caused about $1.3 billion of debt and over $1 million in losses per day, which led AHERF to file for bankruptcy that year,² the country’s largest nonprofit healthcare bankruptcy at the time.¹ That same year, Tenet Healthcare Corporation, a for-profit healthcare company, bought AHERF’s assets in the Philadelphia region from bankruptcy for $345 million, acquiring eight hospitals, as well as all of AHREF’s physician practices.² Ultimately, Tenet sold or closed six of the acquired hospitals by 2007, leaving just Hahnemann and St. Christopher’s Hospital for Children,³ while Drexel University, a private, nonprofit university, came forward to salvage AHERF’s educational programs, creating the Drexel University College of Medicine.² Under the ownership of Tenet, Hahnemann’s financial health declined as its patient population included a growing proportion of those utilizing Medicare, Medicaid, and charity care, which resulted in a negative operating profit margin annually for the final 14 years under Tenet.^3,4 In this setting, American Academic Health System, LLC (AAHS) stepped in to purchase Hahnemann and St. Christopher’s from Tenet and, eventually, chose to close Hahnemann.⁴

That Hahnemann found itself in the hands of a private equity firm was not surprising. Such investment firms’ acquisitions of hospitals and physician practices have become increasingly more common, with the number of these types of deals increasing by 48% and reaching a value of $42.6 billion from 2010 to 2017.⁵ While for-profit hospitals have been shown to have higher mortality⁶ and lower patient satisfaction⁷ than nonprofit hospitals, the relatively new and growing trend of private equity investment in healthcare has not been rigorously evaluated. By nature, these firms use investor capital to acquire assets with the goal of increasing their value and selling them off at a profit after about 3-7 years.⁵ Thus, healthcare services provided by private equity–owned facilities are valued and supported based on their profitability. Low-profit services, such as primary care and psychiatry, are minimized while more profitable services, such as same-day surgery, are maximized.⁵ In addition, given that for-profit hospitals tend to invest less in charity care⁸ and population health⁹ as compared with nonprofit institutions, private equity–owned hospitals likely follow suit, in contrast to the humanistic values of academic medicine. Ultimately, Hahnemann’s decades-long financial troubles set the stage for a buyout by private equity investors. But this transaction was the death knell for this teaching hospital and eventually proved to be a disadvantage for the community it served.

Purchasing Hahnemann and St Christopher’s from Tenet in early 2018 for $170 million, AAHS—an affiliate of the private equity firm, Paladin Healthcare Capital, LLC, led by investment banker Joel Freedman—entered the Philadelphia healthcare market in partnership with Chicago-based healthcare real estate private equity firm, Harrison Street Real Estate Capital, LLC.⁴ Paladin had previously invested in smaller hospitals serving underserved communities,⁴ and as it began its venture with this large teaching hospital, Paladin’s president, Barry Wolfman, stated that the company’s goal was “to return [Hahnemann] to its rightful place in the landscape of healthcare.”³ However, given the real estate firm’s involvement in the deal and the permissive tier of zoning for Hahnemann’s real estate,1⁰ there were suspicions that the purchase of the hospital was a means to acquire and develop the valuable Center City real estate rather than to serve the community.³

Within months of the hospital purchase, AAHS‘s Philadelphia venture proved difficult. Four CEOs came and went as time passed, with some holding their position for only a couple of months.1¹ About 175 of Hahnemann’s nurses, support staff, and managers were laid off in April of 2019, but the hospital finances did not improve significantly.1² As it became evident that AAHS planned to close the hospital, efforts were made to prevent the closure. Drexel University filed an unsuccessful lawsuit, claiming that it would be a violation of the academic agreement between the university and hospital.1³ Once AAHS announced plans for hospital closure, the Pennsylvania Secretary of Health, Rachel Levine, MD, wrote to AAHS leadership ordering a “cease and desist” of any action toward hospital closure.¹² Despite this, AAHS began cutting vital hospital services, including trauma and cardiothoracic surgery services, within days of the closure announcement.¹⁴ While there is a state law that a hospital cannot be closed with less than 90 days’ notice, AAHS filed for bankruptcy and shut down Hahnemann’s service to the community in about half that time.¹³ The hospital real estate was separated from the operating businesses and was excluded from the bankruptcy filing,¹⁰ which further cemented suspicions that the involved private equity firms looked to profit off the land once the hospital closed.

The immediate and long-term effects of the closure of Hahnemann University Hospital on healthcare and medical education in Philadelphia are yet to be rigorously measured and evaluated. However, the hasty closure of a large inner-city teaching hospital that served as a healthcare safety net for a largely underserved minority population with 50,000 ED visits per year⁴ is a dangerous disruption to a community. The way that the hospital was closed not only defied regulatory attempts at protecting the community but also defied the values of the healthcare workers working in the hospital. Because AAHS ceased payments to hospital vendors, medical supplies were low during the final weeks at Hahnemann, which didn’t even have enough cups on the wards to provide drinking water for patients.¹⁵ Nurses reported feeling shame as they used scissors to cut wash cloths in half to have enough to wash their patients.¹⁵ The teaching hospital’s humanistic and social capital was being liquidated quickly. Even after Hahnemann’s 570 graduate medical trainees endured the stressful and chaotic process of being displaced and fortunately taken in by other programs,¹⁶ AAHS attempted to auction off Hahnemann’s graduate medical education (GME) slots and their associated government funding to the highest bidder. While a US bankruptcy judge initially approved the sale of those GME slots to a consortium of academic institutions in the Philadelphia area,¹⁷ the Center for Medicare & Medicaid Services (CMS) has appealed that decision, which resulted in a current stay on the transaction.¹⁷ AAHS treating GME trainee positions as assets to be bought and sold is a dangerous precedent to set, especially since it attempts to bypass CMS’s existing regulated process for redistributing the slots.

While time will reveal the effects of the hospital closure, the most concerning element of this story is that the methods of a private equity firm in closing a large inner-city teaching hospital flouted attempts by regulatory agencies acting to preserve the hospital’s mission to the community. The governor of Pennsylvania, Tom Wolf (D), and mayor of Philadelphia, Jim Kenney (D), issued a joint statement chastising the actions of AAHS: “The situation at Hahnemann University Hospital, caused by CEO Joel Freedman and his team of venture capitalists, is an absolute disgrace and shows a greed-driven lack of care for the community.”1⁸ This chaotic situation inspired Philadelphia Councilperson Helen Gym (D) to propose city legislation requiring 180 days’ notice of a hospital closure, bestowing a strong local means of protecting the city’s people from similar healthcare fiascos in the future.¹⁵

At its core, healthcare is a human-to-human interaction with the purpose of improving and maintaining the health and life of the patient. Adding to that the noble efforts in educating students and trainees to provide that public good, academic medicine is a virtuous endeavor. The new and growing phenomenon of private equity in healthcare prioritizes maximizing a return on investment, so the closure of Hahnemann University Hospital in Philadelphia highlights manifestations of the discordance of the missions of private equity and academic medicine and serves as “the canary in the coal mine,” warning teaching hospitals and communities that this disconnect necessitates regulatory policies to protect academic medicine’s service to the community while private equity investment continues to spread in healthcare.

The recent closure of Hahnemann University Hospital, a 500-bed teaching hospital in downtown Philadelphia, Pennsylvania, offers a case study of a new form of for-profit business involvement in academic medicine —private equity investment. Though the closure of this 171-year-old institution is the result of multiple factors affecting the hospital’s financial health over decades and may not have been avoidable, the hospital’s final years in the hands of a private equity firm led to a closure process that was chaotic, uncoordinated, and fundamentally not aligned with the needs of the patients and trainees that make up the core constituents of a teaching hospital. This hospital’s story involves a concerning trend that underscores the dissonance in mission of private equity and academic medicine. In an era of competition and market consolidation, other teaching hospitals may be forced to close under similar circumstances in the future, making it vital that the medical and academic communities be aware of these discordant missions to guide policy-making efforts and ensure that the needs of patients and trainees take priority in transition planning rather than the needs of investors.

Tracing the hospital’s history, much of its financial troubles began over 20 years ago. In 1993, the Allegheny Health, Education, and Research Foundation (AHERF), a nonprofit Pittsburgh-based hospital and physician practice organization, acquired Hahnemann Medical College. Forming the MCP-Hahnemann Medical School, AHERF merged the institution with another acquisition, Medical College of Pennsylvania (MCP),¹ formerly known as the Woman’s Medical College of Pennsylvania, one of the first American medical schools devoted to exclusively training female physicians.^1,2 This was part of AHERF’s aggressive growth strategy at the time and resulted in the acquisition of 14 hospitals and more than 300 Philadelphia-area primary care physician practices by 1998. This caused about $1.3 billion of debt and over $1 million in losses per day, which led AHERF to file for bankruptcy that year,² the country’s largest nonprofit healthcare bankruptcy at the time.¹ That same year, Tenet Healthcare Corporation, a for-profit healthcare company, bought AHERF’s assets in the Philadelphia region from bankruptcy for $345 million, acquiring eight hospitals, as well as all of AHREF’s physician practices.² Ultimately, Tenet sold or closed six of the acquired hospitals by 2007, leaving just Hahnemann and St. Christopher’s Hospital for Children,³ while Drexel University, a private, nonprofit university, came forward to salvage AHERF’s educational programs, creating the Drexel University College of Medicine.² Under the ownership of Tenet, Hahnemann’s financial health declined as its patient population included a growing proportion of those utilizing Medicare, Medicaid, and charity care, which resulted in a negative operating profit margin annually for the final 14 years under Tenet.^3,4 In this setting, American Academic Health System, LLC (AAHS) stepped in to purchase Hahnemann and St. Christopher’s from Tenet and, eventually, chose to close Hahnemann.⁴

That Hahnemann found itself in the hands of a private equity firm was not surprising. Such investment firms’ acquisitions of hospitals and physician practices have become increasingly more common, with the number of these types of deals increasing by 48% and reaching a value of $42.6 billion from 2010 to 2017.⁵ While for-profit hospitals have been shown to have higher mortality⁶ and lower patient satisfaction⁷ than nonprofit hospitals, the relatively new and growing trend of private equity investment in healthcare has not been rigorously evaluated. By nature, these firms use investor capital to acquire assets with the goal of increasing their value and selling them off at a profit after about 3-7 years.⁵ Thus, healthcare services provided by private equity–owned facilities are valued and supported based on their profitability. Low-profit services, such as primary care and psychiatry, are minimized while more profitable services, such as same-day surgery, are maximized.⁵ In addition, given that for-profit hospitals tend to invest less in charity care⁸ and population health⁹ as compared with nonprofit institutions, private equity–owned hospitals likely follow suit, in contrast to the humanistic values of academic medicine. Ultimately, Hahnemann’s decades-long financial troubles set the stage for a buyout by private equity investors. But this transaction was the death knell for this teaching hospital and eventually proved to be a disadvantage for the community it served.

Purchasing Hahnemann and St Christopher’s from Tenet in early 2018 for $170 million, AAHS—an affiliate of the private equity firm, Paladin Healthcare Capital, LLC, led by investment banker Joel Freedman—entered the Philadelphia healthcare market in partnership with Chicago-based healthcare real estate private equity firm, Harrison Street Real Estate Capital, LLC.⁴ Paladin had previously invested in smaller hospitals serving underserved communities,⁴ and as it began its venture with this large teaching hospital, Paladin’s president, Barry Wolfman, stated that the company’s goal was “to return [Hahnemann] to its rightful place in the landscape of healthcare.”³ However, given the real estate firm’s involvement in the deal and the permissive tier of zoning for Hahnemann’s real estate,1⁰ there were suspicions that the purchase of the hospital was a means to acquire and develop the valuable Center City real estate rather than to serve the community.³

Within months of the hospital purchase, AAHS‘s Philadelphia venture proved difficult. Four CEOs came and went as time passed, with some holding their position for only a couple of months.1¹ About 175 of Hahnemann’s nurses, support staff, and managers were laid off in April of 2019, but the hospital finances did not improve significantly.1² As it became evident that AAHS planned to close the hospital, efforts were made to prevent the closure. Drexel University filed an unsuccessful lawsuit, claiming that it would be a violation of the academic agreement between the university and hospital.1³ Once AAHS announced plans for hospital closure, the Pennsylvania Secretary of Health, Rachel Levine, MD, wrote to AAHS leadership ordering a “cease and desist” of any action toward hospital closure.¹² Despite this, AAHS began cutting vital hospital services, including trauma and cardiothoracic surgery services, within days of the closure announcement.¹⁴ While there is a state law that a hospital cannot be closed with less than 90 days’ notice, AAHS filed for bankruptcy and shut down Hahnemann’s service to the community in about half that time.¹³ The hospital real estate was separated from the operating businesses and was excluded from the bankruptcy filing,¹⁰ which further cemented suspicions that the involved private equity firms looked to profit off the land once the hospital closed.

The immediate and long-term effects of the closure of Hahnemann University Hospital on healthcare and medical education in Philadelphia are yet to be rigorously measured and evaluated. However, the hasty closure of a large inner-city teaching hospital that served as a healthcare safety net for a largely underserved minority population with 50,000 ED visits per year⁴ is a dangerous disruption to a community. The way that the hospital was closed not only defied regulatory attempts at protecting the community but also defied the values of the healthcare workers working in the hospital. Because AAHS ceased payments to hospital vendors, medical supplies were low during the final weeks at Hahnemann, which didn’t even have enough cups on the wards to provide drinking water for patients.¹⁵ Nurses reported feeling shame as they used scissors to cut wash cloths in half to have enough to wash their patients.¹⁵ The teaching hospital’s humanistic and social capital was being liquidated quickly. Even after Hahnemann’s 570 graduate medical trainees endured the stressful and chaotic process of being displaced and fortunately taken in by other programs,¹⁶ AAHS attempted to auction off Hahnemann’s graduate medical education (GME) slots and their associated government funding to the highest bidder. While a US bankruptcy judge initially approved the sale of those GME slots to a consortium of academic institutions in the Philadelphia area,¹⁷ the Center for Medicare & Medicaid Services (CMS) has appealed that decision, which resulted in a current stay on the transaction.¹⁷ AAHS treating GME trainee positions as assets to be bought and sold is a dangerous precedent to set, especially since it attempts to bypass CMS’s existing regulated process for redistributing the slots.

While time will reveal the effects of the hospital closure, the most concerning element of this story is that the methods of a private equity firm in closing a large inner-city teaching hospital flouted attempts by regulatory agencies acting to preserve the hospital’s mission to the community. The governor of Pennsylvania, Tom Wolf (D), and mayor of Philadelphia, Jim Kenney (D), issued a joint statement chastising the actions of AAHS: “The situation at Hahnemann University Hospital, caused by CEO Joel Freedman and his team of venture capitalists, is an absolute disgrace and shows a greed-driven lack of care for the community.”1⁸ This chaotic situation inspired Philadelphia Councilperson Helen Gym (D) to propose city legislation requiring 180 days’ notice of a hospital closure, bestowing a strong local means of protecting the city’s people from similar healthcare fiascos in the future.¹⁵

At its core, healthcare is a human-to-human interaction with the purpose of improving and maintaining the health and life of the patient. Adding to that the noble efforts in educating students and trainees to provide that public good, academic medicine is a virtuous endeavor. The new and growing phenomenon of private equity in healthcare prioritizes maximizing a return on investment, so the closure of Hahnemann University Hospital in Philadelphia highlights manifestations of the discordance of the missions of private equity and academic medicine and serves as “the canary in the coal mine,” warning teaching hospitals and communities that this disconnect necessitates regulatory policies to protect academic medicine’s service to the community while private equity investment continues to spread in healthcare.

The recent closure of Hahnemann University Hospital, a 500-bed teaching hospital in downtown Philadelphia, Pennsylvania, offers a case study of a new form of for-profit business involvement in academic medicine —private equity investment. Though the closure of this 171-year-old institution is the result of multiple factors affecting the hospital’s financial health over decades and may not have been avoidable, the hospital’s final years in the hands of a private equity firm led to a closure process that was chaotic, uncoordinated, and fundamentally not aligned with the needs of the patients and trainees that make up the core constituents of a teaching hospital. This hospital’s story involves a concerning trend that underscores the dissonance in mission of private equity and academic medicine. In an era of competition and market consolidation, other teaching hospitals may be forced to close under similar circumstances in the future, making it vital that the medical and academic communities be aware of these discordant missions to guide policy-making efforts and ensure that the needs of patients and trainees take priority in transition planning rather than the needs of investors.

Tracing the hospital’s history, much of its financial troubles began over 20 years ago. In 1993, the Allegheny Health, Education, and Research Foundation (AHERF), a nonprofit Pittsburgh-based hospital and physician practice organization, acquired Hahnemann Medical College. Forming the MCP-Hahnemann Medical School, AHERF merged the institution with another acquisition, Medical College of Pennsylvania (MCP),¹ formerly known as the Woman’s Medical College of Pennsylvania, one of the first American medical schools devoted to exclusively training female physicians.^1,2 This was part of AHERF’s aggressive growth strategy at the time and resulted in the acquisition of 14 hospitals and more than 300 Philadelphia-area primary care physician practices by 1998. This caused about $1.3 billion of debt and over $1 million in losses per day, which led AHERF to file for bankruptcy that year,² the country’s largest nonprofit healthcare bankruptcy at the time.¹ That same year, Tenet Healthcare Corporation, a for-profit healthcare company, bought AHERF’s assets in the Philadelphia region from bankruptcy for $345 million, acquiring eight hospitals, as well as all of AHREF’s physician practices.² Ultimately, Tenet sold or closed six of the acquired hospitals by 2007, leaving just Hahnemann and St. Christopher’s Hospital for Children,³ while Drexel University, a private, nonprofit university, came forward to salvage AHERF’s educational programs, creating the Drexel University College of Medicine.² Under the ownership of Tenet, Hahnemann’s financial health declined as its patient population included a growing proportion of those utilizing Medicare, Medicaid, and charity care, which resulted in a negative operating profit margin annually for the final 14 years under Tenet.^3,4 In this setting, American Academic Health System, LLC (AAHS) stepped in to purchase Hahnemann and St. Christopher’s from Tenet and, eventually, chose to close Hahnemann.⁴

That Hahnemann found itself in the hands of a private equity firm was not surprising. Such investment firms’ acquisitions of hospitals and physician practices have become increasingly more common, with the number of these types of deals increasing by 48% and reaching a value of $42.6 billion from 2010 to 2017.⁵ While for-profit hospitals have been shown to have higher mortality⁶ and lower patient satisfaction⁷ than nonprofit hospitals, the relatively new and growing trend of private equity investment in healthcare has not been rigorously evaluated. By nature, these firms use investor capital to acquire assets with the goal of increasing their value and selling them off at a profit after about 3-7 years.⁵ Thus, healthcare services provided by private equity–owned facilities are valued and supported based on their profitability. Low-profit services, such as primary care and psychiatry, are minimized while more profitable services, such as same-day surgery, are maximized.⁵ In addition, given that for-profit hospitals tend to invest less in charity care⁸ and population health⁹ as compared with nonprofit institutions, private equity–owned hospitals likely follow suit, in contrast to the humanistic values of academic medicine. Ultimately, Hahnemann’s decades-long financial troubles set the stage for a buyout by private equity investors. But this transaction was the death knell for this teaching hospital and eventually proved to be a disadvantage for the community it served.

Purchasing Hahnemann and St Christopher’s from Tenet in early 2018 for $170 million, AAHS—an affiliate of the private equity firm, Paladin Healthcare Capital, LLC, led by investment banker Joel Freedman—entered the Philadelphia healthcare market in partnership with Chicago-based healthcare real estate private equity firm, Harrison Street Real Estate Capital, LLC.⁴ Paladin had previously invested in smaller hospitals serving underserved communities,⁴ and as it began its venture with this large teaching hospital, Paladin’s president, Barry Wolfman, stated that the company’s goal was “to return [Hahnemann] to its rightful place in the landscape of healthcare.”³ However, given the real estate firm’s involvement in the deal and the permissive tier of zoning for Hahnemann’s real estate,1⁰ there were suspicions that the purchase of the hospital was a means to acquire and develop the valuable Center City real estate rather than to serve the community.³

Within months of the hospital purchase, AAHS‘s Philadelphia venture proved difficult. Four CEOs came and went as time passed, with some holding their position for only a couple of months.1¹ About 175 of Hahnemann’s nurses, support staff, and managers were laid off in April of 2019, but the hospital finances did not improve significantly.1² As it became evident that AAHS planned to close the hospital, efforts were made to prevent the closure. Drexel University filed an unsuccessful lawsuit, claiming that it would be a violation of the academic agreement between the university and hospital.1³ Once AAHS announced plans for hospital closure, the Pennsylvania Secretary of Health, Rachel Levine, MD, wrote to AAHS leadership ordering a “cease and desist” of any action toward hospital closure.¹² Despite this, AAHS began cutting vital hospital services, including trauma and cardiothoracic surgery services, within days of the closure announcement.¹⁴ While there is a state law that a hospital cannot be closed with less than 90 days’ notice, AAHS filed for bankruptcy and shut down Hahnemann’s service to the community in about half that time.¹³ The hospital real estate was separated from the operating businesses and was excluded from the bankruptcy filing,¹⁰ which further cemented suspicions that the involved private equity firms looked to profit off the land once the hospital closed.

The immediate and long-term effects of the closure of Hahnemann University Hospital on healthcare and medical education in Philadelphia are yet to be rigorously measured and evaluated. However, the hasty closure of a large inner-city teaching hospital that served as a healthcare safety net for a largely underserved minority population with 50,000 ED visits per year⁴ is a dangerous disruption to a community. The way that the hospital was closed not only defied regulatory attempts at protecting the community but also defied the values of the healthcare workers working in the hospital. Because AAHS ceased payments to hospital vendors, medical supplies were low during the final weeks at Hahnemann, which didn’t even have enough cups on the wards to provide drinking water for patients.¹⁵ Nurses reported feeling shame as they used scissors to cut wash cloths in half to have enough to wash their patients.¹⁵ The teaching hospital’s humanistic and social capital was being liquidated quickly. Even after Hahnemann’s 570 graduate medical trainees endured the stressful and chaotic process of being displaced and fortunately taken in by other programs,¹⁶ AAHS attempted to auction off Hahnemann’s graduate medical education (GME) slots and their associated government funding to the highest bidder. While a US bankruptcy judge initially approved the sale of those GME slots to a consortium of academic institutions in the Philadelphia area,¹⁷ the Center for Medicare & Medicaid Services (CMS) has appealed that decision, which resulted in a current stay on the transaction.¹⁷ AAHS treating GME trainee positions as assets to be bought and sold is a dangerous precedent to set, especially since it attempts to bypass CMS’s existing regulated process for redistributing the slots.

While time will reveal the effects of the hospital closure, the most concerning element of this story is that the methods of a private equity firm in closing a large inner-city teaching hospital flouted attempts by regulatory agencies acting to preserve the hospital’s mission to the community. The governor of Pennsylvania, Tom Wolf (D), and mayor of Philadelphia, Jim Kenney (D), issued a joint statement chastising the actions of AAHS: “The situation at Hahnemann University Hospital, caused by CEO Joel Freedman and his team of venture capitalists, is an absolute disgrace and shows a greed-driven lack of care for the community.”1⁸ This chaotic situation inspired Philadelphia Councilperson Helen Gym (D) to propose city legislation requiring 180 days’ notice of a hospital closure, bestowing a strong local means of protecting the city’s people from similar healthcare fiascos in the future.¹⁵

At its core, healthcare is a human-to-human interaction with the purpose of improving and maintaining the health and life of the patient. Adding to that the noble efforts in educating students and trainees to provide that public good, academic medicine is a virtuous endeavor. The new and growing phenomenon of private equity in healthcare prioritizes maximizing a return on investment, so the closure of Hahnemann University Hospital in Philadelphia highlights manifestations of the discordance of the missions of private equity and academic medicine and serves as “the canary in the coal mine,” warning teaching hospitals and communities that this disconnect necessitates regulatory policies to protect academic medicine’s service to the community while private equity investment continues to spread in healthcare.

Since the last National Heart, Lung, and Blood Institute’s (NHLBI) guidelines that were released in 2007, additional evidence has emerged in several areas of asthma care.¹ To provide a concise clinical update relevant to the practice of pediatric hospital medicine, we searched PubMed for asthma publications in the last 10 years with a particular focus on articles published in the last 5 years. We used a validated pediatric search filter to identify pediatric studies, MeSH term for “Asthma,” and the following terms: “Clinical Pathways,” “Clinical Protocols,” “Dexamethasone,” and “Albuterol.” From these articles, we identified three areas of emerging evidence supporting practice change relative to the inpatient care of children with asthma, which are summarized in this brief review. This clinical practice update covers the emerging evidence supporting dexamethasone use for acute asthma exacerbations, the shift away from nebulized albuterol toward metered dose inhaler (MDI) albuterol, and the utility of asthma clinical pathways.

In the last decade, emergency departments (EDs) have increasingly prescribed dexamethasone over prednisone because it is noninferior and has a superior side-effect profile, including less vomiting.² However, the evidence for dexamethasone use in hospitalized children lagged behind ED practice change. This led to uncertainty among pediatric hospitalists regarding the most appropriate oral steroid to use, particularly for children who received dexamethasone in the ED prior to admission.³

Several studies have been published to address this gap in the literature. In 2015 Parikh et al. published a multicenter retrospective cohort study of dexamethasone vs prednisone among hospitalized children using the Pediatric Health Information Systems (PHIS) database. ⁴ The authors compared 1,166 patients who received dexamethasone only with a propensity-matched cohort of 1,284 patients receiving only prednisone/prednisolone. Outcomes included the proportion with a length of stay (LOS) greater than 3 days, all-cause readmission at 7 and 30 days, and cost of admission. A greater proportion of patients receiving prednisone/prednisolone had a LOS greater than 3 days when compared with those in the dexamethasone cohort. There were no significant differences in all cause 7- or 30-day readmission. The dexamethasone cohort had statistically significantly lower costs. The authors concluded that dexamethasone may be a viable alternative to prednisone/prednisolone for children admitted for acute asthma exacerbation not requiring admission to the pediatric intensive care unit (PICU).

In 2019, Tyler et al. published a single-center, retrospective, cohort study that used interrupted time series analysis to evaluate outcomes for inpatients with asthma before and after an ED’s protocol was changed to dexamethasone.⁵ Outcomes analyzed included LOS, hospital charges, and PICU transfer rates. The study included 1,015 subjects over a 36-month period. In the post–protocol change group, 65% of the subjects received dexamethasone only while 28% received a combination of dexamethasone and prednisone/prednisolone. The authors found no immediate significant differences in LOS, ICU transfers, or charges after the protocol change. However, they did see an overall 10% increased rate of PICU transfers in the period following the protocol change, a trend that could have been caused by difficult-to-measure differences in severity of patients before and after the protocol change. If the increase in PICU transfer rate was temporally associated with the ED protocol change, an immediate change in rate would be expected, and this was not seen. The authors speculated that dexamethasone may be inferior to prednisone for inpatients with the highest severity of asthma.

Combined with the practical benefit of dexamethasone’s shorter treatment course and decreased vomiting,² these two studies support the use of dexamethasone in the inpatient setting for patients who don’t require ICU level care. A feasibility trial to determine noninferiority of dexamethasone vs prednisone is currently enrolling, according to clinicaltrials.gov.

The 2007 NHLBI guidelines are clear that short-acting beta-2 agonists (SABA), delivered via nebulization or metered-dose inhaler (MDI) with a valved holding chamber (VHC), along with systemic steroids, should be the primary treatment in pediatric acute asthma exacerbations.¹ The guidelines caution that nebulization therapy might be needed for patients who are ineffective in using MDIs because of age, level of agitation, or severity of asthma symptoms. Specific recommendations for management in the inpatient setting are brief but note that inpatient medication administration and care should mirror ED management strategies.¹ Specific in-hospital management recommendations regarding nebulization vs MDI are not addressed.

A Cochrane Review by Cates et al. assessed pediatric and adult randomized trials comparing SABA delivery via MDI-VHC with that via nebulization.⁶ The analysis included 39 trials with a total of 729 adults and 1,897 children. Six of the included trials were conducted in an inpatient setting (207 enrolled children in these studies). The authors found that mechanism of SABA delivery did not affect ED admission rates or significantly influence other markers of treatment response (peak flow and forced expiratory volumes). In children, MDI-VHC use was associated with shorter ED length of stay, as well as a decreased frequency of common SABA side effects (ie, tachycardia and tremor). This review cites several areas in which research is needed, including MDI use in severe asthma exacerbations. This population often falls outside pediatric hospitalists’ scope of practice because these patients often require ICU-level care.

A recent systematic review of pediatric acute asthma management strategies by Castro-Rodriguez et al. found that using MDI-VHC to deliver SABA was superior to using nebulization as measured by decreased ED admission rates and ED length of stay, improved asthma clinical scores, and reduced SABA side effects.⁷ A 2016 prospective randomized trial of MDI-VHC vs nebulization in preschool-aged children presenting to an ED with asthma or virally mediated wheeze found that the SABA delivered via MDI-VHC was at least as effective as that delivered via nebulization.⁸

International asthma management guidelines more strongly recommend MDI-only treatment for pediatric patients admitted with moderate asthma.⁹ Despite this guidance, and the literature supporting transition in inpatient settings to bronchodilator administration via MDI, there are several barriers to exclusive MDI use in the inpatient setting. As mentioned by Cates et al., a recognized challenge in MDI-VHC adoption is overcoming the “nebulizer culture” in treating pediatric acute asthma symptoms.⁶ Perhaps not surprisingly, Press et al., in a retrospective secondary analysis of 25 institutions managing adults and children with acute asthma symptoms, found that 32% of all pediatric patients assessed received only nebulized SABA treatments during their hospitalization.¹⁰ Transitioning from nebulized albuterol to exclusively MDI-VHC albuterol will require significant systems changes.

Clinical pathways operationalize practice guidelines and provide guidance on the treatments, testing, and management of an illness. Use of pediatric asthma pathways has increased steadily in the past decade, with one study of over 300 hospitals finding that, between 2005 to 2015, pathway implementation increased from 27% to 86%.¹¹ This expanded use has coincided with a proliferation of publications evaluating the effects of these pathways. A systematic review examining the implementation and impact of asthma protocols identified over 100 articles published between 1986 and 2010, with the majority published after 2005.¹² The study found implementation of guidelines through an asthma pathway generally improved patient care and provider performance regardless of implementation method.

Since that review, Kaiser et al. investigated the effects of pathway implementation at 42 children’s hospitals.¹³ They used interrupted time series to determine the effect of pathway implementation on LOS. Secondary outcomes included cost, use of bronchodilators, antibiotic use, and 30-day readmissions. This study found pathway implementation was associated with an 8.8% decrease in LOS and 3% decrease in hospital costs while increasing bronchodilator administration and decreasing antibiotic exposure. To determine the factors that allowed successful implementation of asthma pathways (as determined by reduction in LOS), Kaiser et al. performed qualitative interviews of key stakeholders at high- and low-performing hospitals.¹⁴ The most successful hospitals all used rigorous data-driven quality-improvement methodologies, set shared goals with key stakeholders, integrated the pathway into their electronic medical record, allowed nurses and respiratory therapists to titrate albuterol frequency, and engaged hospital leadership to secure needed resources.

Although in each of these studies, pathway implementation led to improvements in the acute management of patients, there was no reduction in pediatric asthma readmissions at 30 days.^12,13 A meta-analysis of asthma-related quality improvement interventions also did not find an association between pathway implementation alone and decreased readmissions or ED revisits.¹⁵ The lack of improvement in these metrics may have been caused by the tendency for pathways to focus on the acute asthma management and lack of focus on chronic asthma severity. Asthma admissions are an opportunity for full evaluation of disease severity, allergen exposures, and education on medication and spacer technique. Refinement of pathways with a focus on chronic control and on transition from hospital to home may move the needle on decreasing the long-term morbidity of pediatric asthma.

Current evidence suggests pediatric hospitalists should consider transitioning from prednisolone/prednisone to dexamethasone and from nebulized albuterol delivery to MDI albuterol delivery for children admitted for acute asthma exacerbation who do not require ICU-level care. Implementing asthma clinical pathways that use rigorous quality improvement methods is an effective approach to adopt these and other evidence-based practice changes.

Disclosures

The authors have nothing to disclose.

Since the last National Heart, Lung, and Blood Institute’s (NHLBI) guidelines that were released in 2007, additional evidence has emerged in several areas of asthma care.¹ To provide a concise clinical update relevant to the practice of pediatric hospital medicine, we searched PubMed for asthma publications in the last 10 years with a particular focus on articles published in the last 5 years. We used a validated pediatric search filter to identify pediatric studies, MeSH term for “Asthma,” and the following terms: “Clinical Pathways,” “Clinical Protocols,” “Dexamethasone,” and “Albuterol.” From these articles, we identified three areas of emerging evidence supporting practice change relative to the inpatient care of children with asthma, which are summarized in this brief review. This clinical practice update covers the emerging evidence supporting dexamethasone use for acute asthma exacerbations, the shift away from nebulized albuterol toward metered dose inhaler (MDI) albuterol, and the utility of asthma clinical pathways.

In the last decade, emergency departments (EDs) have increasingly prescribed dexamethasone over prednisone because it is noninferior and has a superior side-effect profile, including less vomiting.² However, the evidence for dexamethasone use in hospitalized children lagged behind ED practice change. This led to uncertainty among pediatric hospitalists regarding the most appropriate oral steroid to use, particularly for children who received dexamethasone in the ED prior to admission.³

Several studies have been published to address this gap in the literature. In 2015 Parikh et al. published a multicenter retrospective cohort study of dexamethasone vs prednisone among hospitalized children using the Pediatric Health Information Systems (PHIS) database. ⁴ The authors compared 1,166 patients who received dexamethasone only with a propensity-matched cohort of 1,284 patients receiving only prednisone/prednisolone. Outcomes included the proportion with a length of stay (LOS) greater than 3 days, all-cause readmission at 7 and 30 days, and cost of admission. A greater proportion of patients receiving prednisone/prednisolone had a LOS greater than 3 days when compared with those in the dexamethasone cohort. There were no significant differences in all cause 7- or 30-day readmission. The dexamethasone cohort had statistically significantly lower costs. The authors concluded that dexamethasone may be a viable alternative to prednisone/prednisolone for children admitted for acute asthma exacerbation not requiring admission to the pediatric intensive care unit (PICU).

In 2019, Tyler et al. published a single-center, retrospective, cohort study that used interrupted time series analysis to evaluate outcomes for inpatients with asthma before and after an ED’s protocol was changed to dexamethasone.⁵ Outcomes analyzed included LOS, hospital charges, and PICU transfer rates. The study included 1,015 subjects over a 36-month period. In the post–protocol change group, 65% of the subjects received dexamethasone only while 28% received a combination of dexamethasone and prednisone/prednisolone. The authors found no immediate significant differences in LOS, ICU transfers, or charges after the protocol change. However, they did see an overall 10% increased rate of PICU transfers in the period following the protocol change, a trend that could have been caused by difficult-to-measure differences in severity of patients before and after the protocol change. If the increase in PICU transfer rate was temporally associated with the ED protocol change, an immediate change in rate would be expected, and this was not seen. The authors speculated that dexamethasone may be inferior to prednisone for inpatients with the highest severity of asthma.

Combined with the practical benefit of dexamethasone’s shorter treatment course and decreased vomiting,² these two studies support the use of dexamethasone in the inpatient setting for patients who don’t require ICU level care. A feasibility trial to determine noninferiority of dexamethasone vs prednisone is currently enrolling, according to clinicaltrials.gov.

The 2007 NHLBI guidelines are clear that short-acting beta-2 agonists (SABA), delivered via nebulization or metered-dose inhaler (MDI) with a valved holding chamber (VHC), along with systemic steroids, should be the primary treatment in pediatric acute asthma exacerbations.¹ The guidelines caution that nebulization therapy might be needed for patients who are ineffective in using MDIs because of age, level of agitation, or severity of asthma symptoms. Specific recommendations for management in the inpatient setting are brief but note that inpatient medication administration and care should mirror ED management strategies.¹ Specific in-hospital management recommendations regarding nebulization vs MDI are not addressed.

A Cochrane Review by Cates et al. assessed pediatric and adult randomized trials comparing SABA delivery via MDI-VHC with that via nebulization.⁶ The analysis included 39 trials with a total of 729 adults and 1,897 children. Six of the included trials were conducted in an inpatient setting (207 enrolled children in these studies). The authors found that mechanism of SABA delivery did not affect ED admission rates or significantly influence other markers of treatment response (peak flow and forced expiratory volumes). In children, MDI-VHC use was associated with shorter ED length of stay, as well as a decreased frequency of common SABA side effects (ie, tachycardia and tremor). This review cites several areas in which research is needed, including MDI use in severe asthma exacerbations. This population often falls outside pediatric hospitalists’ scope of practice because these patients often require ICU-level care.

A recent systematic review of pediatric acute asthma management strategies by Castro-Rodriguez et al. found that using MDI-VHC to deliver SABA was superior to using nebulization as measured by decreased ED admission rates and ED length of stay, improved asthma clinical scores, and reduced SABA side effects.⁷ A 2016 prospective randomized trial of MDI-VHC vs nebulization in preschool-aged children presenting to an ED with asthma or virally mediated wheeze found that the SABA delivered via MDI-VHC was at least as effective as that delivered via nebulization.⁸

International asthma management guidelines more strongly recommend MDI-only treatment for pediatric patients admitted with moderate asthma.⁹ Despite this guidance, and the literature supporting transition in inpatient settings to bronchodilator administration via MDI, there are several barriers to exclusive MDI use in the inpatient setting. As mentioned by Cates et al., a recognized challenge in MDI-VHC adoption is overcoming the “nebulizer culture” in treating pediatric acute asthma symptoms.⁶ Perhaps not surprisingly, Press et al., in a retrospective secondary analysis of 25 institutions managing adults and children with acute asthma symptoms, found that 32% of all pediatric patients assessed received only nebulized SABA treatments during their hospitalization.¹⁰ Transitioning from nebulized albuterol to exclusively MDI-VHC albuterol will require significant systems changes.

Clinical pathways operationalize practice guidelines and provide guidance on the treatments, testing, and management of an illness. Use of pediatric asthma pathways has increased steadily in the past decade, with one study of over 300 hospitals finding that, between 2005 to 2015, pathway implementation increased from 27% to 86%.¹¹ This expanded use has coincided with a proliferation of publications evaluating the effects of these pathways. A systematic review examining the implementation and impact of asthma protocols identified over 100 articles published between 1986 and 2010, with the majority published after 2005.¹² The study found implementation of guidelines through an asthma pathway generally improved patient care and provider performance regardless of implementation method.

Since that review, Kaiser et al. investigated the effects of pathway implementation at 42 children’s hospitals.¹³ They used interrupted time series to determine the effect of pathway implementation on LOS. Secondary outcomes included cost, use of bronchodilators, antibiotic use, and 30-day readmissions. This study found pathway implementation was associated with an 8.8% decrease in LOS and 3% decrease in hospital costs while increasing bronchodilator administration and decreasing antibiotic exposure. To determine the factors that allowed successful implementation of asthma pathways (as determined by reduction in LOS), Kaiser et al. performed qualitative interviews of key stakeholders at high- and low-performing hospitals.¹⁴ The most successful hospitals all used rigorous data-driven quality-improvement methodologies, set shared goals with key stakeholders, integrated the pathway into their electronic medical record, allowed nurses and respiratory therapists to titrate albuterol frequency, and engaged hospital leadership to secure needed resources.

Although in each of these studies, pathway implementation led to improvements in the acute management of patients, there was no reduction in pediatric asthma readmissions at 30 days.^12,13 A meta-analysis of asthma-related quality improvement interventions also did not find an association between pathway implementation alone and decreased readmissions or ED revisits.¹⁵ The lack of improvement in these metrics may have been caused by the tendency for pathways to focus on the acute asthma management and lack of focus on chronic asthma severity. Asthma admissions are an opportunity for full evaluation of disease severity, allergen exposures, and education on medication and spacer technique. Refinement of pathways with a focus on chronic control and on transition from hospital to home may move the needle on decreasing the long-term morbidity of pediatric asthma.

Current evidence suggests pediatric hospitalists should consider transitioning from prednisolone/prednisone to dexamethasone and from nebulized albuterol delivery to MDI albuterol delivery for children admitted for acute asthma exacerbation who do not require ICU-level care. Implementing asthma clinical pathways that use rigorous quality improvement methods is an effective approach to adopt these and other evidence-based practice changes.

Disclosures

The authors have nothing to disclose.

Since the last National Heart, Lung, and Blood Institute’s (NHLBI) guidelines that were released in 2007, additional evidence has emerged in several areas of asthma care.¹ To provide a concise clinical update relevant to the practice of pediatric hospital medicine, we searched PubMed for asthma publications in the last 10 years with a particular focus on articles published in the last 5 years. We used a validated pediatric search filter to identify pediatric studies, MeSH term for “Asthma,” and the following terms: “Clinical Pathways,” “Clinical Protocols,” “Dexamethasone,” and “Albuterol.” From these articles, we identified three areas of emerging evidence supporting practice change relative to the inpatient care of children with asthma, which are summarized in this brief review. This clinical practice update covers the emerging evidence supporting dexamethasone use for acute asthma exacerbations, the shift away from nebulized albuterol toward metered dose inhaler (MDI) albuterol, and the utility of asthma clinical pathways.

In the last decade, emergency departments (EDs) have increasingly prescribed dexamethasone over prednisone because it is noninferior and has a superior side-effect profile, including less vomiting.² However, the evidence for dexamethasone use in hospitalized children lagged behind ED practice change. This led to uncertainty among pediatric hospitalists regarding the most appropriate oral steroid to use, particularly for children who received dexamethasone in the ED prior to admission.³

Several studies have been published to address this gap in the literature. In 2015 Parikh et al. published a multicenter retrospective cohort study of dexamethasone vs prednisone among hospitalized children using the Pediatric Health Information Systems (PHIS) database. ⁴ The authors compared 1,166 patients who received dexamethasone only with a propensity-matched cohort of 1,284 patients receiving only prednisone/prednisolone. Outcomes included the proportion with a length of stay (LOS) greater than 3 days, all-cause readmission at 7 and 30 days, and cost of admission. A greater proportion of patients receiving prednisone/prednisolone had a LOS greater than 3 days when compared with those in the dexamethasone cohort. There were no significant differences in all cause 7- or 30-day readmission. The dexamethasone cohort had statistically significantly lower costs. The authors concluded that dexamethasone may be a viable alternative to prednisone/prednisolone for children admitted for acute asthma exacerbation not requiring admission to the pediatric intensive care unit (PICU).

In 2019, Tyler et al. published a single-center, retrospective, cohort study that used interrupted time series analysis to evaluate outcomes for inpatients with asthma before and after an ED’s protocol was changed to dexamethasone.⁵ Outcomes analyzed included LOS, hospital charges, and PICU transfer rates. The study included 1,015 subjects over a 36-month period. In the post–protocol change group, 65% of the subjects received dexamethasone only while 28% received a combination of dexamethasone and prednisone/prednisolone. The authors found no immediate significant differences in LOS, ICU transfers, or charges after the protocol change. However, they did see an overall 10% increased rate of PICU transfers in the period following the protocol change, a trend that could have been caused by difficult-to-measure differences in severity of patients before and after the protocol change. If the increase in PICU transfer rate was temporally associated with the ED protocol change, an immediate change in rate would be expected, and this was not seen. The authors speculated that dexamethasone may be inferior to prednisone for inpatients with the highest severity of asthma.

Combined with the practical benefit of dexamethasone’s shorter treatment course and decreased vomiting,² these two studies support the use of dexamethasone in the inpatient setting for patients who don’t require ICU level care. A feasibility trial to determine noninferiority of dexamethasone vs prednisone is currently enrolling, according to clinicaltrials.gov.

The 2007 NHLBI guidelines are clear that short-acting beta-2 agonists (SABA), delivered via nebulization or metered-dose inhaler (MDI) with a valved holding chamber (VHC), along with systemic steroids, should be the primary treatment in pediatric acute asthma exacerbations.¹ The guidelines caution that nebulization therapy might be needed for patients who are ineffective in using MDIs because of age, level of agitation, or severity of asthma symptoms. Specific recommendations for management in the inpatient setting are brief but note that inpatient medication administration and care should mirror ED management strategies.¹ Specific in-hospital management recommendations regarding nebulization vs MDI are not addressed.

A Cochrane Review by Cates et al. assessed pediatric and adult randomized trials comparing SABA delivery via MDI-VHC with that via nebulization.⁶ The analysis included 39 trials with a total of 729 adults and 1,897 children. Six of the included trials were conducted in an inpatient setting (207 enrolled children in these studies). The authors found that mechanism of SABA delivery did not affect ED admission rates or significantly influence other markers of treatment response (peak flow and forced expiratory volumes). In children, MDI-VHC use was associated with shorter ED length of stay, as well as a decreased frequency of common SABA side effects (ie, tachycardia and tremor). This review cites several areas in which research is needed, including MDI use in severe asthma exacerbations. This population often falls outside pediatric hospitalists’ scope of practice because these patients often require ICU-level care.

A recent systematic review of pediatric acute asthma management strategies by Castro-Rodriguez et al. found that using MDI-VHC to deliver SABA was superior to using nebulization as measured by decreased ED admission rates and ED length of stay, improved asthma clinical scores, and reduced SABA side effects.⁷ A 2016 prospective randomized trial of MDI-VHC vs nebulization in preschool-aged children presenting to an ED with asthma or virally mediated wheeze found that the SABA delivered via MDI-VHC was at least as effective as that delivered via nebulization.⁸

International asthma management guidelines more strongly recommend MDI-only treatment for pediatric patients admitted with moderate asthma.⁹ Despite this guidance, and the literature supporting transition in inpatient settings to bronchodilator administration via MDI, there are several barriers to exclusive MDI use in the inpatient setting. As mentioned by Cates et al., a recognized challenge in MDI-VHC adoption is overcoming the “nebulizer culture” in treating pediatric acute asthma symptoms.⁶ Perhaps not surprisingly, Press et al., in a retrospective secondary analysis of 25 institutions managing adults and children with acute asthma symptoms, found that 32% of all pediatric patients assessed received only nebulized SABA treatments during their hospitalization.¹⁰ Transitioning from nebulized albuterol to exclusively MDI-VHC albuterol will require significant systems changes.

Clinical pathways operationalize practice guidelines and provide guidance on the treatments, testing, and management of an illness. Use of pediatric asthma pathways has increased steadily in the past decade, with one study of over 300 hospitals finding that, between 2005 to 2015, pathway implementation increased from 27% to 86%.¹¹ This expanded use has coincided with a proliferation of publications evaluating the effects of these pathways. A systematic review examining the implementation and impact of asthma protocols identified over 100 articles published between 1986 and 2010, with the majority published after 2005.¹² The study found implementation of guidelines through an asthma pathway generally improved patient care and provider performance regardless of implementation method.

Since that review, Kaiser et al. investigated the effects of pathway implementation at 42 children’s hospitals.¹³ They used interrupted time series to determine the effect of pathway implementation on LOS. Secondary outcomes included cost, use of bronchodilators, antibiotic use, and 30-day readmissions. This study found pathway implementation was associated with an 8.8% decrease in LOS and 3% decrease in hospital costs while increasing bronchodilator administration and decreasing antibiotic exposure. To determine the factors that allowed successful implementation of asthma pathways (as determined by reduction in LOS), Kaiser et al. performed qualitative interviews of key stakeholders at high- and low-performing hospitals.¹⁴ The most successful hospitals all used rigorous data-driven quality-improvement methodologies, set shared goals with key stakeholders, integrated the pathway into their electronic medical record, allowed nurses and respiratory therapists to titrate albuterol frequency, and engaged hospital leadership to secure needed resources.

Although in each of these studies, pathway implementation led to improvements in the acute management of patients, there was no reduction in pediatric asthma readmissions at 30 days.^12,13 A meta-analysis of asthma-related quality improvement interventions also did not find an association between pathway implementation alone and decreased readmissions or ED revisits.¹⁵ The lack of improvement in these metrics may have been caused by the tendency for pathways to focus on the acute asthma management and lack of focus on chronic asthma severity. Asthma admissions are an opportunity for full evaluation of disease severity, allergen exposures, and education on medication and spacer technique. Refinement of pathways with a focus on chronic control and on transition from hospital to home may move the needle on decreasing the long-term morbidity of pediatric asthma.

Current evidence suggests pediatric hospitalists should consider transitioning from prednisolone/prednisone to dexamethasone and from nebulized albuterol delivery to MDI albuterol delivery for children admitted for acute asthma exacerbation who do not require ICU-level care. Implementing asthma clinical pathways that use rigorous quality improvement methods is an effective approach to adopt these and other evidence-based practice changes.

Disclosures

The authors have nothing to disclose.

Readmissions following hospitalization for exacerbations of chronic obstructive pulmonary disease (COPD) are common and economically burdensome.¹ The Affordable Care Act² outlined the Hospital Readmissions Reduction Program (HRRP),³ which aims to improve the quality of care and reduce the costs for patients with pneumonia, myocardial infarction, congestive heart failure, and COPD.³ With the implementation of the HRRP, readmission reduction has become a key priority of health systems.

Multiple approaches to reduce readmissions are published, with variable degrees of success across respiratory and all-cause rehospitalizations.⁴ Patient self-management programs are heterogenous with inconsistent utilization reductions.^5-7 While some transitional care programs demonstrate benefits,^8-10 one notable study of an intensive transitional care and self-management program showed increaseNod acute care utilization without improving health-related quality of life.^11-13 Another study of COPD comprehensive care management was stopped prematurely for increased mortality in the intervention group.¹⁴ Telehealth monitoring may predict exacerbations,^15,16 but inconsistent effects on quality of life and utilization are observed.^17,18 Pulmonary rehabilitation improves quality of life but not healthcare utilization.¹⁹ Dispensing respiratory medications at hospital discharge shows improved prescription fills and fewer readmissions,²⁰ further reinforced by inhaler training prior to discharge.²¹ Postdischarge oxygen therapy does not improve health-related quality of life or acute care utilization.²² The fact that these approaches have not reliably succeeded raises the need for further study on the drivers of readmissions in COPD. Previous studies found differences in factors associated with the timing of COPD readmissions and return diagnoses.^23,24 While HRRP is Medicare-specific, health systems likely use programs targeting their entire population when planning readmission reduction strategies. Previous analyses were primarily single-center studies²⁵ and Medicare²⁴ or private insurance claims.²⁶

In this analysis, we explore how comorbidity burden^27-29 may differentially influence readmissions for recurrent COPD exacerbations versus other diagnoses. Our approach uses a national all-payer sample that covers a diverse geographic area across the United States, providing robust estimates of factors influencing readmission and valuable insights for planning and implementing effective readmission reduction programs. By including data from a period that encompasses the implementation of HRRP, we also provide new information on the factors in the HRRP postimplementation that are not yet available in published literature.

Data Source

The Nationwide Readmissions Database (NRD) is a nationally representative, all-payer, 100% sample of community acute care hospital discharges from multiple states.³⁰ We pooled COPD discharge records spanning 2010-2016, excluding those where the patients were not residents of the state in which they were hospitalized to minimize loss to follow-up.

Inclusion/Exclusion Criteria

Selection criteria mirrored the methodology used by the HRRP,^31,32 defining an index discharge as a patient ≥40 years of age with a qualifying COPD diagnosis (Appendix Tables 1-2), discharged alive, with at least 30 days elapsed since previous hospitalization. We excluded discharges against medical advice or those from a hospital with fewer than 25 COPD discharges in that calendar year as per HRRP,^31,32 as well as those involving lung transplants. In this pooled cross-sectional analysis, record identifiers were not reliably unique across years. We restricted to observations originating February-November because January stays may not have had the requisite HRRP 30-day washout period from last admission and December stays could not be tracked into the subsequent January.

Outcomes

We defined a readmission as subsequent hospitalization for any cause within 30 days of the index discharge, with exemptions defined by the HRRP (Appendix Figure 1).^31,32 We segmented the readmission outcome into two parts: those readmitted with diagnoses that met the COPD HRRP criteria versus for any other diagnoses. We also tabulated diagnosis-related groups (DRGs) coded for the readmission observation to capture attributable cause for rehospitalization.

Our main independent variable was the Elixhauser Comorbidity Index score,³³ constructed using adaptations of published software,^34,35 having previously validated its use for modeling COPD readmissions.³⁶ We involved covariates provided with the database, including sociodemographic variables (eg, age, sex, community characteristics, payer, and median income at patient’s ZIP code) and hospital characteristics (eg, size, ownership, teaching status). We constructed additional covariates to account for in-hospital events by aggregating ICD diagnosis and procedure codes (eg, mechanical ventilation), hospital discharge volume, and proportion of annual within-hospital Medicaid patient days as a surrogate marker for safety-net hospitals. A detailed explanation of database construction and selection criteria is found in the Supplemental Methods Appendix.

Statistical Analysis

We tabulated patient-level descriptive statistics across the three outcomes of interest (ie, not readmitted, readmitted for a stay that would have qualified as COPD-related by HRRP criteria and readmitted for any other diagnosis). Continuous variables were compared using Welch’s t-tests (ie, unequal variance) and categorical variables using Chi-squared tests. At the hospital level, we tabulated the proportions of hospitals within categories in key variables of interest and a sub-population readmission rate for that particular characteristic, compared using Chi-squared tests.

We fit a multilevel multinomial logistic regression with random intercepts at the hospital cluster level, with the tripartite readmission outcome described above with “not readmitted” as the reference group. We included fixed effects for year, Elixhauser score, and patient- and hospital-level covariates as described above. Time to readmission for each group was plotted to assess the time distribution for each outcome. In-hospital mortality during each readmission event was tabulated.

Sensitivity Analyses and Missing Data

We conducted sensitivity analyses to determine whether a lower age cutoff (≥18 years) affects modeling. We also tested the stability of our estimates across each individual year of the pooled analysis. To test the effect of time to differential readmission, we fit a Cox proportional hazards model within the readmitted patient subgroup with Huber-White standard errors clustered at the hospital level to estimate the differential hazard of readmission for COPD versus non-COPD diagnoses across the same variables of interest as a sensitivity analysis. We also tested using a liberal classification of readmission diagnoses by sorting into “respiratory” versus “nonrespiratory” returns, with DRGs 163 through 208 for “respiratory” versus all others, respectively. We tested the agreement between the HRRP ICD-based classification and DRG classification using Cohen’s kappa.

We designated a threshold of 10% missing data to necessitate imputation techniques, determined a priori for our main variables, none of which met this level. Complete case analyses were used for all models. Analyses were performed in Stata version 15.1 (StataCorp, College Station, Texas) with weighted estimates reported using patient-level survey weights for national representativeness.³⁷ The study protocol was reviewed by the institutional review board at the University of California, Los Angeles, and deemed exempt from oversight due to the publicly available, deidentified nature of the data (IRB# 18-001208).

Out of 104,897,595 hospitalizations in the NRD, a final sample of 1,622,983 COPD discharges was identified for our analysis (sample weighted effective population 3,743,164). The overall readmission rate was 17.25%, with 7.69% of patients readmitted for COPD and 9.56% readmitted for other diagnoses. Those with COPD readmissions were significantly younger with a lower proportion of Medicare and a higher proportion of Medicaid as the primary payer compared with those readmitted for all other causes (Table 1). Compared with non-COPD-readmitted patients, COPD-readmitted patients were more frequently discharged home without services and had shorter lengths of stay. Noninvasive ventilation was more common among COPD readmissions while mechanical ventilation and tracheostomy placement were less frequent compared with non-COPD readmissions. Compared with non-COPD-readmitted patients, COPD-readmitted patients had significantly lower mean Elixhauser Comorbidity Index scores (17.8 vs 22.8), rates of congestive heart failure (28.3% vs 38.6%), and renal failure (11.8% vs 21.5%; Appendix Table 3).

Readmission rates were significantly higher for non-COPD causes than for COPD causes across all hospital types by ownership, teaching status, or size (Table 2). Parallel patterns were observed for non-COPD and COPD readmissions across hospital types, with two key exceptions. Across categories of hospital ownership, for-profit hospitals had the highest rates for non-COPD readmissions, with no differences in hospital control for COPD rehospitalizations. While rates did not vary for non-COPD readmissions by within-hospital Medicaid prevalence, COPD readmission rates significantly increased as Medicaid-paid patient-days increased within hospitals.

In this assessment of readmission odds following hospitalizations for COPD in a nationally representative all-payer sample, we demonstrate that 55% of rehospitalizations following COPD exacerbations are attributable to non-COPD diagnoses and describe the important role of comorbidity on influencing diagnoses at rehospitalization. These findings are consistent with a prior study of Medicare patients by Shah et al.²⁴ and expand upon the results of Jacobs et al. using a pre-HRRP sample of the NRD.²³ Our study offers an expanded analysis by including data spanning HRRP implementation, which went into effect for COPD in October 2014.³ Effect estimates were stable across all seven years of our study in sensitivity analyses, demonstrating the robustness of our findings. Our analysis also adds to the existing body of literature by assessing which factors are associated with readmissions related to ongoing COPD versus other diagnoses.

In our study, an increase in aggregated comorbidity by the Elixhauser Index was associated with a significantly higher readmission odds, with over four times the effect size for non-COPD than COPD returns. Comorbidity also moderated the effect of other factors, such as income and discharge disposition. While overall readmission rates declined across the course of the study period, the effect of comorbidity on readmission odds for both groups remained significant in annualized models. We also observed higher rates of nearly every individual Elixhauser component comorbidity in those readmitted for non-COPD causes compared with those readmitted for COPD causes. Taken together, these results underscore the need to account for comorbidities at the individual and composite levels when identifying those at highest risk for readmissions and necessitate a multidisciplinary approach to reduce risk for the multimorbid patient.

In a 2018 report, the American Thoracic Society highlighted the focus of programs on adherence to guidelines and reducing variability in COPD care as a potential pitfall in efforts to reduce COPD readmissions.³⁹ We demonstrate that a majority of patients who are readmitted return for diagnoses other than COPD. This finding further highlights that readmission reduction programs need not only focus on COPD control but on the overall management of the patient’s complex medical comorbidities. HRRP penalties are assessed for all-cause readmissions,^31,32 and attention to the entire range of diagnoses leading to return to hospital is important to reduce readmission rates and expenditures. Use of strategies such as multispecialty clinics or integrated practice units may be useful in mitigating risk in multimorbid COPD patients.

Other significant factors that deserve further investigation include the use of postacute care services, including home health and skilled nursing facilities. Both factors were associated with higher likelihood of returning for non-COPD than for COPD-related diagnoses. This finding may be collinear to some degree with comorbidity because complex patients are probably less likely to be discharged home directly. Interestingly, those discharged to a postacute care facility had substantially high odds of readmission for a non-COPD cause. Transitional care programs, including short stays in a nursing home, are often employed to mitigate the risk of adverse outcomes after discharge in sicker patients,⁴⁰ which may be insufficient based on these data.

We applied the HRRP criteria for coding a COPD-related admission to the readmission diagnoses, which is more stringent than using only a principal diagnosis or DRGs, to maintain the same standard for defining the index and readmission event. In the sensitivity analyses, we did not find significant differences in our estimates of comorbidity’s effect on outcomes using a more liberal DRG classification system.

We also used DRGs to classify the readmission causes in order to use the same grouping logic that a payer would use when determining the cause. When evaluating which DRG patients returned for following a COPD exacerbation, pneumonia or other respiratory infections make up 13.8%, which may represent the evolution of respiratory infections that provoked the original exacerbation. Heart failure comprised 9.1% of the non-COPD causes, with about one-third of our COPD cohort having known comorbid heart failure at the time of index admission, illustrating significant overlap between these two conditions. Heart failure and pneumonia are conditions of interest in the HRRP and would potentially garner their own penalties had sufficient time elapsed since a prior hospitalization. Among other causes in the top 20 return DRGs were esophagitis, gastritis, gastrointestinal bleeding, and psychoses, which may be potentially associated with the use of corticosteroids to treat a COPD exacerbation, as described in other population studies.^41,42 Lack of medication regimen data in our analysis precludes further attribution of these causes, but the potential associations are interesting and warrant additional study.

The structure of our data as pooled annual cross sections rather than a true longitudinal cohort limited us to use only 10 months (February to November) of index hospitalizations in order to stay aligned with HRRP policy inclusion criteria. As such, we may have missed some important observations during peak respiratory virus season. As in any administrative data analysis, we are limited to codes in the discharge records, which may not reflect the entire nature of a hospitalization. Administrative data are particularly problematic in identifying true COPD exacerbations, particularly with multiple comorbid cardiopulmonary conditions.^43,44 Validating coding algorithms for identifying COPD was beyond the scope of our evaluation, which purposefully used HRRP methodology. Further study thereof would be a useful endeavor, especially with transition to ICD-10, considering that previously published evaluation was limited to ICD-9.⁴⁴ Despite these limitations, we were left with a robust and representative national cohort, which is an acceptable tradeoff.

Our study highlights the importance of understanding comorbidity as a major determinant of readmissions following COPD exacerbations, particularly in distinguishing which patients will return for COPD versus non-COPD-related diagnoses. At the health system level, readmission programs should be designed with the multimorbid patient in mind. Engagement of care teams, facilitating communication, and shared decision making are strategies to mitigate readmission risk in addition to COPD-focused disease management.³⁹ These data highlight the need to use risk prediction tools in assigning resources to reduce readmissions,⁴⁵ as well as the need to move readmission reduction programs beyond COPD management alone. Developing such systems to prospectively identify which patients are at risk of returning for both COPD and non-COPD reasons may further elucidate readmission mitigation strategies and should be a subject of future prospective study.

Acknowledgments

Data were made available through the Agency for Healthcare Research and Quality’s Healthcare Utilization Project. A full list of partner organizations providing data for the Nationwide Readmission Database can be found at https://www.hcup-us.ahrq.gov/db/hcupdatapartners.jsp.

Prior Presentation

Portions of this work were presented in abstract form at the 2018 American Thoracic Society International Conference (May 2018, San Diego, CA). This manuscript is derived from the doctoral dissertation for the degree of PhD in Health Policy and Management of the corresponding author, conferred in June 2019.

Disclaimer

This article does not necessarily represent the views and policies of the Department of Veterans Affairs or the USPSTF.

Readmissions following hospitalization for exacerbations of chronic obstructive pulmonary disease (COPD) are common and economically burdensome.¹ The Affordable Care Act² outlined the Hospital Readmissions Reduction Program (HRRP),³ which aims to improve the quality of care and reduce the costs for patients with pneumonia, myocardial infarction, congestive heart failure, and COPD.³ With the implementation of the HRRP, readmission reduction has become a key priority of health systems.

Multiple approaches to reduce readmissions are published, with variable degrees of success across respiratory and all-cause rehospitalizations.⁴ Patient self-management programs are heterogenous with inconsistent utilization reductions.^5-7 While some transitional care programs demonstrate benefits,^8-10 one notable study of an intensive transitional care and self-management program showed increaseNod acute care utilization without improving health-related quality of life.^11-13 Another study of COPD comprehensive care management was stopped prematurely for increased mortality in the intervention group.¹⁴ Telehealth monitoring may predict exacerbations,^15,16 but inconsistent effects on quality of life and utilization are observed.^17,18 Pulmonary rehabilitation improves quality of life but not healthcare utilization.¹⁹ Dispensing respiratory medications at hospital discharge shows improved prescription fills and fewer readmissions,²⁰ further reinforced by inhaler training prior to discharge.²¹ Postdischarge oxygen therapy does not improve health-related quality of life or acute care utilization.²² The fact that these approaches have not reliably succeeded raises the need for further study on the drivers of readmissions in COPD. Previous studies found differences in factors associated with the timing of COPD readmissions and return diagnoses.^23,24 While HRRP is Medicare-specific, health systems likely use programs targeting their entire population when planning readmission reduction strategies. Previous analyses were primarily single-center studies²⁵ and Medicare²⁴ or private insurance claims.²⁶

In this analysis, we explore how comorbidity burden^27-29 may differentially influence readmissions for recurrent COPD exacerbations versus other diagnoses. Our approach uses a national all-payer sample that covers a diverse geographic area across the United States, providing robust estimates of factors influencing readmission and valuable insights for planning and implementing effective readmission reduction programs. By including data from a period that encompasses the implementation of HRRP, we also provide new information on the factors in the HRRP postimplementation that are not yet available in published literature.

Data Source

The Nationwide Readmissions Database (NRD) is a nationally representative, all-payer, 100% sample of community acute care hospital discharges from multiple states.³⁰ We pooled COPD discharge records spanning 2010-2016, excluding those where the patients were not residents of the state in which they were hospitalized to minimize loss to follow-up.

Inclusion/Exclusion Criteria

Selection criteria mirrored the methodology used by the HRRP,^31,32 defining an index discharge as a patient ≥40 years of age with a qualifying COPD diagnosis (Appendix Tables 1-2), discharged alive, with at least 30 days elapsed since previous hospitalization. We excluded discharges against medical advice or those from a hospital with fewer than 25 COPD discharges in that calendar year as per HRRP,^31,32 as well as those involving lung transplants. In this pooled cross-sectional analysis, record identifiers were not reliably unique across years. We restricted to observations originating February-November because January stays may not have had the requisite HRRP 30-day washout period from last admission and December stays could not be tracked into the subsequent January.

Outcomes

We defined a readmission as subsequent hospitalization for any cause within 30 days of the index discharge, with exemptions defined by the HRRP (Appendix Figure 1).^31,32 We segmented the readmission outcome into two parts: those readmitted with diagnoses that met the COPD HRRP criteria versus for any other diagnoses. We also tabulated diagnosis-related groups (DRGs) coded for the readmission observation to capture attributable cause for rehospitalization.

Our main independent variable was the Elixhauser Comorbidity Index score,³³ constructed using adaptations of published software,^34,35 having previously validated its use for modeling COPD readmissions.³⁶ We involved covariates provided with the database, including sociodemographic variables (eg, age, sex, community characteristics, payer, and median income at patient’s ZIP code) and hospital characteristics (eg, size, ownership, teaching status). We constructed additional covariates to account for in-hospital events by aggregating ICD diagnosis and procedure codes (eg, mechanical ventilation), hospital discharge volume, and proportion of annual within-hospital Medicaid patient days as a surrogate marker for safety-net hospitals. A detailed explanation of database construction and selection criteria is found in the Supplemental Methods Appendix.

Statistical Analysis

We tabulated patient-level descriptive statistics across the three outcomes of interest (ie, not readmitted, readmitted for a stay that would have qualified as COPD-related by HRRP criteria and readmitted for any other diagnosis). Continuous variables were compared using Welch’s t-tests (ie, unequal variance) and categorical variables using Chi-squared tests. At the hospital level, we tabulated the proportions of hospitals within categories in key variables of interest and a sub-population readmission rate for that particular characteristic, compared using Chi-squared tests.

We fit a multilevel multinomial logistic regression with random intercepts at the hospital cluster level, with the tripartite readmission outcome described above with “not readmitted” as the reference group. We included fixed effects for year, Elixhauser score, and patient- and hospital-level covariates as described above. Time to readmission for each group was plotted to assess the time distribution for each outcome. In-hospital mortality during each readmission event was tabulated.

Sensitivity Analyses and Missing Data

We conducted sensitivity analyses to determine whether a lower age cutoff (≥18 years) affects modeling. We also tested the stability of our estimates across each individual year of the pooled analysis. To test the effect of time to differential readmission, we fit a Cox proportional hazards model within the readmitted patient subgroup with Huber-White standard errors clustered at the hospital level to estimate the differential hazard of readmission for COPD versus non-COPD diagnoses across the same variables of interest as a sensitivity analysis. We also tested using a liberal classification of readmission diagnoses by sorting into “respiratory” versus “nonrespiratory” returns, with DRGs 163 through 208 for “respiratory” versus all others, respectively. We tested the agreement between the HRRP ICD-based classification and DRG classification using Cohen’s kappa.

We designated a threshold of 10% missing data to necessitate imputation techniques, determined a priori for our main variables, none of which met this level. Complete case analyses were used for all models. Analyses were performed in Stata version 15.1 (StataCorp, College Station, Texas) with weighted estimates reported using patient-level survey weights for national representativeness.³⁷ The study protocol was reviewed by the institutional review board at the University of California, Los Angeles, and deemed exempt from oversight due to the publicly available, deidentified nature of the data (IRB# 18-001208).

Out of 104,897,595 hospitalizations in the NRD, a final sample of 1,622,983 COPD discharges was identified for our analysis (sample weighted effective population 3,743,164). The overall readmission rate was 17.25%, with 7.69% of patients readmitted for COPD and 9.56% readmitted for other diagnoses. Those with COPD readmissions were significantly younger with a lower proportion of Medicare and a higher proportion of Medicaid as the primary payer compared with those readmitted for all other causes (Table 1). Compared with non-COPD-readmitted patients, COPD-readmitted patients were more frequently discharged home without services and had shorter lengths of stay. Noninvasive ventilation was more common among COPD readmissions while mechanical ventilation and tracheostomy placement were less frequent compared with non-COPD readmissions. Compared with non-COPD-readmitted patients, COPD-readmitted patients had significantly lower mean Elixhauser Comorbidity Index scores (17.8 vs 22.8), rates of congestive heart failure (28.3% vs 38.6%), and renal failure (11.8% vs 21.5%; Appendix Table 3).

Readmission rates were significantly higher for non-COPD causes than for COPD causes across all hospital types by ownership, teaching status, or size (Table 2). Parallel patterns were observed for non-COPD and COPD readmissions across hospital types, with two key exceptions. Across categories of hospital ownership, for-profit hospitals had the highest rates for non-COPD readmissions, with no differences in hospital control for COPD rehospitalizations. While rates did not vary for non-COPD readmissions by within-hospital Medicaid prevalence, COPD readmission rates significantly increased as Medicaid-paid patient-days increased within hospitals.

In this assessment of readmission odds following hospitalizations for COPD in a nationally representative all-payer sample, we demonstrate that 55% of rehospitalizations following COPD exacerbations are attributable to non-COPD diagnoses and describe the important role of comorbidity on influencing diagnoses at rehospitalization. These findings are consistent with a prior study of Medicare patients by Shah et al.²⁴ and expand upon the results of Jacobs et al. using a pre-HRRP sample of the NRD.²³ Our study offers an expanded analysis by including data spanning HRRP implementation, which went into effect for COPD in October 2014.³ Effect estimates were stable across all seven years of our study in sensitivity analyses, demonstrating the robustness of our findings. Our analysis also adds to the existing body of literature by assessing which factors are associated with readmissions related to ongoing COPD versus other diagnoses.

In our study, an increase in aggregated comorbidity by the Elixhauser Index was associated with a significantly higher readmission odds, with over four times the effect size for non-COPD than COPD returns. Comorbidity also moderated the effect of other factors, such as income and discharge disposition. While overall readmission rates declined across the course of the study period, the effect of comorbidity on readmission odds for both groups remained significant in annualized models. We also observed higher rates of nearly every individual Elixhauser component comorbidity in those readmitted for non-COPD causes compared with those readmitted for COPD causes. Taken together, these results underscore the need to account for comorbidities at the individual and composite levels when identifying those at highest risk for readmissions and necessitate a multidisciplinary approach to reduce risk for the multimorbid patient.

In a 2018 report, the American Thoracic Society highlighted the focus of programs on adherence to guidelines and reducing variability in COPD care as a potential pitfall in efforts to reduce COPD readmissions.³⁹ We demonstrate that a majority of patients who are readmitted return for diagnoses other than COPD. This finding further highlights that readmission reduction programs need not only focus on COPD control but on the overall management of the patient’s complex medical comorbidities. HRRP penalties are assessed for all-cause readmissions,^31,32 and attention to the entire range of diagnoses leading to return to hospital is important to reduce readmission rates and expenditures. Use of strategies such as multispecialty clinics or integrated practice units may be useful in mitigating risk in multimorbid COPD patients.

Other significant factors that deserve further investigation include the use of postacute care services, including home health and skilled nursing facilities. Both factors were associated with higher likelihood of returning for non-COPD than for COPD-related diagnoses. This finding may be collinear to some degree with comorbidity because complex patients are probably less likely to be discharged home directly. Interestingly, those discharged to a postacute care facility had substantially high odds of readmission for a non-COPD cause. Transitional care programs, including short stays in a nursing home, are often employed to mitigate the risk of adverse outcomes after discharge in sicker patients,⁴⁰ which may be insufficient based on these data.

We applied the HRRP criteria for coding a COPD-related admission to the readmission diagnoses, which is more stringent than using only a principal diagnosis or DRGs, to maintain the same standard for defining the index and readmission event. In the sensitivity analyses, we did not find significant differences in our estimates of comorbidity’s effect on outcomes using a more liberal DRG classification system.

We also used DRGs to classify the readmission causes in order to use the same grouping logic that a payer would use when determining the cause. When evaluating which DRG patients returned for following a COPD exacerbation, pneumonia or other respiratory infections make up 13.8%, which may represent the evolution of respiratory infections that provoked the original exacerbation. Heart failure comprised 9.1% of the non-COPD causes, with about one-third of our COPD cohort having known comorbid heart failure at the time of index admission, illustrating significant overlap between these two conditions. Heart failure and pneumonia are conditions of interest in the HRRP and would potentially garner their own penalties had sufficient time elapsed since a prior hospitalization. Among other causes in the top 20 return DRGs were esophagitis, gastritis, gastrointestinal bleeding, and psychoses, which may be potentially associated with the use of corticosteroids to treat a COPD exacerbation, as described in other population studies.^41,42 Lack of medication regimen data in our analysis precludes further attribution of these causes, but the potential associations are interesting and warrant additional study.

The structure of our data as pooled annual cross sections rather than a true longitudinal cohort limited us to use only 10 months (February to November) of index hospitalizations in order to stay aligned with HRRP policy inclusion criteria. As such, we may have missed some important observations during peak respiratory virus season. As in any administrative data analysis, we are limited to codes in the discharge records, which may not reflect the entire nature of a hospitalization. Administrative data are particularly problematic in identifying true COPD exacerbations, particularly with multiple comorbid cardiopulmonary conditions.^43,44 Validating coding algorithms for identifying COPD was beyond the scope of our evaluation, which purposefully used HRRP methodology. Further study thereof would be a useful endeavor, especially with transition to ICD-10, considering that previously published evaluation was limited to ICD-9.⁴⁴ Despite these limitations, we were left with a robust and representative national cohort, which is an acceptable tradeoff.

Our study highlights the importance of understanding comorbidity as a major determinant of readmissions following COPD exacerbations, particularly in distinguishing which patients will return for COPD versus non-COPD-related diagnoses. At the health system level, readmission programs should be designed with the multimorbid patient in mind. Engagement of care teams, facilitating communication, and shared decision making are strategies to mitigate readmission risk in addition to COPD-focused disease management.³⁹ These data highlight the need to use risk prediction tools in assigning resources to reduce readmissions,⁴⁵ as well as the need to move readmission reduction programs beyond COPD management alone. Developing such systems to prospectively identify which patients are at risk of returning for both COPD and non-COPD reasons may further elucidate readmission mitigation strategies and should be a subject of future prospective study.

Acknowledgments

Data were made available through the Agency for Healthcare Research and Quality’s Healthcare Utilization Project. A full list of partner organizations providing data for the Nationwide Readmission Database can be found at https://www.hcup-us.ahrq.gov/db/hcupdatapartners.jsp.

Prior Presentation

Portions of this work were presented in abstract form at the 2018 American Thoracic Society International Conference (May 2018, San Diego, CA). This manuscript is derived from the doctoral dissertation for the degree of PhD in Health Policy and Management of the corresponding author, conferred in June 2019.

Disclaimer

This article does not necessarily represent the views and policies of the Department of Veterans Affairs or the USPSTF.

Readmissions following hospitalization for exacerbations of chronic obstructive pulmonary disease (COPD) are common and economically burdensome.¹ The Affordable Care Act² outlined the Hospital Readmissions Reduction Program (HRRP),³ which aims to improve the quality of care and reduce the costs for patients with pneumonia, myocardial infarction, congestive heart failure, and COPD.³ With the implementation of the HRRP, readmission reduction has become a key priority of health systems.

Multiple approaches to reduce readmissions are published, with variable degrees of success across respiratory and all-cause rehospitalizations.⁴ Patient self-management programs are heterogenous with inconsistent utilization reductions.^5-7 While some transitional care programs demonstrate benefits,^8-10 one notable study of an intensive transitional care and self-management program showed increaseNod acute care utilization without improving health-related quality of life.^11-13 Another study of COPD comprehensive care management was stopped prematurely for increased mortality in the intervention group.¹⁴ Telehealth monitoring may predict exacerbations,^15,16 but inconsistent effects on quality of life and utilization are observed.^17,18 Pulmonary rehabilitation improves quality of life but not healthcare utilization.¹⁹ Dispensing respiratory medications at hospital discharge shows improved prescription fills and fewer readmissions,²⁰ further reinforced by inhaler training prior to discharge.²¹ Postdischarge oxygen therapy does not improve health-related quality of life or acute care utilization.²² The fact that these approaches have not reliably succeeded raises the need for further study on the drivers of readmissions in COPD. Previous studies found differences in factors associated with the timing of COPD readmissions and return diagnoses.^23,24 While HRRP is Medicare-specific, health systems likely use programs targeting their entire population when planning readmission reduction strategies. Previous analyses were primarily single-center studies²⁵ and Medicare²⁴ or private insurance claims.²⁶

In this analysis, we explore how comorbidity burden^27-29 may differentially influence readmissions for recurrent COPD exacerbations versus other diagnoses. Our approach uses a national all-payer sample that covers a diverse geographic area across the United States, providing robust estimates of factors influencing readmission and valuable insights for planning and implementing effective readmission reduction programs. By including data from a period that encompasses the implementation of HRRP, we also provide new information on the factors in the HRRP postimplementation that are not yet available in published literature.

Data Source

The Nationwide Readmissions Database (NRD) is a nationally representative, all-payer, 100% sample of community acute care hospital discharges from multiple states.³⁰ We pooled COPD discharge records spanning 2010-2016, excluding those where the patients were not residents of the state in which they were hospitalized to minimize loss to follow-up.

Inclusion/Exclusion Criteria

Selection criteria mirrored the methodology used by the HRRP,^31,32 defining an index discharge as a patient ≥40 years of age with a qualifying COPD diagnosis (Appendix Tables 1-2), discharged alive, with at least 30 days elapsed since previous hospitalization. We excluded discharges against medical advice or those from a hospital with fewer than 25 COPD discharges in that calendar year as per HRRP,^31,32 as well as those involving lung transplants. In this pooled cross-sectional analysis, record identifiers were not reliably unique across years. We restricted to observations originating February-November because January stays may not have had the requisite HRRP 30-day washout period from last admission and December stays could not be tracked into the subsequent January.

Outcomes

We defined a readmission as subsequent hospitalization for any cause within 30 days of the index discharge, with exemptions defined by the HRRP (Appendix Figure 1).^31,32 We segmented the readmission outcome into two parts: those readmitted with diagnoses that met the COPD HRRP criteria versus for any other diagnoses. We also tabulated diagnosis-related groups (DRGs) coded for the readmission observation to capture attributable cause for rehospitalization.

Our main independent variable was the Elixhauser Comorbidity Index score,³³ constructed using adaptations of published software,^34,35 having previously validated its use for modeling COPD readmissions.³⁶ We involved covariates provided with the database, including sociodemographic variables (eg, age, sex, community characteristics, payer, and median income at patient’s ZIP code) and hospital characteristics (eg, size, ownership, teaching status). We constructed additional covariates to account for in-hospital events by aggregating ICD diagnosis and procedure codes (eg, mechanical ventilation), hospital discharge volume, and proportion of annual within-hospital Medicaid patient days as a surrogate marker for safety-net hospitals. A detailed explanation of database construction and selection criteria is found in the Supplemental Methods Appendix.

Statistical Analysis

We tabulated patient-level descriptive statistics across the three outcomes of interest (ie, not readmitted, readmitted for a stay that would have qualified as COPD-related by HRRP criteria and readmitted for any other diagnosis). Continuous variables were compared using Welch’s t-tests (ie, unequal variance) and categorical variables using Chi-squared tests. At the hospital level, we tabulated the proportions of hospitals within categories in key variables of interest and a sub-population readmission rate for that particular characteristic, compared using Chi-squared tests.

We fit a multilevel multinomial logistic regression with random intercepts at the hospital cluster level, with the tripartite readmission outcome described above with “not readmitted” as the reference group. We included fixed effects for year, Elixhauser score, and patient- and hospital-level covariates as described above. Time to readmission for each group was plotted to assess the time distribution for each outcome. In-hospital mortality during each readmission event was tabulated.

Sensitivity Analyses and Missing Data

We conducted sensitivity analyses to determine whether a lower age cutoff (≥18 years) affects modeling. We also tested the stability of our estimates across each individual year of the pooled analysis. To test the effect of time to differential readmission, we fit a Cox proportional hazards model within the readmitted patient subgroup with Huber-White standard errors clustered at the hospital level to estimate the differential hazard of readmission for COPD versus non-COPD diagnoses across the same variables of interest as a sensitivity analysis. We also tested using a liberal classification of readmission diagnoses by sorting into “respiratory” versus “nonrespiratory” returns, with DRGs 163 through 208 for “respiratory” versus all others, respectively. We tested the agreement between the HRRP ICD-based classification and DRG classification using Cohen’s kappa.

We designated a threshold of 10% missing data to necessitate imputation techniques, determined a priori for our main variables, none of which met this level. Complete case analyses were used for all models. Analyses were performed in Stata version 15.1 (StataCorp, College Station, Texas) with weighted estimates reported using patient-level survey weights for national representativeness.³⁷ The study protocol was reviewed by the institutional review board at the University of California, Los Angeles, and deemed exempt from oversight due to the publicly available, deidentified nature of the data (IRB# 18-001208).

Out of 104,897,595 hospitalizations in the NRD, a final sample of 1,622,983 COPD discharges was identified for our analysis (sample weighted effective population 3,743,164). The overall readmission rate was 17.25%, with 7.69% of patients readmitted for COPD and 9.56% readmitted for other diagnoses. Those with COPD readmissions were significantly younger with a lower proportion of Medicare and a higher proportion of Medicaid as the primary payer compared with those readmitted for all other causes (Table 1). Compared with non-COPD-readmitted patients, COPD-readmitted patients were more frequently discharged home without services and had shorter lengths of stay. Noninvasive ventilation was more common among COPD readmissions while mechanical ventilation and tracheostomy placement were less frequent compared with non-COPD readmissions. Compared with non-COPD-readmitted patients, COPD-readmitted patients had significantly lower mean Elixhauser Comorbidity Index scores (17.8 vs 22.8), rates of congestive heart failure (28.3% vs 38.6%), and renal failure (11.8% vs 21.5%; Appendix Table 3).

Readmission rates were significantly higher for non-COPD causes than for COPD causes across all hospital types by ownership, teaching status, or size (Table 2). Parallel patterns were observed for non-COPD and COPD readmissions across hospital types, with two key exceptions. Across categories of hospital ownership, for-profit hospitals had the highest rates for non-COPD readmissions, with no differences in hospital control for COPD rehospitalizations. While rates did not vary for non-COPD readmissions by within-hospital Medicaid prevalence, COPD readmission rates significantly increased as Medicaid-paid patient-days increased within hospitals.

In this assessment of readmission odds following hospitalizations for COPD in a nationally representative all-payer sample, we demonstrate that 55% of rehospitalizations following COPD exacerbations are attributable to non-COPD diagnoses and describe the important role of comorbidity on influencing diagnoses at rehospitalization. These findings are consistent with a prior study of Medicare patients by Shah et al.²⁴ and expand upon the results of Jacobs et al. using a pre-HRRP sample of the NRD.²³ Our study offers an expanded analysis by including data spanning HRRP implementation, which went into effect for COPD in October 2014.³ Effect estimates were stable across all seven years of our study in sensitivity analyses, demonstrating the robustness of our findings. Our analysis also adds to the existing body of literature by assessing which factors are associated with readmissions related to ongoing COPD versus other diagnoses.

In our study, an increase in aggregated comorbidity by the Elixhauser Index was associated with a significantly higher readmission odds, with over four times the effect size for non-COPD than COPD returns. Comorbidity also moderated the effect of other factors, such as income and discharge disposition. While overall readmission rates declined across the course of the study period, the effect of comorbidity on readmission odds for both groups remained significant in annualized models. We also observed higher rates of nearly every individual Elixhauser component comorbidity in those readmitted for non-COPD causes compared with those readmitted for COPD causes. Taken together, these results underscore the need to account for comorbidities at the individual and composite levels when identifying those at highest risk for readmissions and necessitate a multidisciplinary approach to reduce risk for the multimorbid patient.

In a 2018 report, the American Thoracic Society highlighted the focus of programs on adherence to guidelines and reducing variability in COPD care as a potential pitfall in efforts to reduce COPD readmissions.³⁹ We demonstrate that a majority of patients who are readmitted return for diagnoses other than COPD. This finding further highlights that readmission reduction programs need not only focus on COPD control but on the overall management of the patient’s complex medical comorbidities. HRRP penalties are assessed for all-cause readmissions,^31,32 and attention to the entire range of diagnoses leading to return to hospital is important to reduce readmission rates and expenditures. Use of strategies such as multispecialty clinics or integrated practice units may be useful in mitigating risk in multimorbid COPD patients.

Other significant factors that deserve further investigation include the use of postacute care services, including home health and skilled nursing facilities. Both factors were associated with higher likelihood of returning for non-COPD than for COPD-related diagnoses. This finding may be collinear to some degree with comorbidity because complex patients are probably less likely to be discharged home directly. Interestingly, those discharged to a postacute care facility had substantially high odds of readmission for a non-COPD cause. Transitional care programs, including short stays in a nursing home, are often employed to mitigate the risk of adverse outcomes after discharge in sicker patients,⁴⁰ which may be insufficient based on these data.

We applied the HRRP criteria for coding a COPD-related admission to the readmission diagnoses, which is more stringent than using only a principal diagnosis or DRGs, to maintain the same standard for defining the index and readmission event. In the sensitivity analyses, we did not find significant differences in our estimates of comorbidity’s effect on outcomes using a more liberal DRG classification system.

We also used DRGs to classify the readmission causes in order to use the same grouping logic that a payer would use when determining the cause. When evaluating which DRG patients returned for following a COPD exacerbation, pneumonia or other respiratory infections make up 13.8%, which may represent the evolution of respiratory infections that provoked the original exacerbation. Heart failure comprised 9.1% of the non-COPD causes, with about one-third of our COPD cohort having known comorbid heart failure at the time of index admission, illustrating significant overlap between these two conditions. Heart failure and pneumonia are conditions of interest in the HRRP and would potentially garner their own penalties had sufficient time elapsed since a prior hospitalization. Among other causes in the top 20 return DRGs were esophagitis, gastritis, gastrointestinal bleeding, and psychoses, which may be potentially associated with the use of corticosteroids to treat a COPD exacerbation, as described in other population studies.^41,42 Lack of medication regimen data in our analysis precludes further attribution of these causes, but the potential associations are interesting and warrant additional study.

The structure of our data as pooled annual cross sections rather than a true longitudinal cohort limited us to use only 10 months (February to November) of index hospitalizations in order to stay aligned with HRRP policy inclusion criteria. As such, we may have missed some important observations during peak respiratory virus season. As in any administrative data analysis, we are limited to codes in the discharge records, which may not reflect the entire nature of a hospitalization. Administrative data are particularly problematic in identifying true COPD exacerbations, particularly with multiple comorbid cardiopulmonary conditions.^43,44 Validating coding algorithms for identifying COPD was beyond the scope of our evaluation, which purposefully used HRRP methodology. Further study thereof would be a useful endeavor, especially with transition to ICD-10, considering that previously published evaluation was limited to ICD-9.⁴⁴ Despite these limitations, we were left with a robust and representative national cohort, which is an acceptable tradeoff.

Our study highlights the importance of understanding comorbidity as a major determinant of readmissions following COPD exacerbations, particularly in distinguishing which patients will return for COPD versus non-COPD-related diagnoses. At the health system level, readmission programs should be designed with the multimorbid patient in mind. Engagement of care teams, facilitating communication, and shared decision making are strategies to mitigate readmission risk in addition to COPD-focused disease management.³⁹ These data highlight the need to use risk prediction tools in assigning resources to reduce readmissions,⁴⁵ as well as the need to move readmission reduction programs beyond COPD management alone. Developing such systems to prospectively identify which patients are at risk of returning for both COPD and non-COPD reasons may further elucidate readmission mitigation strategies and should be a subject of future prospective study.

Acknowledgments

Data were made available through the Agency for Healthcare Research and Quality’s Healthcare Utilization Project. A full list of partner organizations providing data for the Nationwide Readmission Database can be found at https://www.hcup-us.ahrq.gov/db/hcupdatapartners.jsp.

Prior Presentation

Portions of this work were presented in abstract form at the 2018 American Thoracic Society International Conference (May 2018, San Diego, CA). This manuscript is derived from the doctoral dissertation for the degree of PhD in Health Policy and Management of the corresponding author, conferred in June 2019.

Disclaimer

This article does not necessarily represent the views and policies of the Department of Veterans Affairs or the USPSTF.

In the past two decades, the incidence rate of opioid use disorder (OUD) among pregnant women has increased by more than 400%, constituting a United States public health crisis.¹ Newborns exposed to intrauterine opioids are at risk for the postnatal withdrawal syndrome known as neonatal abstinence syndrome (NAS), which requires increased hospital resources, such as neonatal intensive care unit (NICU) admission and prolonged length of stay.² Given the medical and psychosocial challenges associated with maternal OUD and NAS, a multidisciplinary, patient-centered approach to hospital care for affected newborns and their mothers is warranted. A large and growing body of research has focused on the epidemiology of NAS and approaches for its prevention, screening, and management. This review appraises updates to the literature within the past five years, with an emphasis on considerations for newborn discharge to promote optimal care for this population.

NAS is a complex disorder arising from the abrupt cessation of placental transfer of opioids after birth, although other maternal substances, including benzodiazepines and other antidepressants, have been less commonly implicated.² The term neonatal opioid withdrawal syndrome is sometimes used to indicate withdrawal from opioids specifically.³ The central and autonomic nervous systems and the gastrointestinal system (eg, tremors, increased muscle tone, high-pitched crying, feeding difficulties) are affected in NAS, with most newborns demonstrating symptoms within the first few days of life.⁴ Previously reported factors associated with NAS include opioid type, timing of exposure during pregnancy, maternal tobacco use, infant sex, and gestational age.⁵ Literature demonstrates that concurrent exposure to other prenatal substances, particularly antidepressants, benzodiazepines, and gabapentin, is significantly associated with increased risk of NAS.⁶ Recent studies also suggest that expression of NAS may relate to newborn genetic variations, particularly at the OPRM1, COMT, and CYP2B6 gene sites.^{7, 8}

State health departments have increasingly deemed NAS as a reportable diagnosis for public health surveillance, which relies on the accurate diagnosis and documentation of NAS during birth hospitalization.⁹ The diagnosis codes for NAS include the International Classification of Diseases, Ninth Revision, Clinical Modification code (ICD-9-CM) 779.5 and the International Classification of Diseases, Tenth Revision, Clinical Modification ICD-10-CM code P96.1.¹⁰ However, given the variation in the presentation and severity of NAS, no consensus has been established with regard to a standardized case definition for reporting across hospitals and states.⁹ In fact, NAS should be conceptualized as a continuum of withdrawal symptoms along which every infant with intrauterine opioid exposure resides; this continuum ranges from minor findings, which do not affect the infant’s ability to grow and develop, to severe withdrawal, resulting in excessive weight loss, dehydration, or seizures.^3,11 Ultimately, the diagnosis of NAS is made clinically based on cardinal symptoms in the setting of known or highly suspected opioid exposure. In a recent study of Tennessee Medicaid claims data, >25% of infants with a confirmed diagnosis code for NAS did not receive pharmacotherapy.¹⁰ Pharmacologic treatment of NAS, therefore, may be more appropriately considered as a marker of disease severity, rather than a requirement for diagnosis.

Although the opioid crisis and resulting rise in NAS have affected communities across the US, substantial statewide variation exists, with extremes ranging from 0.7 per 1,000 births affected by NAS in Hawaii to 33.4 per 1,000 births in West Virginia.¹² Within states, increased maternal OUD and NAS rates have also disproportionately affected rural communities possibly due to reduced access to healthcare and mental health services and poor economic conditions.¹³ A recent national study demonstrated that the proportion of newborns with NAS who were born in rural hospitals increased from 12.9% to 21.2% over the past decade; these rural newborns with NAS are more likely to be publicly insured and to require transfer after birth than newborns in urban hospitals.¹⁴ These data suggest a particular need among rural communities for increased resources targeting NAS care as well as maternal OUD prevention and treatment.

The American College of Obstetricians and Gynecologists (ACOG) recommends early universal screening for maternal substance use at the first prenatal visit with a validated screening tool; examples include the 4Ps (parents, partners, past, and pregnancy), CRAFFT (car, relax, alone, forget, friends, trouble), and the National Institute on Drug Abuse quick screen, which have all been well studied and have a high sensitivity for detecting substance use and misuse.¹⁵

Toxicology Screening

Toxicology testing for both mother and newborn is helpful in identifying or confirming intrauterine exposures, particularly in cases of polysubstance use or when a newborn manifests signs of NAS but whose mother denies opioid use. All toxicology testing should be performed with the mother’s consent, and any potential legal or mandatory ramifications of a positive test should be considered. Although universal maternal toxicology testing improves the identification of newborns at risk for NAS, this approach remains controversial; most hospitals use a risk-based approach for maternal toxicology testing.^16,17

Newborn toxicology testing can be performed from samples of hair, urine, meconium, and umbilical cord. Although frequently used, newborn urine testing has the shortest window of detection, ie, the last few days prior to delivery (Table 1). Meconium drug testing has been considered the gold standard and can detect exposures from the last 20 weeks of gestation, providing information on chronic exposures.¹⁸ In a recent survey, 10% of hospitals reported using umbilical cord toxicology as the primary method for detecting intrauterine exposures.¹⁷ This approach allows greater ease of specimen collection but may not yield results that are exactly equivalent to meconium testing.¹⁹

Close monitoring for development of NAS after birth is indicated for all newborns with confirmed or suspected intrauterine opioid exposure. Although the current American Academy of Pediatrics (AAP) guidelines recommend three days of newborn observation for exposure to short-acting opioids and five to seven days for longer acting opioids, substantial variation has been described across US hospitals in policies related to newborn length of stay for NAS observation.^{17, 20} In most hospitals, monitoring for NAS occurs in the routine postpartum unit (ie, level 1 nursery), with transfer to the NICU if pharmacologic treatment is indicated.¹⁷

The most widely used assessment tool for NAS is the Finnegan Neonatal Abstinence Scoring System (FNASS) or the modified FNASS, which assigns points for the 21 most common opioid withdrawal symptoms based on perceived severity.^{17, 21} This tool allows for assessment of symptoms, helps determine need for pharmacologic intervention, and can guide monitoring of symptoms and weaning of therapy. A commonly used score cutoff of 8 is based on prior research validating scores >8 as indicative of withdrawal symptoms as opposed to normal newborn findings.²² Despite its popularity and widespread usage, FNASS has limitations, including the need for the newborn to be stimulated or disturbed to produce an accurate assessment and scoring for nonspecific signs of withdrawal, including sneezing, yawning, and stuffiness. Recent work has attempted to simplify and shorten the FNASS to elements that are unique and specific for withdrawal.^23,24 Further research is needed to establish the validity of common scoring practices (ie, use of 8 as a cutoff) to determine the need for pharmacologic treatment.²⁵

Recent studies suggest that simple, function-based assessments, such as the Eat, Sleep, Console (ESC) approach developed by Grossman and colleagues, may serve as an alternative to the FNASS for evaluating withdrawal.^26,27 With ESC, the need for pharmacotherapy is evaluated by the newborn’s ability to (1) eat (breastfeed successfully or eat at least 1oz per feed), (2) sleep uninterrupted for at least one hour, and (3) be consoled within 10 minutes. To date, research on the implementation of ESC has primarily focused on reducing length of stay and need for pharmacologic treatment in the context of quality improvement initiatives.^26,27 Further prospective studies are warranted that compare ESC to traditional approaches involving the FNASS, and that evaluate post-discharge outcomes including newborn weight gain, ongoing withdrawal symptoms at home, and readmission.

In recent years, research increasingly supports the critical role of nonpharmacological care in management of all opioid-exposed newborns, regardless of NAS severity.^{11,27, 28} Rooming-in of mothers or caregivers has been shown to decrease the need for pharmacologic treatment, shorten the length of stay, and reduce hospital costs.^28,29 Other well-established practices include maintaining a low stimulus environment for infants with low lighting and sound, swaddling, maximizing caregiver contact with kangaroo care and skin to skin, and minimizing interventions. Therapeutic modalities, such as massage and music therapy, have been used for infants with NAS, but no evidence has supported their use. Recent studies have increasingly supported the use of acupuncture as an emerging modality in treating NAS. ³⁰

Feeding

Breastfeeding is encouraged for mothers who are stable on their methadone or buprenorphine maintenance treatment, are not using heroin or other illicit drugs, and have no other contraindications to breastfeeding, such as human immunodeficiency virus.³¹ Despite the known benefits of breastfeeding, which include decreased NAS severity, decreased need for pharmacological treatment, and shortened length of hospital stay, breastfeeding rates among mothers with OUD are low.³¹ Hospital policies that can promote maternal success in breastfeeding include tailored breastfeeding support, rooming in, and early, consistent maternal education on the benefits and safety of breastfeeding.³² A small percentage of hospitals use donor breastmilk for this population, although data on outcomes are limited.¹⁷ For formula-fed newborns, emerging research suggests that early initiation of high-calorie (22-24 kcal/ounce) formula may be beneficial to prevent excessive weight loss and poor weight gain after intrauterine opioid exposure.³³

When supportive therapy fails to adequately control symptoms of withdrawal, pharmacological management is initiated to improve infant discomfort, allow for adequate feeding and nutrition, and facilitate parental bonding (Table 2).¹¹ Opioids are the primary agent used for pharmacologic treatment, and morphine is the most commonly utilized.¹⁷ Morphine is a short-acting opioid and can be prescribed either as a weight-based weaning protocol or symptom-based regimen. Methadone is also widely used, and as a long-acting opioid, it has the advantage of twice daily dosing after the initial loading dose. Recently, buprenorphine, a partial mu opioid agonist with a long half-life, has emerged as a promising primary opioid treatment agent and has been shown to reduce the length of stay and the number of opioid treatment days compared with morphine and methadone.³⁶

When the signs and symptoms of NAS are not effectively controlled with a primary opioid or in the case of polysubstance exposure, adjunctive agents are often used, with phenobarbital and clonidine being the most common (Table 3).¹¹ Regardless of opioid agent used, multicenter quality improvement initiatives demonstrate that having a standardized weaning protocol is critical to minimizing the overall length of stay and reducing the need for adjunctive agents.^38,39 Additionally, modeling tools such as pharmacometrics for methadone and buprenorphine have shown promise in optimizing dose selection.^40,41 Modeling may include pharmacodynamic data (ie, clinical response to treatment), pharmacokinetics (ie, measures of drug distribution and clearance), and other factors, such as patient demographics, intrauterine exposure type, and symptom severity. Future studies should examine weight versus symptom-based dosing regimens as well as compare weaning schedules versus “as needed” dosing regimens.¹¹

The need for comprehensive medical and psychosocial supports for mothers with OUD cannot be overstated, given the high rates of concurrent illicit or other substance use, comorbid depression and anxiety, physical and sexual trauma, poverty and homelessness, intravenous drug use, and sex-related risk patterns.¹⁵ Significant issues of healthcare-associated stigma and criminality also affect this population. As of 2019, 23 states and the District of Columbia classify substance use during pregnancy as child abuse under civil child-welfare statutes, potentially resulting in termination of parental rights.⁴² Studies of mothers with OUD have demonstrated that they often experience guilt, shame, and fear of loss of custody, all of which can impede their trust in hospital providers and future engagement in care.⁴³ They also report frustration with and mistrust of NAS scoring assessments, which they can perceive to be disruptive and potentially biased.⁴⁴ Multiple approaches should be considered to standardize and improve the hospital experience for this population, in a way that emphasizes the mother’s role as a capable, respected participant in her newborn’s care.

Maternal Support

A coordinated, multidisciplinary approach to comprehensively support mothers with OUD should involve team members from pediatrics, neonatology, obstetrics, nursing, social work, case management, and lactation.³⁵ This support includes screening for adequate resources and a safe, supportive, drug-free home environment as well as evaluating co-occurring mental health conditions. Referrals should be provided as needed to social services, postpartum psychiatry or behavioral health services, OUD treatment and relapse-prevention programs, and harm reduction services (eg, naloxone training). In addition to the healthcare team, other community members can be enlisted to serve as a trusted, consistent, and nonjudgmental support during the hospitalization; examples may include a peer support (another mother with OUD), an OUD program caseworker, or a doula.⁴⁴

Clinical Pathways

Hospitals should establish clinical pathways for women with OUD to standardize care and communication across the continuum of care for themselves and their newborn, with input from all healthcare team members involved (prenatal, intrapartum, and postpartum).³⁵ Early, consistent information should be provided regarding expected newborn hospital course, including toxicology testing, NAS monitoring, possible NICU admission, and involvement of social work.

Provider Training

Educational opportunities in the form of continuing medical education, in-service trainings, etc., should be provided for clinical staff who care for mothers with OUD and their newborns, regarding issues of substance use, stigma, bias, and trauma-informed care.³⁵ Online training resources are available through the American Society of Addiction Medicine, the ACOG, AAP, the Centers for Disease Control and Prevention, and the Substance Abuse and Mental Health Services Administration.

Regardless of whether or not NAS is treated pharmacologically, newborns with opioid exposure may experience residual symptoms of withdrawal that persist for months.⁴ Current research suggests increased risk for morbidity, emergency department utilization, and rehospitalization after discharge in this population as well as difficulty in accessing and engaging with pediatric preventative care.^{45, 46}

A clear plan should be established upon discharge to ensure optimal newborn care and follow-up. A complete record of the newborn’s hospital stay, including maternal toxicology screenings and summary of any social work documentation, should be communicated to the primary care provider upon discharge. Close postdischarge monitoring involves addressing parenting knowledge gaps, assessing illness and injury risk, and evaluating for the presence of ongoing withdrawal symptoms.⁴ Primary care providers can also play a key role in assessing maternal stress, coping, and parenting skills as well as helping families connect to resources. Further research is warranted on how pediatric primary care systems can better build maternal trust, address parenting needs, and engage this population in routine well-child care.⁴⁷

Child Welfare, Early Intervention, and Other Services

In general, newborn safety and keeping families intact should be prioritized, with disposition into foster care only in cases of concern for child maltreatment or neglect. Under the Child Abuse Prevention and Treatment Act (CAPTA), states are required to develop Plans of Safe Care for women and newborns affected by OUD, with the goal of fostering collaboration between healthcare and social service organizations around care of these families.⁴⁸ Given the variable interpretation of Plans of Safe Care across the U.S., providers should be knowledgeable about state and local statutes and reporting requirements related to parental substance use.

As part of Plans of Safe Care, providers may be well-positioned to initiate referrals for early intervention, home visiting, and other programs designed to provide developmental or wrap-around support for families. Under Part C of the Individuals with Disabilities Education Act, many states offer early intervention on the basis of NAS as an automatic qualifying diagnosis; however, attrition of eligible families along the referral and enrollment process is substantial.⁴⁹ A standardized approach to discharging opioid-exposed newborns includes referrals to available resources and discussion of their importance with families and may increase utilization and decrease variation in care.⁵⁰

Maternal OUD presents a unique combination of medical and psychosocial challenges that affect hospital care for mothers and their newborns. Optimal care for this population warrants a multidisciplinary team of providers who are knowledgeable, collaborative, and mindful of the important role of the mother as a key participant in her newborn’s care. Despite a large and growing body of research focused on NAS prevention, screening, and treatment, ongoing efforts are needed to create hospital policies and clinical pathways that are responsive to the healthcare needs of this population, navigate sensitive issues of criminality and stigma, and ultimately support maternal parenting success.

Disclosures

The authors have no financial relationships and conflicts of interest relevant to this article to disclose.

Funding

Funding for this work was provided by Cincinnati Children’s Hospital Medical Center and Nemours/AI duPont Hospital for Children.

In the past two decades, the incidence rate of opioid use disorder (OUD) among pregnant women has increased by more than 400%, constituting a United States public health crisis.¹ Newborns exposed to intrauterine opioids are at risk for the postnatal withdrawal syndrome known as neonatal abstinence syndrome (NAS), which requires increased hospital resources, such as neonatal intensive care unit (NICU) admission and prolonged length of stay.² Given the medical and psychosocial challenges associated with maternal OUD and NAS, a multidisciplinary, patient-centered approach to hospital care for affected newborns and their mothers is warranted. A large and growing body of research has focused on the epidemiology of NAS and approaches for its prevention, screening, and management. This review appraises updates to the literature within the past five years, with an emphasis on considerations for newborn discharge to promote optimal care for this population.

NAS is a complex disorder arising from the abrupt cessation of placental transfer of opioids after birth, although other maternal substances, including benzodiazepines and other antidepressants, have been less commonly implicated.² The term neonatal opioid withdrawal syndrome is sometimes used to indicate withdrawal from opioids specifically.³ The central and autonomic nervous systems and the gastrointestinal system (eg, tremors, increased muscle tone, high-pitched crying, feeding difficulties) are affected in NAS, with most newborns demonstrating symptoms within the first few days of life.⁴ Previously reported factors associated with NAS include opioid type, timing of exposure during pregnancy, maternal tobacco use, infant sex, and gestational age.⁵ Literature demonstrates that concurrent exposure to other prenatal substances, particularly antidepressants, benzodiazepines, and gabapentin, is significantly associated with increased risk of NAS.⁶ Recent studies also suggest that expression of NAS may relate to newborn genetic variations, particularly at the OPRM1, COMT, and CYP2B6 gene sites.^{7, 8}

State health departments have increasingly deemed NAS as a reportable diagnosis for public health surveillance, which relies on the accurate diagnosis and documentation of NAS during birth hospitalization.⁹ The diagnosis codes for NAS include the International Classification of Diseases, Ninth Revision, Clinical Modification code (ICD-9-CM) 779.5 and the International Classification of Diseases, Tenth Revision, Clinical Modification ICD-10-CM code P96.1.¹⁰ However, given the variation in the presentation and severity of NAS, no consensus has been established with regard to a standardized case definition for reporting across hospitals and states.⁹ In fact, NAS should be conceptualized as a continuum of withdrawal symptoms along which every infant with intrauterine opioid exposure resides; this continuum ranges from minor findings, which do not affect the infant’s ability to grow and develop, to severe withdrawal, resulting in excessive weight loss, dehydration, or seizures.^3,11 Ultimately, the diagnosis of NAS is made clinically based on cardinal symptoms in the setting of known or highly suspected opioid exposure. In a recent study of Tennessee Medicaid claims data, >25% of infants with a confirmed diagnosis code for NAS did not receive pharmacotherapy.¹⁰ Pharmacologic treatment of NAS, therefore, may be more appropriately considered as a marker of disease severity, rather than a requirement for diagnosis.

Although the opioid crisis and resulting rise in NAS have affected communities across the US, substantial statewide variation exists, with extremes ranging from 0.7 per 1,000 births affected by NAS in Hawaii to 33.4 per 1,000 births in West Virginia.¹² Within states, increased maternal OUD and NAS rates have also disproportionately affected rural communities possibly due to reduced access to healthcare and mental health services and poor economic conditions.¹³ A recent national study demonstrated that the proportion of newborns with NAS who were born in rural hospitals increased from 12.9% to 21.2% over the past decade; these rural newborns with NAS are more likely to be publicly insured and to require transfer after birth than newborns in urban hospitals.¹⁴ These data suggest a particular need among rural communities for increased resources targeting NAS care as well as maternal OUD prevention and treatment.

The American College of Obstetricians and Gynecologists (ACOG) recommends early universal screening for maternal substance use at the first prenatal visit with a validated screening tool; examples include the 4Ps (parents, partners, past, and pregnancy), CRAFFT (car, relax, alone, forget, friends, trouble), and the National Institute on Drug Abuse quick screen, which have all been well studied and have a high sensitivity for detecting substance use and misuse.¹⁵

Toxicology Screening

Toxicology testing for both mother and newborn is helpful in identifying or confirming intrauterine exposures, particularly in cases of polysubstance use or when a newborn manifests signs of NAS but whose mother denies opioid use. All toxicology testing should be performed with the mother’s consent, and any potential legal or mandatory ramifications of a positive test should be considered. Although universal maternal toxicology testing improves the identification of newborns at risk for NAS, this approach remains controversial; most hospitals use a risk-based approach for maternal toxicology testing.^16,17

Newborn toxicology testing can be performed from samples of hair, urine, meconium, and umbilical cord. Although frequently used, newborn urine testing has the shortest window of detection, ie, the last few days prior to delivery (Table 1). Meconium drug testing has been considered the gold standard and can detect exposures from the last 20 weeks of gestation, providing information on chronic exposures.¹⁸ In a recent survey, 10% of hospitals reported using umbilical cord toxicology as the primary method for detecting intrauterine exposures.¹⁷ This approach allows greater ease of specimen collection but may not yield results that are exactly equivalent to meconium testing.¹⁹

Close monitoring for development of NAS after birth is indicated for all newborns with confirmed or suspected intrauterine opioid exposure. Although the current American Academy of Pediatrics (AAP) guidelines recommend three days of newborn observation for exposure to short-acting opioids and five to seven days for longer acting opioids, substantial variation has been described across US hospitals in policies related to newborn length of stay for NAS observation.^{17, 20} In most hospitals, monitoring for NAS occurs in the routine postpartum unit (ie, level 1 nursery), with transfer to the NICU if pharmacologic treatment is indicated.¹⁷

The most widely used assessment tool for NAS is the Finnegan Neonatal Abstinence Scoring System (FNASS) or the modified FNASS, which assigns points for the 21 most common opioid withdrawal symptoms based on perceived severity.^{17, 21} This tool allows for assessment of symptoms, helps determine need for pharmacologic intervention, and can guide monitoring of symptoms and weaning of therapy. A commonly used score cutoff of 8 is based on prior research validating scores >8 as indicative of withdrawal symptoms as opposed to normal newborn findings.²² Despite its popularity and widespread usage, FNASS has limitations, including the need for the newborn to be stimulated or disturbed to produce an accurate assessment and scoring for nonspecific signs of withdrawal, including sneezing, yawning, and stuffiness. Recent work has attempted to simplify and shorten the FNASS to elements that are unique and specific for withdrawal.^23,24 Further research is needed to establish the validity of common scoring practices (ie, use of 8 as a cutoff) to determine the need for pharmacologic treatment.²⁵

Recent studies suggest that simple, function-based assessments, such as the Eat, Sleep, Console (ESC) approach developed by Grossman and colleagues, may serve as an alternative to the FNASS for evaluating withdrawal.^26,27 With ESC, the need for pharmacotherapy is evaluated by the newborn’s ability to (1) eat (breastfeed successfully or eat at least 1oz per feed), (2) sleep uninterrupted for at least one hour, and (3) be consoled within 10 minutes. To date, research on the implementation of ESC has primarily focused on reducing length of stay and need for pharmacologic treatment in the context of quality improvement initiatives.^26,27 Further prospective studies are warranted that compare ESC to traditional approaches involving the FNASS, and that evaluate post-discharge outcomes including newborn weight gain, ongoing withdrawal symptoms at home, and readmission.

In recent years, research increasingly supports the critical role of nonpharmacological care in management of all opioid-exposed newborns, regardless of NAS severity.^{11,27, 28} Rooming-in of mothers or caregivers has been shown to decrease the need for pharmacologic treatment, shorten the length of stay, and reduce hospital costs.^28,29 Other well-established practices include maintaining a low stimulus environment for infants with low lighting and sound, swaddling, maximizing caregiver contact with kangaroo care and skin to skin, and minimizing interventions. Therapeutic modalities, such as massage and music therapy, have been used for infants with NAS, but no evidence has supported their use. Recent studies have increasingly supported the use of acupuncture as an emerging modality in treating NAS. ³⁰

Feeding

Breastfeeding is encouraged for mothers who are stable on their methadone or buprenorphine maintenance treatment, are not using heroin or other illicit drugs, and have no other contraindications to breastfeeding, such as human immunodeficiency virus.³¹ Despite the known benefits of breastfeeding, which include decreased NAS severity, decreased need for pharmacological treatment, and shortened length of hospital stay, breastfeeding rates among mothers with OUD are low.³¹ Hospital policies that can promote maternal success in breastfeeding include tailored breastfeeding support, rooming in, and early, consistent maternal education on the benefits and safety of breastfeeding.³² A small percentage of hospitals use donor breastmilk for this population, although data on outcomes are limited.¹⁷ For formula-fed newborns, emerging research suggests that early initiation of high-calorie (22-24 kcal/ounce) formula may be beneficial to prevent excessive weight loss and poor weight gain after intrauterine opioid exposure.³³

When supportive therapy fails to adequately control symptoms of withdrawal, pharmacological management is initiated to improve infant discomfort, allow for adequate feeding and nutrition, and facilitate parental bonding (Table 2).¹¹ Opioids are the primary agent used for pharmacologic treatment, and morphine is the most commonly utilized.¹⁷ Morphine is a short-acting opioid and can be prescribed either as a weight-based weaning protocol or symptom-based regimen. Methadone is also widely used, and as a long-acting opioid, it has the advantage of twice daily dosing after the initial loading dose. Recently, buprenorphine, a partial mu opioid agonist with a long half-life, has emerged as a promising primary opioid treatment agent and has been shown to reduce the length of stay and the number of opioid treatment days compared with morphine and methadone.³⁶

When the signs and symptoms of NAS are not effectively controlled with a primary opioid or in the case of polysubstance exposure, adjunctive agents are often used, with phenobarbital and clonidine being the most common (Table 3).¹¹ Regardless of opioid agent used, multicenter quality improvement initiatives demonstrate that having a standardized weaning protocol is critical to minimizing the overall length of stay and reducing the need for adjunctive agents.^38,39 Additionally, modeling tools such as pharmacometrics for methadone and buprenorphine have shown promise in optimizing dose selection.^40,41 Modeling may include pharmacodynamic data (ie, clinical response to treatment), pharmacokinetics (ie, measures of drug distribution and clearance), and other factors, such as patient demographics, intrauterine exposure type, and symptom severity. Future studies should examine weight versus symptom-based dosing regimens as well as compare weaning schedules versus “as needed” dosing regimens.¹¹

The need for comprehensive medical and psychosocial supports for mothers with OUD cannot be overstated, given the high rates of concurrent illicit or other substance use, comorbid depression and anxiety, physical and sexual trauma, poverty and homelessness, intravenous drug use, and sex-related risk patterns.¹⁵ Significant issues of healthcare-associated stigma and criminality also affect this population. As of 2019, 23 states and the District of Columbia classify substance use during pregnancy as child abuse under civil child-welfare statutes, potentially resulting in termination of parental rights.⁴² Studies of mothers with OUD have demonstrated that they often experience guilt, shame, and fear of loss of custody, all of which can impede their trust in hospital providers and future engagement in care.⁴³ They also report frustration with and mistrust of NAS scoring assessments, which they can perceive to be disruptive and potentially biased.⁴⁴ Multiple approaches should be considered to standardize and improve the hospital experience for this population, in a way that emphasizes the mother’s role as a capable, respected participant in her newborn’s care.

Maternal Support

A coordinated, multidisciplinary approach to comprehensively support mothers with OUD should involve team members from pediatrics, neonatology, obstetrics, nursing, social work, case management, and lactation.³⁵ This support includes screening for adequate resources and a safe, supportive, drug-free home environment as well as evaluating co-occurring mental health conditions. Referrals should be provided as needed to social services, postpartum psychiatry or behavioral health services, OUD treatment and relapse-prevention programs, and harm reduction services (eg, naloxone training). In addition to the healthcare team, other community members can be enlisted to serve as a trusted, consistent, and nonjudgmental support during the hospitalization; examples may include a peer support (another mother with OUD), an OUD program caseworker, or a doula.⁴⁴

Clinical Pathways

Hospitals should establish clinical pathways for women with OUD to standardize care and communication across the continuum of care for themselves and their newborn, with input from all healthcare team members involved (prenatal, intrapartum, and postpartum).³⁵ Early, consistent information should be provided regarding expected newborn hospital course, including toxicology testing, NAS monitoring, possible NICU admission, and involvement of social work.

Provider Training

Educational opportunities in the form of continuing medical education, in-service trainings, etc., should be provided for clinical staff who care for mothers with OUD and their newborns, regarding issues of substance use, stigma, bias, and trauma-informed care.³⁵ Online training resources are available through the American Society of Addiction Medicine, the ACOG, AAP, the Centers for Disease Control and Prevention, and the Substance Abuse and Mental Health Services Administration.

Regardless of whether or not NAS is treated pharmacologically, newborns with opioid exposure may experience residual symptoms of withdrawal that persist for months.⁴ Current research suggests increased risk for morbidity, emergency department utilization, and rehospitalization after discharge in this population as well as difficulty in accessing and engaging with pediatric preventative care.^{45, 46}

A clear plan should be established upon discharge to ensure optimal newborn care and follow-up. A complete record of the newborn’s hospital stay, including maternal toxicology screenings and summary of any social work documentation, should be communicated to the primary care provider upon discharge. Close postdischarge monitoring involves addressing parenting knowledge gaps, assessing illness and injury risk, and evaluating for the presence of ongoing withdrawal symptoms.⁴ Primary care providers can also play a key role in assessing maternal stress, coping, and parenting skills as well as helping families connect to resources. Further research is warranted on how pediatric primary care systems can better build maternal trust, address parenting needs, and engage this population in routine well-child care.⁴⁷

Child Welfare, Early Intervention, and Other Services

In general, newborn safety and keeping families intact should be prioritized, with disposition into foster care only in cases of concern for child maltreatment or neglect. Under the Child Abuse Prevention and Treatment Act (CAPTA), states are required to develop Plans of Safe Care for women and newborns affected by OUD, with the goal of fostering collaboration between healthcare and social service organizations around care of these families.⁴⁸ Given the variable interpretation of Plans of Safe Care across the U.S., providers should be knowledgeable about state and local statutes and reporting requirements related to parental substance use.

As part of Plans of Safe Care, providers may be well-positioned to initiate referrals for early intervention, home visiting, and other programs designed to provide developmental or wrap-around support for families. Under Part C of the Individuals with Disabilities Education Act, many states offer early intervention on the basis of NAS as an automatic qualifying diagnosis; however, attrition of eligible families along the referral and enrollment process is substantial.⁴⁹ A standardized approach to discharging opioid-exposed newborns includes referrals to available resources and discussion of their importance with families and may increase utilization and decrease variation in care.⁵⁰

Maternal OUD presents a unique combination of medical and psychosocial challenges that affect hospital care for mothers and their newborns. Optimal care for this population warrants a multidisciplinary team of providers who are knowledgeable, collaborative, and mindful of the important role of the mother as a key participant in her newborn’s care. Despite a large and growing body of research focused on NAS prevention, screening, and treatment, ongoing efforts are needed to create hospital policies and clinical pathways that are responsive to the healthcare needs of this population, navigate sensitive issues of criminality and stigma, and ultimately support maternal parenting success.

Disclosures

The authors have no financial relationships and conflicts of interest relevant to this article to disclose.

Funding

Funding for this work was provided by Cincinnati Children’s Hospital Medical Center and Nemours/AI duPont Hospital for Children.

In the past two decades, the incidence rate of opioid use disorder (OUD) among pregnant women has increased by more than 400%, constituting a United States public health crisis.¹ Newborns exposed to intrauterine opioids are at risk for the postnatal withdrawal syndrome known as neonatal abstinence syndrome (NAS), which requires increased hospital resources, such as neonatal intensive care unit (NICU) admission and prolonged length of stay.² Given the medical and psychosocial challenges associated with maternal OUD and NAS, a multidisciplinary, patient-centered approach to hospital care for affected newborns and their mothers is warranted. A large and growing body of research has focused on the epidemiology of NAS and approaches for its prevention, screening, and management. This review appraises updates to the literature within the past five years, with an emphasis on considerations for newborn discharge to promote optimal care for this population.

NAS is a complex disorder arising from the abrupt cessation of placental transfer of opioids after birth, although other maternal substances, including benzodiazepines and other antidepressants, have been less commonly implicated.² The term neonatal opioid withdrawal syndrome is sometimes used to indicate withdrawal from opioids specifically.³ The central and autonomic nervous systems and the gastrointestinal system (eg, tremors, increased muscle tone, high-pitched crying, feeding difficulties) are affected in NAS, with most newborns demonstrating symptoms within the first few days of life.⁴ Previously reported factors associated with NAS include opioid type, timing of exposure during pregnancy, maternal tobacco use, infant sex, and gestational age.⁵ Literature demonstrates that concurrent exposure to other prenatal substances, particularly antidepressants, benzodiazepines, and gabapentin, is significantly associated with increased risk of NAS.⁶ Recent studies also suggest that expression of NAS may relate to newborn genetic variations, particularly at the OPRM1, COMT, and CYP2B6 gene sites.^{7, 8}

State health departments have increasingly deemed NAS as a reportable diagnosis for public health surveillance, which relies on the accurate diagnosis and documentation of NAS during birth hospitalization.⁹ The diagnosis codes for NAS include the International Classification of Diseases, Ninth Revision, Clinical Modification code (ICD-9-CM) 779.5 and the International Classification of Diseases, Tenth Revision, Clinical Modification ICD-10-CM code P96.1.¹⁰ However, given the variation in the presentation and severity of NAS, no consensus has been established with regard to a standardized case definition for reporting across hospitals and states.⁹ In fact, NAS should be conceptualized as a continuum of withdrawal symptoms along which every infant with intrauterine opioid exposure resides; this continuum ranges from minor findings, which do not affect the infant’s ability to grow and develop, to severe withdrawal, resulting in excessive weight loss, dehydration, or seizures.^3,11 Ultimately, the diagnosis of NAS is made clinically based on cardinal symptoms in the setting of known or highly suspected opioid exposure. In a recent study of Tennessee Medicaid claims data, >25% of infants with a confirmed diagnosis code for NAS did not receive pharmacotherapy.¹⁰ Pharmacologic treatment of NAS, therefore, may be more appropriately considered as a marker of disease severity, rather than a requirement for diagnosis.

Although the opioid crisis and resulting rise in NAS have affected communities across the US, substantial statewide variation exists, with extremes ranging from 0.7 per 1,000 births affected by NAS in Hawaii to 33.4 per 1,000 births in West Virginia.¹² Within states, increased maternal OUD and NAS rates have also disproportionately affected rural communities possibly due to reduced access to healthcare and mental health services and poor economic conditions.¹³ A recent national study demonstrated that the proportion of newborns with NAS who were born in rural hospitals increased from 12.9% to 21.2% over the past decade; these rural newborns with NAS are more likely to be publicly insured and to require transfer after birth than newborns in urban hospitals.¹⁴ These data suggest a particular need among rural communities for increased resources targeting NAS care as well as maternal OUD prevention and treatment.

The American College of Obstetricians and Gynecologists (ACOG) recommends early universal screening for maternal substance use at the first prenatal visit with a validated screening tool; examples include the 4Ps (parents, partners, past, and pregnancy), CRAFFT (car, relax, alone, forget, friends, trouble), and the National Institute on Drug Abuse quick screen, which have all been well studied and have a high sensitivity for detecting substance use and misuse.¹⁵

Toxicology Screening

Toxicology testing for both mother and newborn is helpful in identifying or confirming intrauterine exposures, particularly in cases of polysubstance use or when a newborn manifests signs of NAS but whose mother denies opioid use. All toxicology testing should be performed with the mother’s consent, and any potential legal or mandatory ramifications of a positive test should be considered. Although universal maternal toxicology testing improves the identification of newborns at risk for NAS, this approach remains controversial; most hospitals use a risk-based approach for maternal toxicology testing.^16,17

Newborn toxicology testing can be performed from samples of hair, urine, meconium, and umbilical cord. Although frequently used, newborn urine testing has the shortest window of detection, ie, the last few days prior to delivery (Table 1). Meconium drug testing has been considered the gold standard and can detect exposures from the last 20 weeks of gestation, providing information on chronic exposures.¹⁸ In a recent survey, 10% of hospitals reported using umbilical cord toxicology as the primary method for detecting intrauterine exposures.¹⁷ This approach allows greater ease of specimen collection but may not yield results that are exactly equivalent to meconium testing.¹⁹

Close monitoring for development of NAS after birth is indicated for all newborns with confirmed or suspected intrauterine opioid exposure. Although the current American Academy of Pediatrics (AAP) guidelines recommend three days of newborn observation for exposure to short-acting opioids and five to seven days for longer acting opioids, substantial variation has been described across US hospitals in policies related to newborn length of stay for NAS observation.^{17, 20} In most hospitals, monitoring for NAS occurs in the routine postpartum unit (ie, level 1 nursery), with transfer to the NICU if pharmacologic treatment is indicated.¹⁷

The most widely used assessment tool for NAS is the Finnegan Neonatal Abstinence Scoring System (FNASS) or the modified FNASS, which assigns points for the 21 most common opioid withdrawal symptoms based on perceived severity.^{17, 21} This tool allows for assessment of symptoms, helps determine need for pharmacologic intervention, and can guide monitoring of symptoms and weaning of therapy. A commonly used score cutoff of 8 is based on prior research validating scores >8 as indicative of withdrawal symptoms as opposed to normal newborn findings.²² Despite its popularity and widespread usage, FNASS has limitations, including the need for the newborn to be stimulated or disturbed to produce an accurate assessment and scoring for nonspecific signs of withdrawal, including sneezing, yawning, and stuffiness. Recent work has attempted to simplify and shorten the FNASS to elements that are unique and specific for withdrawal.^23,24 Further research is needed to establish the validity of common scoring practices (ie, use of 8 as a cutoff) to determine the need for pharmacologic treatment.²⁵

Recent studies suggest that simple, function-based assessments, such as the Eat, Sleep, Console (ESC) approach developed by Grossman and colleagues, may serve as an alternative to the FNASS for evaluating withdrawal.^26,27 With ESC, the need for pharmacotherapy is evaluated by the newborn’s ability to (1) eat (breastfeed successfully or eat at least 1oz per feed), (2) sleep uninterrupted for at least one hour, and (3) be consoled within 10 minutes. To date, research on the implementation of ESC has primarily focused on reducing length of stay and need for pharmacologic treatment in the context of quality improvement initiatives.^26,27 Further prospective studies are warranted that compare ESC to traditional approaches involving the FNASS, and that evaluate post-discharge outcomes including newborn weight gain, ongoing withdrawal symptoms at home, and readmission.

In recent years, research increasingly supports the critical role of nonpharmacological care in management of all opioid-exposed newborns, regardless of NAS severity.^{11,27, 28} Rooming-in of mothers or caregivers has been shown to decrease the need for pharmacologic treatment, shorten the length of stay, and reduce hospital costs.^28,29 Other well-established practices include maintaining a low stimulus environment for infants with low lighting and sound, swaddling, maximizing caregiver contact with kangaroo care and skin to skin, and minimizing interventions. Therapeutic modalities, such as massage and music therapy, have been used for infants with NAS, but no evidence has supported their use. Recent studies have increasingly supported the use of acupuncture as an emerging modality in treating NAS. ³⁰

Feeding

Breastfeeding is encouraged for mothers who are stable on their methadone or buprenorphine maintenance treatment, are not using heroin or other illicit drugs, and have no other contraindications to breastfeeding, such as human immunodeficiency virus.³¹ Despite the known benefits of breastfeeding, which include decreased NAS severity, decreased need for pharmacological treatment, and shortened length of hospital stay, breastfeeding rates among mothers with OUD are low.³¹ Hospital policies that can promote maternal success in breastfeeding include tailored breastfeeding support, rooming in, and early, consistent maternal education on the benefits and safety of breastfeeding.³² A small percentage of hospitals use donor breastmilk for this population, although data on outcomes are limited.¹⁷ For formula-fed newborns, emerging research suggests that early initiation of high-calorie (22-24 kcal/ounce) formula may be beneficial to prevent excessive weight loss and poor weight gain after intrauterine opioid exposure.³³

When supportive therapy fails to adequately control symptoms of withdrawal, pharmacological management is initiated to improve infant discomfort, allow for adequate feeding and nutrition, and facilitate parental bonding (Table 2).¹¹ Opioids are the primary agent used for pharmacologic treatment, and morphine is the most commonly utilized.¹⁷ Morphine is a short-acting opioid and can be prescribed either as a weight-based weaning protocol or symptom-based regimen. Methadone is also widely used, and as a long-acting opioid, it has the advantage of twice daily dosing after the initial loading dose. Recently, buprenorphine, a partial mu opioid agonist with a long half-life, has emerged as a promising primary opioid treatment agent and has been shown to reduce the length of stay and the number of opioid treatment days compared with morphine and methadone.³⁶

When the signs and symptoms of NAS are not effectively controlled with a primary opioid or in the case of polysubstance exposure, adjunctive agents are often used, with phenobarbital and clonidine being the most common (Table 3).¹¹ Regardless of opioid agent used, multicenter quality improvement initiatives demonstrate that having a standardized weaning protocol is critical to minimizing the overall length of stay and reducing the need for adjunctive agents.^38,39 Additionally, modeling tools such as pharmacometrics for methadone and buprenorphine have shown promise in optimizing dose selection.^40,41 Modeling may include pharmacodynamic data (ie, clinical response to treatment), pharmacokinetics (ie, measures of drug distribution and clearance), and other factors, such as patient demographics, intrauterine exposure type, and symptom severity. Future studies should examine weight versus symptom-based dosing regimens as well as compare weaning schedules versus “as needed” dosing regimens.¹¹

The need for comprehensive medical and psychosocial supports for mothers with OUD cannot be overstated, given the high rates of concurrent illicit or other substance use, comorbid depression and anxiety, physical and sexual trauma, poverty and homelessness, intravenous drug use, and sex-related risk patterns.¹⁵ Significant issues of healthcare-associated stigma and criminality also affect this population. As of 2019, 23 states and the District of Columbia classify substance use during pregnancy as child abuse under civil child-welfare statutes, potentially resulting in termination of parental rights.⁴² Studies of mothers with OUD have demonstrated that they often experience guilt, shame, and fear of loss of custody, all of which can impede their trust in hospital providers and future engagement in care.⁴³ They also report frustration with and mistrust of NAS scoring assessments, which they can perceive to be disruptive and potentially biased.⁴⁴ Multiple approaches should be considered to standardize and improve the hospital experience for this population, in a way that emphasizes the mother’s role as a capable, respected participant in her newborn’s care.

Maternal Support

A coordinated, multidisciplinary approach to comprehensively support mothers with OUD should involve team members from pediatrics, neonatology, obstetrics, nursing, social work, case management, and lactation.³⁵ This support includes screening for adequate resources and a safe, supportive, drug-free home environment as well as evaluating co-occurring mental health conditions. Referrals should be provided as needed to social services, postpartum psychiatry or behavioral health services, OUD treatment and relapse-prevention programs, and harm reduction services (eg, naloxone training). In addition to the healthcare team, other community members can be enlisted to serve as a trusted, consistent, and nonjudgmental support during the hospitalization; examples may include a peer support (another mother with OUD), an OUD program caseworker, or a doula.⁴⁴

Clinical Pathways

Hospitals should establish clinical pathways for women with OUD to standardize care and communication across the continuum of care for themselves and their newborn, with input from all healthcare team members involved (prenatal, intrapartum, and postpartum).³⁵ Early, consistent information should be provided regarding expected newborn hospital course, including toxicology testing, NAS monitoring, possible NICU admission, and involvement of social work.

Provider Training

Educational opportunities in the form of continuing medical education, in-service trainings, etc., should be provided for clinical staff who care for mothers with OUD and their newborns, regarding issues of substance use, stigma, bias, and trauma-informed care.³⁵ Online training resources are available through the American Society of Addiction Medicine, the ACOG, AAP, the Centers for Disease Control and Prevention, and the Substance Abuse and Mental Health Services Administration.

Regardless of whether or not NAS is treated pharmacologically, newborns with opioid exposure may experience residual symptoms of withdrawal that persist for months.⁴ Current research suggests increased risk for morbidity, emergency department utilization, and rehospitalization after discharge in this population as well as difficulty in accessing and engaging with pediatric preventative care.^{45, 46}

A clear plan should be established upon discharge to ensure optimal newborn care and follow-up. A complete record of the newborn’s hospital stay, including maternal toxicology screenings and summary of any social work documentation, should be communicated to the primary care provider upon discharge. Close postdischarge monitoring involves addressing parenting knowledge gaps, assessing illness and injury risk, and evaluating for the presence of ongoing withdrawal symptoms.⁴ Primary care providers can also play a key role in assessing maternal stress, coping, and parenting skills as well as helping families connect to resources. Further research is warranted on how pediatric primary care systems can better build maternal trust, address parenting needs, and engage this population in routine well-child care.⁴⁷

Child Welfare, Early Intervention, and Other Services

In general, newborn safety and keeping families intact should be prioritized, with disposition into foster care only in cases of concern for child maltreatment or neglect. Under the Child Abuse Prevention and Treatment Act (CAPTA), states are required to develop Plans of Safe Care for women and newborns affected by OUD, with the goal of fostering collaboration between healthcare and social service organizations around care of these families.⁴⁸ Given the variable interpretation of Plans of Safe Care across the U.S., providers should be knowledgeable about state and local statutes and reporting requirements related to parental substance use.

As part of Plans of Safe Care, providers may be well-positioned to initiate referrals for early intervention, home visiting, and other programs designed to provide developmental or wrap-around support for families. Under Part C of the Individuals with Disabilities Education Act, many states offer early intervention on the basis of NAS as an automatic qualifying diagnosis; however, attrition of eligible families along the referral and enrollment process is substantial.⁴⁹ A standardized approach to discharging opioid-exposed newborns includes referrals to available resources and discussion of their importance with families and may increase utilization and decrease variation in care.⁵⁰

Maternal OUD presents a unique combination of medical and psychosocial challenges that affect hospital care for mothers and their newborns. Optimal care for this population warrants a multidisciplinary team of providers who are knowledgeable, collaborative, and mindful of the important role of the mother as a key participant in her newborn’s care. Despite a large and growing body of research focused on NAS prevention, screening, and treatment, ongoing efforts are needed to create hospital policies and clinical pathways that are responsive to the healthcare needs of this population, navigate sensitive issues of criminality and stigma, and ultimately support maternal parenting success.

Disclosures

The authors have no financial relationships and conflicts of interest relevant to this article to disclose.

Funding

Funding for this work was provided by Cincinnati Children’s Hospital Medical Center and Nemours/AI duPont Hospital for Children.

Urinary tract infections (UTIs) are the most common bacterial infection and one of the most common reasons for hospitalization in young infants.^1,2 The American Academy of Pediatrics (AAP) has published several clinical practice guidelines for the evaluation and management of febrile children ages 2-24 months with first-time UTIs, most recently in 2011 and affirmed in 2016.³ These guidelines do not provide recommendations for infants aged <2 months, which leads to uncertainty regarding the diagnosis and management of UTIs for infants in this age group. We assess the applicability of the AAP UTI Guideline’s action statements for infants aged <2 months presenting with first-time UTIs, with an emphasis on recent evidence. Because the considerations for bacterial infections differ for febrile infants aged <2 months compared with older infants, we do not discuss action statements one and two (determination of the likelihood of UTIs and decision to test urine) and statement seven (medical evaluation for fever after first UTI).³ Additionally, because concomitant bacteremia and meningitis are more common in this age group than in older infants, we review some of the controversies surrounding the diagnosis and treatment of these disease entities.

“Action Statement 3: To establish the diagnosis of UTI, clinicians should require both urinalysis results that suggest infection (pyuria and/or bacteriuria) and the presence of at least 50,000 colony-forming units (CFUs) per mL of a uropathogen cultured from a urine specimen obtained through catheterization or SPA.”³

To distinguish asymptomatic bacteriuria or contamination from a true UTI, the AAP Guideline requires both a positive urinalysis (UA) and culture for a diagnosis of a UTI.³ Historically, the UA was considered to be poorly sensitive for infections in young infants, with older studies reporting sensitivities ranging from 40% to 82% using urine culture as the gold standard.^4-7 Thus, infants aged <2 months with positive urine cultures and negative UAs are often treated as having true UTIs, though this practice varies by institution.⁸ Possible explanations for the low UA sensitivity in this population include rapid bladder emptying, immature immune systems, and inability to concentrate urine. However, a negative UA plus a positive urine culture could also represent a “true negative” UA and a “false positive” culture, a finding that may be more common in young infants in whom sterile urine obtainment is often challenging.

Two recent studies have addressed this issue by evaluating the UA sensitivity in patients with bacteremic UTIs, as growth of the same pathogenic organism from the blood and urine almost certainly represents true infection.^9,10 In a retrospective study of 203 infants aged <3 months with bacteremic UTIs, the presence of any leukocyte esterase (LE) or pyuria (>3 white blood cells per high-powered field [WBC/HPF]) had a sensitivity of 99.5% (95% CI: 98.5%-100%) and specificity of 93.9% (95% CI: 87.8%-93.2%).⁹ In a prospective, multicenter study of 4,147 febrile infants aged ≤60 days, of whom 27 infants had bacteremic UTIs, a positive UA (any LE, >5 WBC/HPF, or nitrite) had a sensitivity and specificity of 1.00 (95% CI: 0.87-1.00) and 0.91 (95% CI: 0.90-0.91), respectively.¹⁰ Although screening tests may appear to have higher sensitivity in more severely diseased populations (“spectrum bias”),¹¹ it is not clear that infants with bacteremic UTIs are definitively sicker than infants with nonbacteremic UTIs (see “bacteremic UTI” section below). Additionally, this study found similarly excellent sensitivity (0.94 [95% CI: 0.90-0.96]) and specificity (0.91 [95% CI: 0.90-0.91]) of the UA among infants with nonbacteremic UTIs, including infants <28 days old.¹⁰

UA sensitivity (using urine culture as the gold standard) may be lower for non-Escherichia coli UTIs.^9,10,12 In a retrospective study that included 90 infants <2 months old with UTIs, urine cultures yielding Pseudomonas aeruginosa, Enterococcus, or Klebsiella species were significantly less likely (odds ratio [95% CI]: 0.19 [0.06-0.60]; 0.14 [0.07-0.28]; 0.34 [0.17-0.68], respectively) to have pyuria (≥5 WBC/HPF) or LE (1+ or greater) than urine cultures yielding E. coli.,¹² though an alternative explanation for this finding is that these organisms may be more likely to cause asymptomatic bacteriuria or contamination.¹³

The appropriate CFU/mL threshold to define a UTI and the extent that this threshold should vary by urine collection methods are still unclear. In the aforementioned bacteremic UTI study,⁹ 12 patients with E. coli bacteremia had urine cultures with <50,000 CFU/mL plus pyuria (WBC or LE) in the UA, indicating that true UTIs may occur with <50,000 CFU/mL.

Based on these recent studies, we believe that the recommendation to incorporate UA results into the diagnoses of UTIs can be applied to infants <2 months old, as well as consideration for a UTI for colony counts of ≥10,000 CFU/mL if the UA is positive. For infants with positive urine cultures and negative UAs who have not received antibiotics, we suggest repeating both studies if treatment is being considered. For those who have started antibiotics, the pretest probability of a UTI, initial illness severity, and risks and benefits of continuing treatment should be considered.

“Action Statement 4a: When initiating treatment, the clinician should base the choice of route of administration on practical considerations. Initiating treatment orally or parenterally is equally efficacious. The clinician should base the choice of agent on local antimicrobial sensitivity patterns (if available) and should adjust the choice according to sensitivity testing of the isolated uropathogen.”³

Most infants <2 months old with UTIs are hospitalized initially because of fever. Therefore, the decision point for most clinicians is not whether to hospitalize but for how long to hospitalize and treat with intravenous (IV) antibiotics prior to discharging home on oral antibiotics. Although all-oral antibiotic regimens are used to treat UTIs in older infants and children,^14-18 to our knowledge, there are no randomized controlled trials (RCTs) comparing all-IV vs all-oral antibiotics or a longer vs shorter initial IV course that include infants <1 month old. In the trials that do include infants aged 1-2 months,^14,18 the number of subjects in this age group is too small to draw conclusions, a finding supported by a 2014 Cochrane review.¹⁹ An adequately powered RCT of different IV antibiotic durations in this age group would be challenging. For example, nearly 1,000 subjects would be needed to demonstrate a statistically significant difference between a 5% and 10% relapse risk between groups, a difference that some may find clinically important.

The paucity of evidence in this age group may explain the considerable variability in the approach to IV antibiotic duration in young infants. Concerns about enteral absorption and underdeveloped immune systems may prompt some physicians to treat the youngest patients more aggressively. One study demonstrated that the proportion of patients <2 months old receiving prolonged courses (≥4 days) of IV antibiotics for UTIs in 46 U.S. children’s hospitals ranged from 0% to 67%.²⁰ Similar variability across hospitals has been described in other observational studies^21,22 and across subspecialties in one survey of pediatricians.²³

Several observational studies provide additional evidence supporting shorter IV courses. In two studies that examined administrative databases, there was no difference in treatment failure rates between infants aged <2 months²⁰ and <6 months²¹ receiving longer (≥4 days) vs shorter IV courses. In a study of 172 infants <1 month old with UTIs, the median IV duration was 4 days (range 2-12 days), and no subjects experienced treatment failure or relapse.²⁴ In a multicenter study of 251 infants <3 months old with bacteremic UTIs, mean IV antibiotic durations ranged from 5.5–12 days, and no patient had a relapsed bacteremic UTI. Six infants (2.4%) had a relapsed UTI without bacteremia, with no association between IV antibiotic duration and relapse.²²

Based on the available data and known risks of hospitalization and prolonged IV therapy, a reasonable approach for infants <1 month old would be to hospitalize for two to three days while awaiting blood and cerebral spinal fluid (CSF) culture results. Given the possibility of Enterococcus or Enterobacteriaceae that are resistant to third-generation cephalosporins, standard therapy of ampicillin and gentamicin for febrile neonates is reasonable, assuming there is no concern for meningitis. Antibiotics should be narrowed when susceptibilities are known. Once culture results return and signs and symptoms have resolved, discharge home on oral antibiotics is justifiable based on the available literature. For well-appearing infants aged 1-2 months with a presumptive UTI (based on UA results), if hospitalization is not warranted for other reasons, then we recommend outpatient treatment with oral or intramuscular therapy based on local susceptibilities (typically a cephalosporin) and close follow-up for one to two days while awaiting culture results. Although empiric cephalosporin therapy may not provide 100% coverage for all potential organisms, clinical deterioration is uncommon in infants and children receiving discordant therapy.²⁵

“Action Statement 4b: The clinician should choose 7 to 14 days as the duration of antimicrobial therapy.”³

The AAP’s recommendation to provide antibiotics (by oral or parenteral route) for a minimum of seven days total stems from a 2002 meta-analysis comparing long (7-14 days) vs short (≤3 days) courses, where the pooled relative risk of treatment failure with short-course therapy was 1.94 (95% CI: 1.19-3.15).²⁶ However, in this analysis, the trials that demonstrated inferiority with short courses were all trials that used single doses of antibiotics, and a similar Cochrane review comparing 2-4 days with 7-14 days demonstrated no differences in outcomes.²⁷ Therefore, shorter total courses, but not a single dose, are probably appropriate for most UTIs in children. Although there are no obvious biologic reasons why longer total courses would be needed in young infants, there are unfortunately limited data comparing different total antibiotic durations in this age group. We believe that 7-14 days of total therapy is a reasonable recommendation for infants <2 months old, and that future studies should investigate shorter total courses.

“Action Statement 5: Febrile infants with UTIs should undergo renal and bladder ultrasonography (RBUS).”³

The AAP Guideline acknowledges that the RBUS is a poor screening test for the detection of genitourinary abnormalities in infants.³ The RBUS can be normal in infants with vesicoureteral reflux (VUR) or show nonspecific findings of unclear clinical significance.²⁸ In a prospective study of 220 infants <3 months old by Tsai et al, 9/39 infants (23%) with grade III-V VUR had normal RBUS.²⁹ Studies that included older infants have found a similar false-negative rate of 0%-40% for detecting grade IV-V VUR by RBUS.²⁸ Nonetheless, since a RBUS is safe and noninvasive, we feel that the benefits of screening for abnormalities such as hydronephrosis (that could indicate posterior urethral valves or ureteropelvic junction obstruction) outweigh the risks (eg, false positives, overdiagnosis, and cost) of performing a RBUS after a first-time UTI.

“Action Statement 6a: Voiding cystourethrography (VCUG) should not be performed routinely after the first febrile UTI; VCUG is indicated if RBUS reveals hydronephrosis, scarring, or other findings that would suggest either high-grade VUR or obstructive uropathy, as well as in other atypical or complex clinical circumstances.”³

“Action Statement 6b: Further evaluation should be conducted if there is a recurrence of febrile UTI.”³

The RBUS may be normal in infants with VUR. Therefore, the AAP’s recommendation to perform a VCUG only if the RBUS is abnormal or after a recurrent UTI concedes that there will be infants with VUR who are missed after the first UTI.³

The United Kingdom’s National Institute for Health and Care Excellence guideline recommends a VCUG for infants <6 months old with a bacteremic or non-E. coli UTI.³⁰ Whether high-grade VUR is more common in young infants with bacteremic UTIs than nonbacteremic UTIs remains inconclusive. In the Honkinen et al. study that included 87 infants <3 months old with bacteremic UTIs, the prevalence of grade IV-V VUR (10%) and obstruction (7%) was higher than that of the 88 nonbacteremic infants (2% grade IV-V VUR and 2% with obstruction). In the multicenter study of 251 infants <3 months old with bacteremic UTIs, the prevalence of grade IV-V VUR was 12.1%.³¹ This is higher than that of the nonbacteremic infants in Honkinen et al.’s study³² but more similar to the prevalence of grade IV-V VUR found in Tsai et al. (8.2%) and Ismaili et al.’s (7.0%) studies of UTIs in general.^29,33

There does appear to be a higher prevalence of urinary tract abnormalities in young infants with non-E. coli vs E. coli UTIs.^31,32,34,35 The odds of an abnormal VCUG was 8.0 (95% CI: 2.3-28) times higher for non-E. coli than E. coli UTIs in the study of 251 bacteremic infants.³¹ In a study of 122 infants <3 months old, the odds of grade III-V VUR was 10 (95% CI 2.6-41) times higher for non-E. coli than E. coli UTIs.³⁵

However, the need for early detection of VUR is controversial, and VCUGs are invasive, involve ionizing radiation, and may require sedation. Two recent trials (one which included only children with VUR and another in which 42% of subjects had VUR) demonstrated a modest effect of prophylactic antibiotics in preventing recurrent UTIs (>5,000 doses of antibiotics needed to prevent one UTI recurrence), but the effect size did not differ by the presence or degree of VUR, and neither demonstrated any benefit in reducing future renal scarring.^{36, 37} The benefit of surgical interventions for VUR also remains unclear, though studies are limited.³⁸ Overall, there is no evidence suggesting that infants <2 months old require more vigilance for VUR detection than the 2-24 month age group.

Bacteremic UTI

The prevalence of bacteremia in infants ≤60 days old with UTIs was 9% in a study conducted from 2008 to 2013 in 26 EDs and has ranged from 3% to 17% in older studies.^{10, 22} Many studies have described similar clinical and laboratory findings in young infants with bacteremic and nonbacteremic UTIs.^39-41 Despite this, bacteremic UTIs have been associated with prolonged parenteral antibiotic courses, resulting in longer hospitalizations and increased costs.⁴⁰ Two recent multicenter studies of infants with bacteremic UTIs (251 infants <3 months old²² and 115 infants ≤60 days old⁴²) demonstrated variable IV courses and no association between IV duration and relapsed UTI. The latter study showed no risk difference in the adjusted 30-day UTI recurrence (risk difference 3%, 95% CI: −5.8 to 12.7) or all-cause reutilization (risk difference 3%, 95% CI: −14.5 to 20.6) between long and short IV groups.⁴² Neither study had patients with relapsed bacteremic UTIs or reported that patients suffered clinical deterioration while on oral antibiotics.^22,42

Based on these data demonstrating that adverse outcomes are rare in infants with bacteremic UTIs and not associated with parenteral antibiotic duration, we recommend short parenteral courses (2-3 days) with conversion to oral therapy once infants have clinically improved.

Positive Urinalysis and Testing for Meningitis

Multiple risk stratification algorithms for febrile infants aged ≤60 days categorize infants with a positive UA (and therefore likely UTI) as high-risk for having concomitant bacteremia or meningitis, for which lumbar puncture (LP) is typically recommended.^43-45 The risk of not testing CSF is the potential to insufficiently treat meningitis because treatment for UTIs and meningitis differ in dosing, route, and duration. Recent studies have challenged the practice of routine LPs for infants aged 1-2 months with a suspected UTI due to the low prevalence (0%-0.3%) of concomitant meningitis.^39,46-48 A meta-analysis of 20 studies reporting rates of concomitant meningitis with UTI in infants aged 29-90 days found a pooled prevalence of 0.25% (95% CI: 0.09%-0.70%).⁴⁹ Furthermore, a study of febrile infants ages 29-60 days found that the prevalence of meningitis did not differ between those with a positive vs negative UA (3/337 [0.9%] vs 5/498 [1.0%], respectively), suggesting that a positive UA alone should not modify the pretest probability of meningitis in this age group.⁵⁰

Two studies have also examined the risk of delayed meningitis among infants ≤60 days old treated for UTIs without CSF testing. A northern California study that examined 345 episodes among 341 UA-positive infants aged 29-60 days found zero cases (95% CI: 0%-1.1%) of delayed meningitis within 30 days of evaluation.⁵⁰ A multicenter study of well-appearing febrile infants aged 7-60 days found 0/505 cases (95% CI: 0%-0.6%) of delayed meningitis within 7 days of discharge; 407 (81%) were aged 31-60 days.⁵¹ In summary, studies have shown a low rate of concomitant meningitis and a low risk of delayed meningitis in infants aged 1-2 months treated for UTI without CSF testing. Given this, clinically targeted (eg, based on ill appearance and/or lethargy), rather than routine, CSF testing in this age group can be considered.

While the AAP UTI Guideline is directed toward 2-24-month-old infants, recent evidence suggests that action statements 3-6 apply to infants <2 months old. Incorporation of pyuria as a diagnostic criterion for UTIs, early transition to oral therapy, and selective VCUG testing are all warranted based on the available evidence and consideration of known risks and benefits. Future studies with larger sample sizes that include infants <2 months old would be beneficial to ensure that the available studies, which have relatively small cohorts, do not suffer from type II error. We propose that future studies examine shorter (<7 days) vs longer total antibiotic duration, shorter vs longer initial IV antibiotics (especially in infants <1 month old or with bacteremic UTIs), and whether RBUS can be performed in a targeted manner. RCTs comparing universal vs targeted imaging strategies would help ascertain whether the increased diagnostic yield that accompanies more aggressive imaging strategies translates into improved outcomes. Application of these AAP guidelines to the <2-month age group and enhancement of the evidence base can promote the high-value care of young infants with UTIs.

Urinary tract infections (UTIs) are the most common bacterial infection and one of the most common reasons for hospitalization in young infants.^1,2 The American Academy of Pediatrics (AAP) has published several clinical practice guidelines for the evaluation and management of febrile children ages 2-24 months with first-time UTIs, most recently in 2011 and affirmed in 2016.³ These guidelines do not provide recommendations for infants aged <2 months, which leads to uncertainty regarding the diagnosis and management of UTIs for infants in this age group. We assess the applicability of the AAP UTI Guideline’s action statements for infants aged <2 months presenting with first-time UTIs, with an emphasis on recent evidence. Because the considerations for bacterial infections differ for febrile infants aged <2 months compared with older infants, we do not discuss action statements one and two (determination of the likelihood of UTIs and decision to test urine) and statement seven (medical evaluation for fever after first UTI).³ Additionally, because concomitant bacteremia and meningitis are more common in this age group than in older infants, we review some of the controversies surrounding the diagnosis and treatment of these disease entities.

“Action Statement 3: To establish the diagnosis of UTI, clinicians should require both urinalysis results that suggest infection (pyuria and/or bacteriuria) and the presence of at least 50,000 colony-forming units (CFUs) per mL of a uropathogen cultured from a urine specimen obtained through catheterization or SPA.”³

To distinguish asymptomatic bacteriuria or contamination from a true UTI, the AAP Guideline requires both a positive urinalysis (UA) and culture for a diagnosis of a UTI.³ Historically, the UA was considered to be poorly sensitive for infections in young infants, with older studies reporting sensitivities ranging from 40% to 82% using urine culture as the gold standard.^4-7 Thus, infants aged <2 months with positive urine cultures and negative UAs are often treated as having true UTIs, though this practice varies by institution.⁸ Possible explanations for the low UA sensitivity in this population include rapid bladder emptying, immature immune systems, and inability to concentrate urine. However, a negative UA plus a positive urine culture could also represent a “true negative” UA and a “false positive” culture, a finding that may be more common in young infants in whom sterile urine obtainment is often challenging.

Two recent studies have addressed this issue by evaluating the UA sensitivity in patients with bacteremic UTIs, as growth of the same pathogenic organism from the blood and urine almost certainly represents true infection.^9,10 In a retrospective study of 203 infants aged <3 months with bacteremic UTIs, the presence of any leukocyte esterase (LE) or pyuria (>3 white blood cells per high-powered field [WBC/HPF]) had a sensitivity of 99.5% (95% CI: 98.5%-100%) and specificity of 93.9% (95% CI: 87.8%-93.2%).⁹ In a prospective, multicenter study of 4,147 febrile infants aged ≤60 days, of whom 27 infants had bacteremic UTIs, a positive UA (any LE, >5 WBC/HPF, or nitrite) had a sensitivity and specificity of 1.00 (95% CI: 0.87-1.00) and 0.91 (95% CI: 0.90-0.91), respectively.¹⁰ Although screening tests may appear to have higher sensitivity in more severely diseased populations (“spectrum bias”),¹¹ it is not clear that infants with bacteremic UTIs are definitively sicker than infants with nonbacteremic UTIs (see “bacteremic UTI” section below). Additionally, this study found similarly excellent sensitivity (0.94 [95% CI: 0.90-0.96]) and specificity (0.91 [95% CI: 0.90-0.91]) of the UA among infants with nonbacteremic UTIs, including infants <28 days old.¹⁰

UA sensitivity (using urine culture as the gold standard) may be lower for non-Escherichia coli UTIs.^9,10,12 In a retrospective study that included 90 infants <2 months old with UTIs, urine cultures yielding Pseudomonas aeruginosa, Enterococcus, or Klebsiella species were significantly less likely (odds ratio [95% CI]: 0.19 [0.06-0.60]; 0.14 [0.07-0.28]; 0.34 [0.17-0.68], respectively) to have pyuria (≥5 WBC/HPF) or LE (1+ or greater) than urine cultures yielding E. coli.,¹² though an alternative explanation for this finding is that these organisms may be more likely to cause asymptomatic bacteriuria or contamination.¹³

The appropriate CFU/mL threshold to define a UTI and the extent that this threshold should vary by urine collection methods are still unclear. In the aforementioned bacteremic UTI study,⁹ 12 patients with E. coli bacteremia had urine cultures with <50,000 CFU/mL plus pyuria (WBC or LE) in the UA, indicating that true UTIs may occur with <50,000 CFU/mL.

Based on these recent studies, we believe that the recommendation to incorporate UA results into the diagnoses of UTIs can be applied to infants <2 months old, as well as consideration for a UTI for colony counts of ≥10,000 CFU/mL if the UA is positive. For infants with positive urine cultures and negative UAs who have not received antibiotics, we suggest repeating both studies if treatment is being considered. For those who have started antibiotics, the pretest probability of a UTI, initial illness severity, and risks and benefits of continuing treatment should be considered.

“Action Statement 4a: When initiating treatment, the clinician should base the choice of route of administration on practical considerations. Initiating treatment orally or parenterally is equally efficacious. The clinician should base the choice of agent on local antimicrobial sensitivity patterns (if available) and should adjust the choice according to sensitivity testing of the isolated uropathogen.”³

Most infants <2 months old with UTIs are hospitalized initially because of fever. Therefore, the decision point for most clinicians is not whether to hospitalize but for how long to hospitalize and treat with intravenous (IV) antibiotics prior to discharging home on oral antibiotics. Although all-oral antibiotic regimens are used to treat UTIs in older infants and children,^14-18 to our knowledge, there are no randomized controlled trials (RCTs) comparing all-IV vs all-oral antibiotics or a longer vs shorter initial IV course that include infants <1 month old. In the trials that do include infants aged 1-2 months,^14,18 the number of subjects in this age group is too small to draw conclusions, a finding supported by a 2014 Cochrane review.¹⁹ An adequately powered RCT of different IV antibiotic durations in this age group would be challenging. For example, nearly 1,000 subjects would be needed to demonstrate a statistically significant difference between a 5% and 10% relapse risk between groups, a difference that some may find clinically important.

The paucity of evidence in this age group may explain the considerable variability in the approach to IV antibiotic duration in young infants. Concerns about enteral absorption and underdeveloped immune systems may prompt some physicians to treat the youngest patients more aggressively. One study demonstrated that the proportion of patients <2 months old receiving prolonged courses (≥4 days) of IV antibiotics for UTIs in 46 U.S. children’s hospitals ranged from 0% to 67%.²⁰ Similar variability across hospitals has been described in other observational studies^21,22 and across subspecialties in one survey of pediatricians.²³

Several observational studies provide additional evidence supporting shorter IV courses. In two studies that examined administrative databases, there was no difference in treatment failure rates between infants aged <2 months²⁰ and <6 months²¹ receiving longer (≥4 days) vs shorter IV courses. In a study of 172 infants <1 month old with UTIs, the median IV duration was 4 days (range 2-12 days), and no subjects experienced treatment failure or relapse.²⁴ In a multicenter study of 251 infants <3 months old with bacteremic UTIs, mean IV antibiotic durations ranged from 5.5–12 days, and no patient had a relapsed bacteremic UTI. Six infants (2.4%) had a relapsed UTI without bacteremia, with no association between IV antibiotic duration and relapse.²²

Based on the available data and known risks of hospitalization and prolonged IV therapy, a reasonable approach for infants <1 month old would be to hospitalize for two to three days while awaiting blood and cerebral spinal fluid (CSF) culture results. Given the possibility of Enterococcus or Enterobacteriaceae that are resistant to third-generation cephalosporins, standard therapy of ampicillin and gentamicin for febrile neonates is reasonable, assuming there is no concern for meningitis. Antibiotics should be narrowed when susceptibilities are known. Once culture results return and signs and symptoms have resolved, discharge home on oral antibiotics is justifiable based on the available literature. For well-appearing infants aged 1-2 months with a presumptive UTI (based on UA results), if hospitalization is not warranted for other reasons, then we recommend outpatient treatment with oral or intramuscular therapy based on local susceptibilities (typically a cephalosporin) and close follow-up for one to two days while awaiting culture results. Although empiric cephalosporin therapy may not provide 100% coverage for all potential organisms, clinical deterioration is uncommon in infants and children receiving discordant therapy.²⁵

“Action Statement 4b: The clinician should choose 7 to 14 days as the duration of antimicrobial therapy.”³

The AAP’s recommendation to provide antibiotics (by oral or parenteral route) for a minimum of seven days total stems from a 2002 meta-analysis comparing long (7-14 days) vs short (≤3 days) courses, where the pooled relative risk of treatment failure with short-course therapy was 1.94 (95% CI: 1.19-3.15).²⁶ However, in this analysis, the trials that demonstrated inferiority with short courses were all trials that used single doses of antibiotics, and a similar Cochrane review comparing 2-4 days with 7-14 days demonstrated no differences in outcomes.²⁷ Therefore, shorter total courses, but not a single dose, are probably appropriate for most UTIs in children. Although there are no obvious biologic reasons why longer total courses would be needed in young infants, there are unfortunately limited data comparing different total antibiotic durations in this age group. We believe that 7-14 days of total therapy is a reasonable recommendation for infants <2 months old, and that future studies should investigate shorter total courses.

“Action Statement 5: Febrile infants with UTIs should undergo renal and bladder ultrasonography (RBUS).”³

The AAP Guideline acknowledges that the RBUS is a poor screening test for the detection of genitourinary abnormalities in infants.³ The RBUS can be normal in infants with vesicoureteral reflux (VUR) or show nonspecific findings of unclear clinical significance.²⁸ In a prospective study of 220 infants <3 months old by Tsai et al, 9/39 infants (23%) with grade III-V VUR had normal RBUS.²⁹ Studies that included older infants have found a similar false-negative rate of 0%-40% for detecting grade IV-V VUR by RBUS.²⁸ Nonetheless, since a RBUS is safe and noninvasive, we feel that the benefits of screening for abnormalities such as hydronephrosis (that could indicate posterior urethral valves or ureteropelvic junction obstruction) outweigh the risks (eg, false positives, overdiagnosis, and cost) of performing a RBUS after a first-time UTI.

“Action Statement 6a: Voiding cystourethrography (VCUG) should not be performed routinely after the first febrile UTI; VCUG is indicated if RBUS reveals hydronephrosis, scarring, or other findings that would suggest either high-grade VUR or obstructive uropathy, as well as in other atypical or complex clinical circumstances.”³

“Action Statement 6b: Further evaluation should be conducted if there is a recurrence of febrile UTI.”³

The RBUS may be normal in infants with VUR. Therefore, the AAP’s recommendation to perform a VCUG only if the RBUS is abnormal or after a recurrent UTI concedes that there will be infants with VUR who are missed after the first UTI.³

The United Kingdom’s National Institute for Health and Care Excellence guideline recommends a VCUG for infants <6 months old with a bacteremic or non-E. coli UTI.³⁰ Whether high-grade VUR is more common in young infants with bacteremic UTIs than nonbacteremic UTIs remains inconclusive. In the Honkinen et al. study that included 87 infants <3 months old with bacteremic UTIs, the prevalence of grade IV-V VUR (10%) and obstruction (7%) was higher than that of the 88 nonbacteremic infants (2% grade IV-V VUR and 2% with obstruction). In the multicenter study of 251 infants <3 months old with bacteremic UTIs, the prevalence of grade IV-V VUR was 12.1%.³¹ This is higher than that of the nonbacteremic infants in Honkinen et al.’s study³² but more similar to the prevalence of grade IV-V VUR found in Tsai et al. (8.2%) and Ismaili et al.’s (7.0%) studies of UTIs in general.^29,33

There does appear to be a higher prevalence of urinary tract abnormalities in young infants with non-E. coli vs E. coli UTIs.^31,32,34,35 The odds of an abnormal VCUG was 8.0 (95% CI: 2.3-28) times higher for non-E. coli than E. coli UTIs in the study of 251 bacteremic infants.³¹ In a study of 122 infants <3 months old, the odds of grade III-V VUR was 10 (95% CI 2.6-41) times higher for non-E. coli than E. coli UTIs.³⁵

However, the need for early detection of VUR is controversial, and VCUGs are invasive, involve ionizing radiation, and may require sedation. Two recent trials (one which included only children with VUR and another in which 42% of subjects had VUR) demonstrated a modest effect of prophylactic antibiotics in preventing recurrent UTIs (>5,000 doses of antibiotics needed to prevent one UTI recurrence), but the effect size did not differ by the presence or degree of VUR, and neither demonstrated any benefit in reducing future renal scarring.^{36, 37} The benefit of surgical interventions for VUR also remains unclear, though studies are limited.³⁸ Overall, there is no evidence suggesting that infants <2 months old require more vigilance for VUR detection than the 2-24 month age group.

Bacteremic UTI

The prevalence of bacteremia in infants ≤60 days old with UTIs was 9% in a study conducted from 2008 to 2013 in 26 EDs and has ranged from 3% to 17% in older studies.^{10, 22} Many studies have described similar clinical and laboratory findings in young infants with bacteremic and nonbacteremic UTIs.^39-41 Despite this, bacteremic UTIs have been associated with prolonged parenteral antibiotic courses, resulting in longer hospitalizations and increased costs.⁴⁰ Two recent multicenter studies of infants with bacteremic UTIs (251 infants <3 months old²² and 115 infants ≤60 days old⁴²) demonstrated variable IV courses and no association between IV duration and relapsed UTI. The latter study showed no risk difference in the adjusted 30-day UTI recurrence (risk difference 3%, 95% CI: −5.8 to 12.7) or all-cause reutilization (risk difference 3%, 95% CI: −14.5 to 20.6) between long and short IV groups.⁴² Neither study had patients with relapsed bacteremic UTIs or reported that patients suffered clinical deterioration while on oral antibiotics.^22,42

Based on these data demonstrating that adverse outcomes are rare in infants with bacteremic UTIs and not associated with parenteral antibiotic duration, we recommend short parenteral courses (2-3 days) with conversion to oral therapy once infants have clinically improved.

Positive Urinalysis and Testing for Meningitis

Multiple risk stratification algorithms for febrile infants aged ≤60 days categorize infants with a positive UA (and therefore likely UTI) as high-risk for having concomitant bacteremia or meningitis, for which lumbar puncture (LP) is typically recommended.^43-45 The risk of not testing CSF is the potential to insufficiently treat meningitis because treatment for UTIs and meningitis differ in dosing, route, and duration. Recent studies have challenged the practice of routine LPs for infants aged 1-2 months with a suspected UTI due to the low prevalence (0%-0.3%) of concomitant meningitis.^39,46-48 A meta-analysis of 20 studies reporting rates of concomitant meningitis with UTI in infants aged 29-90 days found a pooled prevalence of 0.25% (95% CI: 0.09%-0.70%).⁴⁹ Furthermore, a study of febrile infants ages 29-60 days found that the prevalence of meningitis did not differ between those with a positive vs negative UA (3/337 [0.9%] vs 5/498 [1.0%], respectively), suggesting that a positive UA alone should not modify the pretest probability of meningitis in this age group.⁵⁰

Two studies have also examined the risk of delayed meningitis among infants ≤60 days old treated for UTIs without CSF testing. A northern California study that examined 345 episodes among 341 UA-positive infants aged 29-60 days found zero cases (95% CI: 0%-1.1%) of delayed meningitis within 30 days of evaluation.⁵⁰ A multicenter study of well-appearing febrile infants aged 7-60 days found 0/505 cases (95% CI: 0%-0.6%) of delayed meningitis within 7 days of discharge; 407 (81%) were aged 31-60 days.⁵¹ In summary, studies have shown a low rate of concomitant meningitis and a low risk of delayed meningitis in infants aged 1-2 months treated for UTI without CSF testing. Given this, clinically targeted (eg, based on ill appearance and/or lethargy), rather than routine, CSF testing in this age group can be considered.

While the AAP UTI Guideline is directed toward 2-24-month-old infants, recent evidence suggests that action statements 3-6 apply to infants <2 months old. Incorporation of pyuria as a diagnostic criterion for UTIs, early transition to oral therapy, and selective VCUG testing are all warranted based on the available evidence and consideration of known risks and benefits. Future studies with larger sample sizes that include infants <2 months old would be beneficial to ensure that the available studies, which have relatively small cohorts, do not suffer from type II error. We propose that future studies examine shorter (<7 days) vs longer total antibiotic duration, shorter vs longer initial IV antibiotics (especially in infants <1 month old or with bacteremic UTIs), and whether RBUS can be performed in a targeted manner. RCTs comparing universal vs targeted imaging strategies would help ascertain whether the increased diagnostic yield that accompanies more aggressive imaging strategies translates into improved outcomes. Application of these AAP guidelines to the <2-month age group and enhancement of the evidence base can promote the high-value care of young infants with UTIs.

Urinary tract infections (UTIs) are the most common bacterial infection and one of the most common reasons for hospitalization in young infants.^1,2 The American Academy of Pediatrics (AAP) has published several clinical practice guidelines for the evaluation and management of febrile children ages 2-24 months with first-time UTIs, most recently in 2011 and affirmed in 2016.³ These guidelines do not provide recommendations for infants aged <2 months, which leads to uncertainty regarding the diagnosis and management of UTIs for infants in this age group. We assess the applicability of the AAP UTI Guideline’s action statements for infants aged <2 months presenting with first-time UTIs, with an emphasis on recent evidence. Because the considerations for bacterial infections differ for febrile infants aged <2 months compared with older infants, we do not discuss action statements one and two (determination of the likelihood of UTIs and decision to test urine) and statement seven (medical evaluation for fever after first UTI).³ Additionally, because concomitant bacteremia and meningitis are more common in this age group than in older infants, we review some of the controversies surrounding the diagnosis and treatment of these disease entities.

“Action Statement 3: To establish the diagnosis of UTI, clinicians should require both urinalysis results that suggest infection (pyuria and/or bacteriuria) and the presence of at least 50,000 colony-forming units (CFUs) per mL of a uropathogen cultured from a urine specimen obtained through catheterization or SPA.”³

To distinguish asymptomatic bacteriuria or contamination from a true UTI, the AAP Guideline requires both a positive urinalysis (UA) and culture for a diagnosis of a UTI.³ Historically, the UA was considered to be poorly sensitive for infections in young infants, with older studies reporting sensitivities ranging from 40% to 82% using urine culture as the gold standard.^4-7 Thus, infants aged <2 months with positive urine cultures and negative UAs are often treated as having true UTIs, though this practice varies by institution.⁸ Possible explanations for the low UA sensitivity in this population include rapid bladder emptying, immature immune systems, and inability to concentrate urine. However, a negative UA plus a positive urine culture could also represent a “true negative” UA and a “false positive” culture, a finding that may be more common in young infants in whom sterile urine obtainment is often challenging.

Two recent studies have addressed this issue by evaluating the UA sensitivity in patients with bacteremic UTIs, as growth of the same pathogenic organism from the blood and urine almost certainly represents true infection.^9,10 In a retrospective study of 203 infants aged <3 months with bacteremic UTIs, the presence of any leukocyte esterase (LE) or pyuria (>3 white blood cells per high-powered field [WBC/HPF]) had a sensitivity of 99.5% (95% CI: 98.5%-100%) and specificity of 93.9% (95% CI: 87.8%-93.2%).⁹ In a prospective, multicenter study of 4,147 febrile infants aged ≤60 days, of whom 27 infants had bacteremic UTIs, a positive UA (any LE, >5 WBC/HPF, or nitrite) had a sensitivity and specificity of 1.00 (95% CI: 0.87-1.00) and 0.91 (95% CI: 0.90-0.91), respectively.¹⁰ Although screening tests may appear to have higher sensitivity in more severely diseased populations (“spectrum bias”),¹¹ it is not clear that infants with bacteremic UTIs are definitively sicker than infants with nonbacteremic UTIs (see “bacteremic UTI” section below). Additionally, this study found similarly excellent sensitivity (0.94 [95% CI: 0.90-0.96]) and specificity (0.91 [95% CI: 0.90-0.91]) of the UA among infants with nonbacteremic UTIs, including infants <28 days old.¹⁰

UA sensitivity (using urine culture as the gold standard) may be lower for non-Escherichia coli UTIs.^9,10,12 In a retrospective study that included 90 infants <2 months old with UTIs, urine cultures yielding Pseudomonas aeruginosa, Enterococcus, or Klebsiella species were significantly less likely (odds ratio [95% CI]: 0.19 [0.06-0.60]; 0.14 [0.07-0.28]; 0.34 [0.17-0.68], respectively) to have pyuria (≥5 WBC/HPF) or LE (1+ or greater) than urine cultures yielding E. coli.,¹² though an alternative explanation for this finding is that these organisms may be more likely to cause asymptomatic bacteriuria or contamination.¹³

The appropriate CFU/mL threshold to define a UTI and the extent that this threshold should vary by urine collection methods are still unclear. In the aforementioned bacteremic UTI study,⁹ 12 patients with E. coli bacteremia had urine cultures with <50,000 CFU/mL plus pyuria (WBC or LE) in the UA, indicating that true UTIs may occur with <50,000 CFU/mL.

Based on these recent studies, we believe that the recommendation to incorporate UA results into the diagnoses of UTIs can be applied to infants <2 months old, as well as consideration for a UTI for colony counts of ≥10,000 CFU/mL if the UA is positive. For infants with positive urine cultures and negative UAs who have not received antibiotics, we suggest repeating both studies if treatment is being considered. For those who have started antibiotics, the pretest probability of a UTI, initial illness severity, and risks and benefits of continuing treatment should be considered.

“Action Statement 4a: When initiating treatment, the clinician should base the choice of route of administration on practical considerations. Initiating treatment orally or parenterally is equally efficacious. The clinician should base the choice of agent on local antimicrobial sensitivity patterns (if available) and should adjust the choice according to sensitivity testing of the isolated uropathogen.”³

Most infants <2 months old with UTIs are hospitalized initially because of fever. Therefore, the decision point for most clinicians is not whether to hospitalize but for how long to hospitalize and treat with intravenous (IV) antibiotics prior to discharging home on oral antibiotics. Although all-oral antibiotic regimens are used to treat UTIs in older infants and children,^14-18 to our knowledge, there are no randomized controlled trials (RCTs) comparing all-IV vs all-oral antibiotics or a longer vs shorter initial IV course that include infants <1 month old. In the trials that do include infants aged 1-2 months,^14,18 the number of subjects in this age group is too small to draw conclusions, a finding supported by a 2014 Cochrane review.¹⁹ An adequately powered RCT of different IV antibiotic durations in this age group would be challenging. For example, nearly 1,000 subjects would be needed to demonstrate a statistically significant difference between a 5% and 10% relapse risk between groups, a difference that some may find clinically important.

The paucity of evidence in this age group may explain the considerable variability in the approach to IV antibiotic duration in young infants. Concerns about enteral absorption and underdeveloped immune systems may prompt some physicians to treat the youngest patients more aggressively. One study demonstrated that the proportion of patients <2 months old receiving prolonged courses (≥4 days) of IV antibiotics for UTIs in 46 U.S. children’s hospitals ranged from 0% to 67%.²⁰ Similar variability across hospitals has been described in other observational studies^21,22 and across subspecialties in one survey of pediatricians.²³

Several observational studies provide additional evidence supporting shorter IV courses. In two studies that examined administrative databases, there was no difference in treatment failure rates between infants aged <2 months²⁰ and <6 months²¹ receiving longer (≥4 days) vs shorter IV courses. In a study of 172 infants <1 month old with UTIs, the median IV duration was 4 days (range 2-12 days), and no subjects experienced treatment failure or relapse.²⁴ In a multicenter study of 251 infants <3 months old with bacteremic UTIs, mean IV antibiotic durations ranged from 5.5–12 days, and no patient had a relapsed bacteremic UTI. Six infants (2.4%) had a relapsed UTI without bacteremia, with no association between IV antibiotic duration and relapse.²²

Based on the available data and known risks of hospitalization and prolonged IV therapy, a reasonable approach for infants <1 month old would be to hospitalize for two to three days while awaiting blood and cerebral spinal fluid (CSF) culture results. Given the possibility of Enterococcus or Enterobacteriaceae that are resistant to third-generation cephalosporins, standard therapy of ampicillin and gentamicin for febrile neonates is reasonable, assuming there is no concern for meningitis. Antibiotics should be narrowed when susceptibilities are known. Once culture results return and signs and symptoms have resolved, discharge home on oral antibiotics is justifiable based on the available literature. For well-appearing infants aged 1-2 months with a presumptive UTI (based on UA results), if hospitalization is not warranted for other reasons, then we recommend outpatient treatment with oral or intramuscular therapy based on local susceptibilities (typically a cephalosporin) and close follow-up for one to two days while awaiting culture results. Although empiric cephalosporin therapy may not provide 100% coverage for all potential organisms, clinical deterioration is uncommon in infants and children receiving discordant therapy.²⁵

“Action Statement 4b: The clinician should choose 7 to 14 days as the duration of antimicrobial therapy.”³

The AAP’s recommendation to provide antibiotics (by oral or parenteral route) for a minimum of seven days total stems from a 2002 meta-analysis comparing long (7-14 days) vs short (≤3 days) courses, where the pooled relative risk of treatment failure with short-course therapy was 1.94 (95% CI: 1.19-3.15).²⁶ However, in this analysis, the trials that demonstrated inferiority with short courses were all trials that used single doses of antibiotics, and a similar Cochrane review comparing 2-4 days with 7-14 days demonstrated no differences in outcomes.²⁷ Therefore, shorter total courses, but not a single dose, are probably appropriate for most UTIs in children. Although there are no obvious biologic reasons why longer total courses would be needed in young infants, there are unfortunately limited data comparing different total antibiotic durations in this age group. We believe that 7-14 days of total therapy is a reasonable recommendation for infants <2 months old, and that future studies should investigate shorter total courses.

“Action Statement 5: Febrile infants with UTIs should undergo renal and bladder ultrasonography (RBUS).”³

The AAP Guideline acknowledges that the RBUS is a poor screening test for the detection of genitourinary abnormalities in infants.³ The RBUS can be normal in infants with vesicoureteral reflux (VUR) or show nonspecific findings of unclear clinical significance.²⁸ In a prospective study of 220 infants <3 months old by Tsai et al, 9/39 infants (23%) with grade III-V VUR had normal RBUS.²⁹ Studies that included older infants have found a similar false-negative rate of 0%-40% for detecting grade IV-V VUR by RBUS.²⁸ Nonetheless, since a RBUS is safe and noninvasive, we feel that the benefits of screening for abnormalities such as hydronephrosis (that could indicate posterior urethral valves or ureteropelvic junction obstruction) outweigh the risks (eg, false positives, overdiagnosis, and cost) of performing a RBUS after a first-time UTI.

“Action Statement 6a: Voiding cystourethrography (VCUG) should not be performed routinely after the first febrile UTI; VCUG is indicated if RBUS reveals hydronephrosis, scarring, or other findings that would suggest either high-grade VUR or obstructive uropathy, as well as in other atypical or complex clinical circumstances.”³

“Action Statement 6b: Further evaluation should be conducted if there is a recurrence of febrile UTI.”³

The RBUS may be normal in infants with VUR. Therefore, the AAP’s recommendation to perform a VCUG only if the RBUS is abnormal or after a recurrent UTI concedes that there will be infants with VUR who are missed after the first UTI.³

The United Kingdom’s National Institute for Health and Care Excellence guideline recommends a VCUG for infants <6 months old with a bacteremic or non-E. coli UTI.³⁰ Whether high-grade VUR is more common in young infants with bacteremic UTIs than nonbacteremic UTIs remains inconclusive. In the Honkinen et al. study that included 87 infants <3 months old with bacteremic UTIs, the prevalence of grade IV-V VUR (10%) and obstruction (7%) was higher than that of the 88 nonbacteremic infants (2% grade IV-V VUR and 2% with obstruction). In the multicenter study of 251 infants <3 months old with bacteremic UTIs, the prevalence of grade IV-V VUR was 12.1%.³¹ This is higher than that of the nonbacteremic infants in Honkinen et al.’s study³² but more similar to the prevalence of grade IV-V VUR found in Tsai et al. (8.2%) and Ismaili et al.’s (7.0%) studies of UTIs in general.^29,33

There does appear to be a higher prevalence of urinary tract abnormalities in young infants with non-E. coli vs E. coli UTIs.^31,32,34,35 The odds of an abnormal VCUG was 8.0 (95% CI: 2.3-28) times higher for non-E. coli than E. coli UTIs in the study of 251 bacteremic infants.³¹ In a study of 122 infants <3 months old, the odds of grade III-V VUR was 10 (95% CI 2.6-41) times higher for non-E. coli than E. coli UTIs.³⁵

However, the need for early detection of VUR is controversial, and VCUGs are invasive, involve ionizing radiation, and may require sedation. Two recent trials (one which included only children with VUR and another in which 42% of subjects had VUR) demonstrated a modest effect of prophylactic antibiotics in preventing recurrent UTIs (>5,000 doses of antibiotics needed to prevent one UTI recurrence), but the effect size did not differ by the presence or degree of VUR, and neither demonstrated any benefit in reducing future renal scarring.^{36, 37} The benefit of surgical interventions for VUR also remains unclear, though studies are limited.³⁸ Overall, there is no evidence suggesting that infants <2 months old require more vigilance for VUR detection than the 2-24 month age group.

Bacteremic UTI

The prevalence of bacteremia in infants ≤60 days old with UTIs was 9% in a study conducted from 2008 to 2013 in 26 EDs and has ranged from 3% to 17% in older studies.^{10, 22} Many studies have described similar clinical and laboratory findings in young infants with bacteremic and nonbacteremic UTIs.^39-41 Despite this, bacteremic UTIs have been associated with prolonged parenteral antibiotic courses, resulting in longer hospitalizations and increased costs.⁴⁰ Two recent multicenter studies of infants with bacteremic UTIs (251 infants <3 months old²² and 115 infants ≤60 days old⁴²) demonstrated variable IV courses and no association between IV duration and relapsed UTI. The latter study showed no risk difference in the adjusted 30-day UTI recurrence (risk difference 3%, 95% CI: −5.8 to 12.7) or all-cause reutilization (risk difference 3%, 95% CI: −14.5 to 20.6) between long and short IV groups.⁴² Neither study had patients with relapsed bacteremic UTIs or reported that patients suffered clinical deterioration while on oral antibiotics.^22,42

Based on these data demonstrating that adverse outcomes are rare in infants with bacteremic UTIs and not associated with parenteral antibiotic duration, we recommend short parenteral courses (2-3 days) with conversion to oral therapy once infants have clinically improved.

Positive Urinalysis and Testing for Meningitis

Multiple risk stratification algorithms for febrile infants aged ≤60 days categorize infants with a positive UA (and therefore likely UTI) as high-risk for having concomitant bacteremia or meningitis, for which lumbar puncture (LP) is typically recommended.^43-45 The risk of not testing CSF is the potential to insufficiently treat meningitis because treatment for UTIs and meningitis differ in dosing, route, and duration. Recent studies have challenged the practice of routine LPs for infants aged 1-2 months with a suspected UTI due to the low prevalence (0%-0.3%) of concomitant meningitis.^39,46-48 A meta-analysis of 20 studies reporting rates of concomitant meningitis with UTI in infants aged 29-90 days found a pooled prevalence of 0.25% (95% CI: 0.09%-0.70%).⁴⁹ Furthermore, a study of febrile infants ages 29-60 days found that the prevalence of meningitis did not differ between those with a positive vs negative UA (3/337 [0.9%] vs 5/498 [1.0%], respectively), suggesting that a positive UA alone should not modify the pretest probability of meningitis in this age group.⁵⁰

Two studies have also examined the risk of delayed meningitis among infants ≤60 days old treated for UTIs without CSF testing. A northern California study that examined 345 episodes among 341 UA-positive infants aged 29-60 days found zero cases (95% CI: 0%-1.1%) of delayed meningitis within 30 days of evaluation.⁵⁰ A multicenter study of well-appearing febrile infants aged 7-60 days found 0/505 cases (95% CI: 0%-0.6%) of delayed meningitis within 7 days of discharge; 407 (81%) were aged 31-60 days.⁵¹ In summary, studies have shown a low rate of concomitant meningitis and a low risk of delayed meningitis in infants aged 1-2 months treated for UTI without CSF testing. Given this, clinically targeted (eg, based on ill appearance and/or lethargy), rather than routine, CSF testing in this age group can be considered.

While the AAP UTI Guideline is directed toward 2-24-month-old infants, recent evidence suggests that action statements 3-6 apply to infants <2 months old. Incorporation of pyuria as a diagnostic criterion for UTIs, early transition to oral therapy, and selective VCUG testing are all warranted based on the available evidence and consideration of known risks and benefits. Future studies with larger sample sizes that include infants <2 months old would be beneficial to ensure that the available studies, which have relatively small cohorts, do not suffer from type II error. We propose that future studies examine shorter (<7 days) vs longer total antibiotic duration, shorter vs longer initial IV antibiotics (especially in infants <1 month old or with bacteremic UTIs), and whether RBUS can be performed in a targeted manner. RCTs comparing universal vs targeted imaging strategies would help ascertain whether the increased diagnostic yield that accompanies more aggressive imaging strategies translates into improved outcomes. Application of these AAP guidelines to the <2-month age group and enhancement of the evidence base can promote the high-value care of young infants with UTIs.

Challenges in conducting and completing studies of drugs in vulnerable populations, such as hospitalized children, include weak study designs and lack of sufficient sample sizes to achieve adequate power.¹ Limitations in the amount of blood that can be safely drawn in children and low parental consent rates due to concerns for anemia or pain, if venipuncture is required, lead to an insufficient number of patients enrolled in traditional clinical studies.² Thus, sample size targets are often not met. Recognizing the limited pediatric data for many drugs routinely prescribed off-label in children, the Food and Drug Administration implemented the Best Pharmaceuticals Children Act and the Pediatric Research Equity Act (PREA) in 2003; these legislative acts require clinical studies to assess the safety and efficacy of new drugs in children.¹ While studies conducted under these acts have provided important information for the clinical care of children, only one-third of mandatory pediatric postmarketing studies of the 114 new drugs and new indications subject to PREA requirements between 2007 and 2014 had been completed within seven years.³

Despite the challenges in conducting studies of drugs in children, robust pediatric data must be generated in children, especially in those with medical complexity or with chronic medical diseases and who have significant risk of experiencing adverse drug events. Data in adults cannot simply be extrapolated to children. In addition, studies from healthy children may not apply to hospitalized pediatric patients because of significant physiologic changes that occur in children who are ill enough to be hospitalized. Opportunistic sampling can provide robust drug disposition data and overcome some of the challenges encountered by traditional drug studies. In this Methodologic Progress Note, we describe the utility of opportunistic sampling as a research tool for hospitalists, in partnership with clinical pharmacologists, to study drug pharmacokinetics (PK) in hospitalized children.

Opportunistic sampling relies on the use of blood samples that are ordered for clinical purposes, and its use is endorsed by the Pediatric Trials Network.^2,5 Opportunistic sampling approaches have two types: sparse sampling and scavenged or remnant sampling. In sparse opportunistic sampling, additional blood is obtained at the same time clinical samples are ordered, avoiding the need for additional punctures.⁵ This approach requires bedside personnel to obtain additional blood that is sent to the research team for further processing. Scavenged sampling relies on leftover residual blood from clinical samples.^2,5 After the clinical laboratory performs the laboratory test ordered by the clinical team, the research team can scavenge residual blood for measurement of drug concentrations. When drug concentrations are measured from multiple patients, clinical pharmacologists can perform population PK modeling to characterize the pharmacokinetics of the drug and its variability within the population level.

The Figure shows how scavenged samples from hypothetical patients could be used to generate a PK curve. In this example, three patients are admitted for osteomyelitis and treated with the same antibiotic administered every eight hours, as shown by the theoretical concentration versus time profiles in the top panel. To determine the effectiveness of treatment and timing of transition to enteral antibiotics, the clinical team orders C-reactive protein (CRP) approximately every 48 hours for each patient. Each patient has his/her first dose of antibiotic at a different time of day depending on the time of admission or surgical drainage. Therefore, the timing of the blood draw with respect to the most recent antibiotic dose varies between patients even if blood draws are ordered at the same time for all patients (ie, 4 am lab draw). For patient 1, the blood draws occur approximately three to five hours after the second and eighth antibiotic doses (Figure, top panel). After the clinical laboratory measures the CRP, the research team scavenges residual blood from the lab samples and measures antibiotic concentrations. The antibiotic concentrations are then plotted on a concentration vs time after most recent dose. (Figure, bottom panel). Patient 2 has blood drawn five to seven hours after the first and seventh antibiotic doses. The third patient has blood drawn within two hours after the second and eighth antibiotic doses. As more samples are collected from additional patients, population PK modeling provides a robust description of the central tendency of the concentration vs time profile. More important, as more patients are included, the interpatient variability in concentrations can be described within the population, which often cannot be performed well with the smaller numbers of patients enrolled in traditional PK studies.

Opportunistic sampling has advantages over traditional intensive PK studies that often require multiple blood draws (typically >8-10) within one dosing interval to adequately describe the phases of absorption, distribution, metabolism, and elimination. The number of vascular punctures can be painful if blood cannot be drawn from existing vascular access, and the large amount of blood (sometimes >1 mL/sample) required for these studies can be impractical, burdensome, and even dangerous in young children and neonates. Scavenged sampling reduces the risk of anemia because no additional blood is drawn beyond what is obtained for clinical purposes, and it does not disrupt nursing workflow or add to nursing workload. Approval to use scavenged blood requires approval from the institutional review board. At some institutions, the consent to treat form on admission may address the use of scavenged samples and therefore allow for waiver of consent. In addition, the consent process may occur retroactively after samples are collected. These methods lead to increased enrollment.

Limitations in this approach are that drugs may degrade over time in whole blood or processed samples. Therefore, the process by which the clinical laboratory stores the residual blood after clinical tests must be understood, and the stability of the drug or metabolite of interest in blood or plasma over time must be ensured. In addition, residual blood may not be present after a clinical test, and recording times of the drug administration and lab draws may be inaccurate.^2,5

Challenges in conducting and completing studies of drugs in vulnerable populations, such as hospitalized children, include weak study designs and lack of sufficient sample sizes to achieve adequate power.¹ Limitations in the amount of blood that can be safely drawn in children and low parental consent rates due to concerns for anemia or pain, if venipuncture is required, lead to an insufficient number of patients enrolled in traditional clinical studies.² Thus, sample size targets are often not met. Recognizing the limited pediatric data for many drugs routinely prescribed off-label in children, the Food and Drug Administration implemented the Best Pharmaceuticals Children Act and the Pediatric Research Equity Act (PREA) in 2003; these legislative acts require clinical studies to assess the safety and efficacy of new drugs in children.¹ While studies conducted under these acts have provided important information for the clinical care of children, only one-third of mandatory pediatric postmarketing studies of the 114 new drugs and new indications subject to PREA requirements between 2007 and 2014 had been completed within seven years.³

Despite the challenges in conducting studies of drugs in children, robust pediatric data must be generated in children, especially in those with medical complexity or with chronic medical diseases and who have significant risk of experiencing adverse drug events. Data in adults cannot simply be extrapolated to children. In addition, studies from healthy children may not apply to hospitalized pediatric patients because of significant physiologic changes that occur in children who are ill enough to be hospitalized. Opportunistic sampling can provide robust drug disposition data and overcome some of the challenges encountered by traditional drug studies. In this Methodologic Progress Note, we describe the utility of opportunistic sampling as a research tool for hospitalists, in partnership with clinical pharmacologists, to study drug pharmacokinetics (PK) in hospitalized children.

Opportunistic sampling relies on the use of blood samples that are ordered for clinical purposes, and its use is endorsed by the Pediatric Trials Network.^2,5 Opportunistic sampling approaches have two types: sparse sampling and scavenged or remnant sampling. In sparse opportunistic sampling, additional blood is obtained at the same time clinical samples are ordered, avoiding the need for additional punctures.⁵ This approach requires bedside personnel to obtain additional blood that is sent to the research team for further processing. Scavenged sampling relies on leftover residual blood from clinical samples.^2,5 After the clinical laboratory performs the laboratory test ordered by the clinical team, the research team can scavenge residual blood for measurement of drug concentrations. When drug concentrations are measured from multiple patients, clinical pharmacologists can perform population PK modeling to characterize the pharmacokinetics of the drug and its variability within the population level.

The Figure shows how scavenged samples from hypothetical patients could be used to generate a PK curve. In this example, three patients are admitted for osteomyelitis and treated with the same antibiotic administered every eight hours, as shown by the theoretical concentration versus time profiles in the top panel. To determine the effectiveness of treatment and timing of transition to enteral antibiotics, the clinical team orders C-reactive protein (CRP) approximately every 48 hours for each patient. Each patient has his/her first dose of antibiotic at a different time of day depending on the time of admission or surgical drainage. Therefore, the timing of the blood draw with respect to the most recent antibiotic dose varies between patients even if blood draws are ordered at the same time for all patients (ie, 4 am lab draw). For patient 1, the blood draws occur approximately three to five hours after the second and eighth antibiotic doses (Figure, top panel). After the clinical laboratory measures the CRP, the research team scavenges residual blood from the lab samples and measures antibiotic concentrations. The antibiotic concentrations are then plotted on a concentration vs time after most recent dose. (Figure, bottom panel). Patient 2 has blood drawn five to seven hours after the first and seventh antibiotic doses. The third patient has blood drawn within two hours after the second and eighth antibiotic doses. As more samples are collected from additional patients, population PK modeling provides a robust description of the central tendency of the concentration vs time profile. More important, as more patients are included, the interpatient variability in concentrations can be described within the population, which often cannot be performed well with the smaller numbers of patients enrolled in traditional PK studies.

Opportunistic sampling has advantages over traditional intensive PK studies that often require multiple blood draws (typically >8-10) within one dosing interval to adequately describe the phases of absorption, distribution, metabolism, and elimination. The number of vascular punctures can be painful if blood cannot be drawn from existing vascular access, and the large amount of blood (sometimes >1 mL/sample) required for these studies can be impractical, burdensome, and even dangerous in young children and neonates. Scavenged sampling reduces the risk of anemia because no additional blood is drawn beyond what is obtained for clinical purposes, and it does not disrupt nursing workflow or add to nursing workload. Approval to use scavenged blood requires approval from the institutional review board. At some institutions, the consent to treat form on admission may address the use of scavenged samples and therefore allow for waiver of consent. In addition, the consent process may occur retroactively after samples are collected. These methods lead to increased enrollment.

Limitations in this approach are that drugs may degrade over time in whole blood or processed samples. Therefore, the process by which the clinical laboratory stores the residual blood after clinical tests must be understood, and the stability of the drug or metabolite of interest in blood or plasma over time must be ensured. In addition, residual blood may not be present after a clinical test, and recording times of the drug administration and lab draws may be inaccurate.^2,5

Challenges in conducting and completing studies of drugs in vulnerable populations, such as hospitalized children, include weak study designs and lack of sufficient sample sizes to achieve adequate power.¹ Limitations in the amount of blood that can be safely drawn in children and low parental consent rates due to concerns for anemia or pain, if venipuncture is required, lead to an insufficient number of patients enrolled in traditional clinical studies.² Thus, sample size targets are often not met. Recognizing the limited pediatric data for many drugs routinely prescribed off-label in children, the Food and Drug Administration implemented the Best Pharmaceuticals Children Act and the Pediatric Research Equity Act (PREA) in 2003; these legislative acts require clinical studies to assess the safety and efficacy of new drugs in children.¹ While studies conducted under these acts have provided important information for the clinical care of children, only one-third of mandatory pediatric postmarketing studies of the 114 new drugs and new indications subject to PREA requirements between 2007 and 2014 had been completed within seven years.³

Despite the challenges in conducting studies of drugs in children, robust pediatric data must be generated in children, especially in those with medical complexity or with chronic medical diseases and who have significant risk of experiencing adverse drug events. Data in adults cannot simply be extrapolated to children. In addition, studies from healthy children may not apply to hospitalized pediatric patients because of significant physiologic changes that occur in children who are ill enough to be hospitalized. Opportunistic sampling can provide robust drug disposition data and overcome some of the challenges encountered by traditional drug studies. In this Methodologic Progress Note, we describe the utility of opportunistic sampling as a research tool for hospitalists, in partnership with clinical pharmacologists, to study drug pharmacokinetics (PK) in hospitalized children.

Opportunistic sampling relies on the use of blood samples that are ordered for clinical purposes, and its use is endorsed by the Pediatric Trials Network.^2,5 Opportunistic sampling approaches have two types: sparse sampling and scavenged or remnant sampling. In sparse opportunistic sampling, additional blood is obtained at the same time clinical samples are ordered, avoiding the need for additional punctures.⁵ This approach requires bedside personnel to obtain additional blood that is sent to the research team for further processing. Scavenged sampling relies on leftover residual blood from clinical samples.^2,5 After the clinical laboratory performs the laboratory test ordered by the clinical team, the research team can scavenge residual blood for measurement of drug concentrations. When drug concentrations are measured from multiple patients, clinical pharmacologists can perform population PK modeling to characterize the pharmacokinetics of the drug and its variability within the population level.

The Figure shows how scavenged samples from hypothetical patients could be used to generate a PK curve. In this example, three patients are admitted for osteomyelitis and treated with the same antibiotic administered every eight hours, as shown by the theoretical concentration versus time profiles in the top panel. To determine the effectiveness of treatment and timing of transition to enteral antibiotics, the clinical team orders C-reactive protein (CRP) approximately every 48 hours for each patient. Each patient has his/her first dose of antibiotic at a different time of day depending on the time of admission or surgical drainage. Therefore, the timing of the blood draw with respect to the most recent antibiotic dose varies between patients even if blood draws are ordered at the same time for all patients (ie, 4 am lab draw). For patient 1, the blood draws occur approximately three to five hours after the second and eighth antibiotic doses (Figure, top panel). After the clinical laboratory measures the CRP, the research team scavenges residual blood from the lab samples and measures antibiotic concentrations. The antibiotic concentrations are then plotted on a concentration vs time after most recent dose. (Figure, bottom panel). Patient 2 has blood drawn five to seven hours after the first and seventh antibiotic doses. The third patient has blood drawn within two hours after the second and eighth antibiotic doses. As more samples are collected from additional patients, population PK modeling provides a robust description of the central tendency of the concentration vs time profile. More important, as more patients are included, the interpatient variability in concentrations can be described within the population, which often cannot be performed well with the smaller numbers of patients enrolled in traditional PK studies.

Opportunistic sampling has advantages over traditional intensive PK studies that often require multiple blood draws (typically >8-10) within one dosing interval to adequately describe the phases of absorption, distribution, metabolism, and elimination. The number of vascular punctures can be painful if blood cannot be drawn from existing vascular access, and the large amount of blood (sometimes >1 mL/sample) required for these studies can be impractical, burdensome, and even dangerous in young children and neonates. Scavenged sampling reduces the risk of anemia because no additional blood is drawn beyond what is obtained for clinical purposes, and it does not disrupt nursing workflow or add to nursing workload. Approval to use scavenged blood requires approval from the institutional review board. At some institutions, the consent to treat form on admission may address the use of scavenged samples and therefore allow for waiver of consent. In addition, the consent process may occur retroactively after samples are collected. These methods lead to increased enrollment.

Limitations in this approach are that drugs may degrade over time in whole blood or processed samples. Therefore, the process by which the clinical laboratory stores the residual blood after clinical tests must be understood, and the stability of the drug or metabolite of interest in blood or plasma over time must be ensured. In addition, residual blood may not be present after a clinical test, and recording times of the drug administration and lab draws may be inaccurate.^2,5

Pediatric hospital medicine (PHM) is in the midst of an exciting period of growth. In 2016, the American Board of Medical Specialties approved the petition for PHM to become the newest pediatric subspecialty, taking PHM on a divergent path from the Focused Practice in Hospital Medicine designation established for adult hospitalists. Establishment as a subspecialty has allowed PHM to define the unique skills and qualifications that hospitalists bring to patients and the healthcare system. These skills and qualifications are delineated in the PHM core competencies and national fellowship curriculum.^1,2 In order to realize the vision of PHM to improve care for hospitalized children described by Roberts et al.,³ concerted efforts are needed to train and retain a workforce that is equipped with the skills to catalyze improvements in inpatient pediatric care. We discuss challenges and opportunities facing PHM in workforce development, sustainability of clinical work models, and interhospital collaboration.

The development of PHM as a subspecialty was driven by a number of factors.⁴ The acuity of hospitalized children has increased significantly, with a population comprised of more children with complex chronic conditions and/or technology dependence, serious complications of acute conditions, and acute mental health problems. At the same time, the medical and behavioral conditions seen by outpatient general pediatricians have become more complex and time intensive, with these practitioners less likely to work in inpatient settings. Hospitalist care has positive impacts on healthcare efficiency and value, and both parents and primary care pediatricians report high levels of satisfaction with the healthcare delivered by PHM services.⁴

A national count of the number of pediatric hospitalists is currently lacking. Conservative estimates suggest that at least 3,000 pediatric hospitalists currently practice in the United States.⁵ These hospitalists have highly varied scopes of practice and work across diverse settings—more diverse, perhaps, than any other pediatric subspecialty. Although difficult to quantify, we estimate that approximately one-third of pediatric hospitalists in the US work in community hospitals and the remainder practice at children’s hospitals.⁶ Many of the needs of hospitalized children differ across these settings, and the roles and challenges faced by hospitalists in these settings correspondingly differ. Community hospitalists frequently take active roles in newborn care and emergency department consultation, often without the support of other pediatric subspecialties.⁷ In contrast, hospitalists working at children’s hospitals more frequently care for highly complex patients, often collaborate across multiple specialties and assume nonclinical roles in quality improvement (QI), research, and medical education.

Residents graduating in July 2019 were the last cohort of residents eligible to pursue PHM subspecialty certification via the practice pathway. Accordingly, future residency graduates interested in PHM subspecialty certification will need to complete a PHM fellowship at an accredited program in the US or Canada. Since 2008, PHM fellowship directors have met yearly to collaborate and share best practices,⁸ developing the two-year fellowship curriculum that forms the basis for the American Board of Pediatrics training pathway.² The curriculum allows significant flexibility to meet diverse needs, including tailored content for fellows planning to practice in community settings, fellows planning research careers, medicine-pediatrics hospitalist careers, and those desiring increased training in QI, medical education, or leadership/administration.² In the spring of 2019, Pediatric Research in Inpatient Settings (PRIS) leadership, directors of existing PHM fellowship programs, and national academic society representatives met to develop a fellows’ research curriculum, training resources, and guidelines around scholarship expectations.⁹ This collaboration aims to accelerate the growth of high-quality clinical training and scholarship to benefit hospitalized children across many different settings.

Such collaboration is essential to address an emerging workforce challenge in PHM. Although the number of PHM fellowship positions is expected to grow in the coming years, there is currently a shortage relative to the anticipated demand. With approximately 2,800 US pediatric residents graduating annually and data indicating that 7% of graduating residents enter and remain in PHM for at least five years,^10,11 almost 200 fellowship spots may be needed each year. As of November 2019, 77 fellowship positions were available for residents graduating in 2020,¹² which is less than half of the potential demand. To address this mismatch, the PHM Fellowship Directors’ Council has led an annual training for new and potential fellowship directors, and 18 new programs are under development.¹³ However, this growth may be inadequate to meet the needs of the field. The extent to which limited PHM fellowship positions will adversely affect the pipeline of pediatricians pursuing PHM is unknown.

Efforts to support institutions in creating and expanding fellowship programs will be needed to address the potential shortage of fellowship positions. Continued guidance from the PHM Fellowship Directors’ Council in the many aspects of fellowship program development (eg, curriculum design, assessment) will be crucial in this endeavor. Furthermore, given that fellowships must support fellows to conduct scholarly work and demonstrate evidence of robust faculty scholarly activities to attain accreditation, an essential area of focus is faculty development. Considering barriers such as lack of time, mentorship, and resources, some divisions interested in starting a fellowship may find it challenging to achieve these standards.¹⁴ However, hospitalists are often engaged in areas such as QI and medical education, and there is potential to turn ongoing work into meaningful scholarship with appropriate guidance. Many of our supporting organizations (eg, Academic Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine) provide training programs for faculty in areas such as educational scholarship, research, and QI; however, more may be needed. Leaders of PHM programs will need to be mindful and creative in accessing local, regional, and national resources to invest in faculty development.

As a group, pediatric hospitalists report high levels of satisfaction with their jobs.¹¹ Despite this finding, there are a number of threats to the sustainability of current work models, some of which are unique to pediatrics given the overall lower patient volumes and greater seasonal variation compared with adult hospital medicine. Both university and community-based hospitalist programs report high weekend, overnight, and in-house clinical effort.^7,15 Recent studies reported that a significant proportion of PHM program leaders (50% of division directors at university-affiliated programs and 37% of community program leaders) perceive their program to be unsustainable.^7,15 Among university-affiliated programs, a higher burden of weekend work as well as university employment were associated with perceived unsustainability, while no specific program or employer characteristic was associated with this perception in community programs.

These findings indicate that efforts are needed to address PHM program sustainability and that different work models and interventions may be needed for university-based and community PHM programs. Wide variability exists in the ways that programs address overall clinical burden, with strategies including census caps, seasonal expansion of coverage, and formal back-up systems.^7,15 Additional potential solutions may include differential weighting or financial incentives for nights and weekends, support for nonclinical work, loan repayment programs, and competitive salaries.¹¹ In addition, structuring clinical and nonclinical roles to facilitate career development and advancement may enhance career longevity.¹⁵ Lessons learned from pediatric emergency medicine (PEM), which developed as a field a few decades ahead of PHM, may predict future challenges. A 2015 survey of PEM faculty found that despite a 15% decrease in weekly work hours over a 15-year period, a substantial number of PEM faculty report concerns about burnout, with 40% reporting a plan to decrease their clinical workload and 13% planning to leave the field within five years.¹⁶ Like PEM, the field of PHM may benefit from the development of best practice guidelines to improve well-being and career longevity.¹⁷

The culture of collaboration within PHM places the field in a solid position to address both workforce challenges and barriers to high-quality care for hospitalized children. There are several hospital-based learning networks actively working to strengthen our knowledge base and improve healthcare quality. The PRIS network (www.prisnetwork.org) aims to improve healthcare for children through multihospital studies, boasting 114 sites in the US and Canada. Numerous collaborative projects have linked hospitalists across programs to tackle problems ranging from handoff communication¹⁸ to eliminating monitor overuse.¹⁹ The Value in Inpatient Pediatrics network has similarly leveraged collaborations across multiple children’s and community hospitals to improve transitions of care²⁰ and care for common conditions such as bronchiolitis, febrile infants, and asthma.²¹ These networks serve as models of effective collaboration between children’s hospitals and community hospitals, more of which is needed to increase research and QI initiatives in community hospitals, where the majority of US children receive their hospital-based care.^6,22

With the rapid growth of scholarly networks in research, QI, and education, PHM has a solid infrastructure on which to base continued development as a subspeciality. Building on this infrastructure will be essential in order to address current challenges in workforce development, fellowship training, and program sustainability. Ultimately, achieving a strong, stable, and skilled workforce will enable PHM to fulfill its promise of improving the care of children across the diversity of settings where they receive their hospital-based care.

Disclosures

Dr. Leyenaar provides consultative services to the American Board of Pediatrics Foundation, which is not associated with this manuscript. Drs. Wang and Shaughnessy have no disclosures

Pediatric hospital medicine (PHM) is in the midst of an exciting period of growth. In 2016, the American Board of Medical Specialties approved the petition for PHM to become the newest pediatric subspecialty, taking PHM on a divergent path from the Focused Practice in Hospital Medicine designation established for adult hospitalists. Establishment as a subspecialty has allowed PHM to define the unique skills and qualifications that hospitalists bring to patients and the healthcare system. These skills and qualifications are delineated in the PHM core competencies and national fellowship curriculum.^1,2 In order to realize the vision of PHM to improve care for hospitalized children described by Roberts et al.,³ concerted efforts are needed to train and retain a workforce that is equipped with the skills to catalyze improvements in inpatient pediatric care. We discuss challenges and opportunities facing PHM in workforce development, sustainability of clinical work models, and interhospital collaboration.

The development of PHM as a subspecialty was driven by a number of factors.⁴ The acuity of hospitalized children has increased significantly, with a population comprised of more children with complex chronic conditions and/or technology dependence, serious complications of acute conditions, and acute mental health problems. At the same time, the medical and behavioral conditions seen by outpatient general pediatricians have become more complex and time intensive, with these practitioners less likely to work in inpatient settings. Hospitalist care has positive impacts on healthcare efficiency and value, and both parents and primary care pediatricians report high levels of satisfaction with the healthcare delivered by PHM services.⁴

A national count of the number of pediatric hospitalists is currently lacking. Conservative estimates suggest that at least 3,000 pediatric hospitalists currently practice in the United States.⁵ These hospitalists have highly varied scopes of practice and work across diverse settings—more diverse, perhaps, than any other pediatric subspecialty. Although difficult to quantify, we estimate that approximately one-third of pediatric hospitalists in the US work in community hospitals and the remainder practice at children’s hospitals.⁶ Many of the needs of hospitalized children differ across these settings, and the roles and challenges faced by hospitalists in these settings correspondingly differ. Community hospitalists frequently take active roles in newborn care and emergency department consultation, often without the support of other pediatric subspecialties.⁷ In contrast, hospitalists working at children’s hospitals more frequently care for highly complex patients, often collaborate across multiple specialties and assume nonclinical roles in quality improvement (QI), research, and medical education.

Residents graduating in July 2019 were the last cohort of residents eligible to pursue PHM subspecialty certification via the practice pathway. Accordingly, future residency graduates interested in PHM subspecialty certification will need to complete a PHM fellowship at an accredited program in the US or Canada. Since 2008, PHM fellowship directors have met yearly to collaborate and share best practices,⁸ developing the two-year fellowship curriculum that forms the basis for the American Board of Pediatrics training pathway.² The curriculum allows significant flexibility to meet diverse needs, including tailored content for fellows planning to practice in community settings, fellows planning research careers, medicine-pediatrics hospitalist careers, and those desiring increased training in QI, medical education, or leadership/administration.² In the spring of 2019, Pediatric Research in Inpatient Settings (PRIS) leadership, directors of existing PHM fellowship programs, and national academic society representatives met to develop a fellows’ research curriculum, training resources, and guidelines around scholarship expectations.⁹ This collaboration aims to accelerate the growth of high-quality clinical training and scholarship to benefit hospitalized children across many different settings.

Such collaboration is essential to address an emerging workforce challenge in PHM. Although the number of PHM fellowship positions is expected to grow in the coming years, there is currently a shortage relative to the anticipated demand. With approximately 2,800 US pediatric residents graduating annually and data indicating that 7% of graduating residents enter and remain in PHM for at least five years,^10,11 almost 200 fellowship spots may be needed each year. As of November 2019, 77 fellowship positions were available for residents graduating in 2020,¹² which is less than half of the potential demand. To address this mismatch, the PHM Fellowship Directors’ Council has led an annual training for new and potential fellowship directors, and 18 new programs are under development.¹³ However, this growth may be inadequate to meet the needs of the field. The extent to which limited PHM fellowship positions will adversely affect the pipeline of pediatricians pursuing PHM is unknown.

Efforts to support institutions in creating and expanding fellowship programs will be needed to address the potential shortage of fellowship positions. Continued guidance from the PHM Fellowship Directors’ Council in the many aspects of fellowship program development (eg, curriculum design, assessment) will be crucial in this endeavor. Furthermore, given that fellowships must support fellows to conduct scholarly work and demonstrate evidence of robust faculty scholarly activities to attain accreditation, an essential area of focus is faculty development. Considering barriers such as lack of time, mentorship, and resources, some divisions interested in starting a fellowship may find it challenging to achieve these standards.¹⁴ However, hospitalists are often engaged in areas such as QI and medical education, and there is potential to turn ongoing work into meaningful scholarship with appropriate guidance. Many of our supporting organizations (eg, Academic Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine) provide training programs for faculty in areas such as educational scholarship, research, and QI; however, more may be needed. Leaders of PHM programs will need to be mindful and creative in accessing local, regional, and national resources to invest in faculty development.

As a group, pediatric hospitalists report high levels of satisfaction with their jobs.¹¹ Despite this finding, there are a number of threats to the sustainability of current work models, some of which are unique to pediatrics given the overall lower patient volumes and greater seasonal variation compared with adult hospital medicine. Both university and community-based hospitalist programs report high weekend, overnight, and in-house clinical effort.^7,15 Recent studies reported that a significant proportion of PHM program leaders (50% of division directors at university-affiliated programs and 37% of community program leaders) perceive their program to be unsustainable.^7,15 Among university-affiliated programs, a higher burden of weekend work as well as university employment were associated with perceived unsustainability, while no specific program or employer characteristic was associated with this perception in community programs.

These findings indicate that efforts are needed to address PHM program sustainability and that different work models and interventions may be needed for university-based and community PHM programs. Wide variability exists in the ways that programs address overall clinical burden, with strategies including census caps, seasonal expansion of coverage, and formal back-up systems.^7,15 Additional potential solutions may include differential weighting or financial incentives for nights and weekends, support for nonclinical work, loan repayment programs, and competitive salaries.¹¹ In addition, structuring clinical and nonclinical roles to facilitate career development and advancement may enhance career longevity.¹⁵ Lessons learned from pediatric emergency medicine (PEM), which developed as a field a few decades ahead of PHM, may predict future challenges. A 2015 survey of PEM faculty found that despite a 15% decrease in weekly work hours over a 15-year period, a substantial number of PEM faculty report concerns about burnout, with 40% reporting a plan to decrease their clinical workload and 13% planning to leave the field within five years.¹⁶ Like PEM, the field of PHM may benefit from the development of best practice guidelines to improve well-being and career longevity.¹⁷

The culture of collaboration within PHM places the field in a solid position to address both workforce challenges and barriers to high-quality care for hospitalized children. There are several hospital-based learning networks actively working to strengthen our knowledge base and improve healthcare quality. The PRIS network (www.prisnetwork.org) aims to improve healthcare for children through multihospital studies, boasting 114 sites in the US and Canada. Numerous collaborative projects have linked hospitalists across programs to tackle problems ranging from handoff communication¹⁸ to eliminating monitor overuse.¹⁹ The Value in Inpatient Pediatrics network has similarly leveraged collaborations across multiple children’s and community hospitals to improve transitions of care²⁰ and care for common conditions such as bronchiolitis, febrile infants, and asthma.²¹ These networks serve as models of effective collaboration between children’s hospitals and community hospitals, more of which is needed to increase research and QI initiatives in community hospitals, where the majority of US children receive their hospital-based care.^6,22

With the rapid growth of scholarly networks in research, QI, and education, PHM has a solid infrastructure on which to base continued development as a subspeciality. Building on this infrastructure will be essential in order to address current challenges in workforce development, fellowship training, and program sustainability. Ultimately, achieving a strong, stable, and skilled workforce will enable PHM to fulfill its promise of improving the care of children across the diversity of settings where they receive their hospital-based care.

Disclosures

Dr. Leyenaar provides consultative services to the American Board of Pediatrics Foundation, which is not associated with this manuscript. Drs. Wang and Shaughnessy have no disclosures

Pediatric hospital medicine (PHM) is in the midst of an exciting period of growth. In 2016, the American Board of Medical Specialties approved the petition for PHM to become the newest pediatric subspecialty, taking PHM on a divergent path from the Focused Practice in Hospital Medicine designation established for adult hospitalists. Establishment as a subspecialty has allowed PHM to define the unique skills and qualifications that hospitalists bring to patients and the healthcare system. These skills and qualifications are delineated in the PHM core competencies and national fellowship curriculum.^1,2 In order to realize the vision of PHM to improve care for hospitalized children described by Roberts et al.,³ concerted efforts are needed to train and retain a workforce that is equipped with the skills to catalyze improvements in inpatient pediatric care. We discuss challenges and opportunities facing PHM in workforce development, sustainability of clinical work models, and interhospital collaboration.

The development of PHM as a subspecialty was driven by a number of factors.⁴ The acuity of hospitalized children has increased significantly, with a population comprised of more children with complex chronic conditions and/or technology dependence, serious complications of acute conditions, and acute mental health problems. At the same time, the medical and behavioral conditions seen by outpatient general pediatricians have become more complex and time intensive, with these practitioners less likely to work in inpatient settings. Hospitalist care has positive impacts on healthcare efficiency and value, and both parents and primary care pediatricians report high levels of satisfaction with the healthcare delivered by PHM services.⁴

A national count of the number of pediatric hospitalists is currently lacking. Conservative estimates suggest that at least 3,000 pediatric hospitalists currently practice in the United States.⁵ These hospitalists have highly varied scopes of practice and work across diverse settings—more diverse, perhaps, than any other pediatric subspecialty. Although difficult to quantify, we estimate that approximately one-third of pediatric hospitalists in the US work in community hospitals and the remainder practice at children’s hospitals.⁶ Many of the needs of hospitalized children differ across these settings, and the roles and challenges faced by hospitalists in these settings correspondingly differ. Community hospitalists frequently take active roles in newborn care and emergency department consultation, often without the support of other pediatric subspecialties.⁷ In contrast, hospitalists working at children’s hospitals more frequently care for highly complex patients, often collaborate across multiple specialties and assume nonclinical roles in quality improvement (QI), research, and medical education.

Residents graduating in July 2019 were the last cohort of residents eligible to pursue PHM subspecialty certification via the practice pathway. Accordingly, future residency graduates interested in PHM subspecialty certification will need to complete a PHM fellowship at an accredited program in the US or Canada. Since 2008, PHM fellowship directors have met yearly to collaborate and share best practices,⁸ developing the two-year fellowship curriculum that forms the basis for the American Board of Pediatrics training pathway.² The curriculum allows significant flexibility to meet diverse needs, including tailored content for fellows planning to practice in community settings, fellows planning research careers, medicine-pediatrics hospitalist careers, and those desiring increased training in QI, medical education, or leadership/administration.² In the spring of 2019, Pediatric Research in Inpatient Settings (PRIS) leadership, directors of existing PHM fellowship programs, and national academic society representatives met to develop a fellows’ research curriculum, training resources, and guidelines around scholarship expectations.⁹ This collaboration aims to accelerate the growth of high-quality clinical training and scholarship to benefit hospitalized children across many different settings.

Such collaboration is essential to address an emerging workforce challenge in PHM. Although the number of PHM fellowship positions is expected to grow in the coming years, there is currently a shortage relative to the anticipated demand. With approximately 2,800 US pediatric residents graduating annually and data indicating that 7% of graduating residents enter and remain in PHM for at least five years,^10,11 almost 200 fellowship spots may be needed each year. As of November 2019, 77 fellowship positions were available for residents graduating in 2020,¹² which is less than half of the potential demand. To address this mismatch, the PHM Fellowship Directors’ Council has led an annual training for new and potential fellowship directors, and 18 new programs are under development.¹³ However, this growth may be inadequate to meet the needs of the field. The extent to which limited PHM fellowship positions will adversely affect the pipeline of pediatricians pursuing PHM is unknown.

Efforts to support institutions in creating and expanding fellowship programs will be needed to address the potential shortage of fellowship positions. Continued guidance from the PHM Fellowship Directors’ Council in the many aspects of fellowship program development (eg, curriculum design, assessment) will be crucial in this endeavor. Furthermore, given that fellowships must support fellows to conduct scholarly work and demonstrate evidence of robust faculty scholarly activities to attain accreditation, an essential area of focus is faculty development. Considering barriers such as lack of time, mentorship, and resources, some divisions interested in starting a fellowship may find it challenging to achieve these standards.¹⁴ However, hospitalists are often engaged in areas such as QI and medical education, and there is potential to turn ongoing work into meaningful scholarship with appropriate guidance. Many of our supporting organizations (eg, Academic Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine) provide training programs for faculty in areas such as educational scholarship, research, and QI; however, more may be needed. Leaders of PHM programs will need to be mindful and creative in accessing local, regional, and national resources to invest in faculty development.

As a group, pediatric hospitalists report high levels of satisfaction with their jobs.¹¹ Despite this finding, there are a number of threats to the sustainability of current work models, some of which are unique to pediatrics given the overall lower patient volumes and greater seasonal variation compared with adult hospital medicine. Both university and community-based hospitalist programs report high weekend, overnight, and in-house clinical effort.^7,15 Recent studies reported that a significant proportion of PHM program leaders (50% of division directors at university-affiliated programs and 37% of community program leaders) perceive their program to be unsustainable.^7,15 Among university-affiliated programs, a higher burden of weekend work as well as university employment were associated with perceived unsustainability, while no specific program or employer characteristic was associated with this perception in community programs.

These findings indicate that efforts are needed to address PHM program sustainability and that different work models and interventions may be needed for university-based and community PHM programs. Wide variability exists in the ways that programs address overall clinical burden, with strategies including census caps, seasonal expansion of coverage, and formal back-up systems.^7,15 Additional potential solutions may include differential weighting or financial incentives for nights and weekends, support for nonclinical work, loan repayment programs, and competitive salaries.¹¹ In addition, structuring clinical and nonclinical roles to facilitate career development and advancement may enhance career longevity.¹⁵ Lessons learned from pediatric emergency medicine (PEM), which developed as a field a few decades ahead of PHM, may predict future challenges. A 2015 survey of PEM faculty found that despite a 15% decrease in weekly work hours over a 15-year period, a substantial number of PEM faculty report concerns about burnout, with 40% reporting a plan to decrease their clinical workload and 13% planning to leave the field within five years.¹⁶ Like PEM, the field of PHM may benefit from the development of best practice guidelines to improve well-being and career longevity.¹⁷

The culture of collaboration within PHM places the field in a solid position to address both workforce challenges and barriers to high-quality care for hospitalized children. There are several hospital-based learning networks actively working to strengthen our knowledge base and improve healthcare quality. The PRIS network (www.prisnetwork.org) aims to improve healthcare for children through multihospital studies, boasting 114 sites in the US and Canada. Numerous collaborative projects have linked hospitalists across programs to tackle problems ranging from handoff communication¹⁸ to eliminating monitor overuse.¹⁹ The Value in Inpatient Pediatrics network has similarly leveraged collaborations across multiple children’s and community hospitals to improve transitions of care²⁰ and care for common conditions such as bronchiolitis, febrile infants, and asthma.²¹ These networks serve as models of effective collaboration between children’s hospitals and community hospitals, more of which is needed to increase research and QI initiatives in community hospitals, where the majority of US children receive their hospital-based care.^6,22

With the rapid growth of scholarly networks in research, QI, and education, PHM has a solid infrastructure on which to base continued development as a subspeciality. Building on this infrastructure will be essential in order to address current challenges in workforce development, fellowship training, and program sustainability. Ultimately, achieving a strong, stable, and skilled workforce will enable PHM to fulfill its promise of improving the care of children across the diversity of settings where they receive their hospital-based care.

Disclosures

Dr. Leyenaar provides consultative services to the American Board of Pediatrics Foundation, which is not associated with this manuscript. Drs. Wang and Shaughnessy have no disclosures