Article

Most practitioners recommend a host of non-medical therapeutic options to their patients with migraine. The best studied and safest, most effective supplements remain magnesium, riboflavin/B₂, and CoQ10. Alpha-lipoic acid (ALA) is a supplement with both antioxidant and anti-inflammatory effects that has showed positive protective effects in a number of medical conditions, including diabetes and episodes of oxidative stress. One migraine study¹ evaluated serum ALA levels and found over 90% of people with migraine to deficient. This study sought to observe the potential benefit of supplementation with ALA in patients with episodic migraine.

This was a randomized, double-blind placebo-controlled trial over the course of 3 months. In this study, 92 female subjects with episodic migraine (defined as experiencing >2 but <15 days of headache per month) were recruited and randomized to receiving 300 mg ALA twice daily or placebo. Patients with chronic migraine, in menopause, pregnant, or lactating were excluded, as were patients with the presence of other chronic medical issues, or patients who had taken antioxidant supplements in the previous 4 months.

The primary outcomes of migraine severity, frequency, and Headache Impact Test (HIT-6) score were found to be significantly improved in the intervention group; duration of headache was not significantly different. Biochemical analysis of the two groups did show a difference in the lactate level of the intervention group, and this was considered a secondary outcome. Relevant side effects were primarily gastrointestinal, including stomach pain (higher in the placebo group), increased appetite, and constipation.

There is a great interest in finding effective non-medical treatments for migraine. These are frequently used as an adjunct to other preventive medications, or potentially as a stand-alone treatment for low frequency migraine. Many patients prefer non-medical options as well, and unfortunately many of the treatments they read about online or in less scientific spaces are unproven or unsafe. Supplementation remains an important part of migraine treatment for many practitioners and patients.

This study argues that ALA can be considered a safe and effective treatment for episodic migraine. When patients ask about non-medical options, ALA can be an additional treatment worth considering. Many patients are already taking multiple supplements before seeing their specialist, and this article  informs us that there may be some treatment benefit for this supplement as well. We may not be recommending this supplement alone as a preventive treatment for migraine, but we can add a new non-medical option to consider to our mix.

Using preventive medication in pediatrics is now more controversial than it had been previously. The well known The Childhood and Adolescent Migraine Prevention (CHAMP) trial² surprised many in the field by revealing that were no significant differences in headache frequency or disability when comparing children with migraine who received preventive medications or placebo. The CHAMP trial spotlighted the effect of non-medical therapies (cognitive behavioral therapy, biofeedback) and education. Many pediatric specialists have altered their practice paradigm in response to these results and have been more reticent to prescribe preventive medications for children with migraine. This is due to concern for potential side effects in light of the absence of direct benefit.

In an observational study of pediatric migraine,³ the investigators followed 186 children with migraine over a 3-year period to determine if the use of a number of preventive medications addresses disability (measured by Pediatric Migraine Disability Assessment [PedMIDAS]) as well as frequency, severity and duration of migraine. Other bothersome features of migraine were followed including the presence of nausea, vomiting, photophobia, analgesic use, and the side effects of the preventive medication.

The preventive medications used were cyproheptadine, flunarazine, propranolol, and topiramate—all at weight based doses. It is important to note that amitriptyline was not used in the study and there was no placebo group. This was a Turkish population, the median age was 14, and 63% were female, all of which are appropriate for a pediatric migraine study. Treatment efficacy was defined as a 50% reduction of symptoms. This was achieved in 90% of subjects in the topiramate group, 75% in the propranolol group, and 52-53% in the flunarazine and cyproheptadine groups.

Medication side effects were divided into minor or significant side effects. The only significant side effect noted was 3% of patient with palpitations; minor side effects were changes in appetite and drowsiness. More than half (57%) of patients taking topiramate experienced some side effect, 51% of the cyproheptadine group did as well, and the propranolol and flunarazine groups were noted to have side effects in 22% and 13%, respectively. Overall, 31.7% of patients had some side effect.  

PedMIDAS scores improved significantly with the use of preventive medications; migraine frequency improved significantly as well, especially in the topiramate group. This study argues for the use of preventive medications in pediatric migraine. One of the most commonly used medications for migraine prevention was not investigated unfortunately. Amitriptyline is widely considered a safe and effective migraine prophylactic medication, especially at low doses. One important takeaway is the frequency of side effects at all, and especially with topiramate. It is unclear how many patients stopped their preventive medications due to a side effect. In light of this study, propranolol, which is often overlooked, might be considered a better choice for children with migraine.

Most of the patients with migraine we see are in their most productive years. Migraine disability can be a major difficulty for our patients, especially as it relates to work. The American Migraine Foundation and American Headache Society have both recently taken on initiatives that relate to migraine in the workplace. Migraine epidemiologic studies have shown that people with migraine are more likely to experience a negative impact on their careers, and migraine disability scores weigh time absent from work as well as lower function at work. Many people with migraine are concerned that having migraine may hold them back from being hired or achieving promotion.

Autio et al performed a retrospective analysis of occupationally active patients treated at a single provider (the Finnish health clinic Terveystalo).⁴ The authors first looked for erenumab responders, who they defined as patients who received two prescriptions for erenumab and no other calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) medication. These patients were followed for 12 months, and their data was compared to the 12-month period prior to initiating erenumab. The authors evaluated headache-related sick days, all-cause sick days, healthcare visits, and prescriptions for all medications based on a registry. This registry also provided an age- and sex-matched control group of patients with migraine not taking any CGRP mAb medication.

A total of 162 patients were included, 82 in the erenumab responder group.  Headache-related sick days decreased by 74%, and headache-related healthcare visits decreased by 44%. Triptan prescription use decreased by 31.5%; all-cause sick days and healthcare visits differences were not statistically significant.

Prevention remains key in improving our patients’ quality of life and a large factor in this is their work life. This study shows that intervention with erenumab significantly decreases migraine-related absenteeism. It could be argued that the other CGRP mAb medications may have the same effect, as can many other preventive therapies. It can also be argued that even with this data we can only assume that patients function better at work with preventive therapies. Further studies will also look at the degree that “presenteeism” plays in the workplace—people who show up to work but are functioning at a lesser extent due to migraine. That said, this is an important step towards recognizing the burden migraine disability has on our patients’ work life, and the extent that prevention can improve their quality of life.

References

1. Kelishadi MR et al. The beneficial effect of Alpha-lipoic acid supplementation as a potential adjunct treatment in episodic migraines. Sci Rep. 2022;12:271 (Jan 7).
2. Powers SW et al. Trial of amitriptyline, topiramate, and placebo for pediatric migraine.  N Engl  J Med. 2017;376(2):115-124. Doi: 10.1056/NEJMoa1610384.
3. Tekin H, Edem P. Effects and side effects of migraine prophylaxis in children. Pediatr Int. 2021 (Dec 14).

1. Autio H et al. Erenumab decreases headache-related sick leave days and health care visits: a retrospective real-world study in working patients with migraine. Neurol Ther. 2021 (Dec 10).

Most practitioners recommend a host of non-medical therapeutic options to their patients with migraine. The best studied and safest, most effective supplements remain magnesium, riboflavin/B₂, and CoQ10. Alpha-lipoic acid (ALA) is a supplement with both antioxidant and anti-inflammatory effects that has showed positive protective effects in a number of medical conditions, including diabetes and episodes of oxidative stress. One migraine study¹ evaluated serum ALA levels and found over 90% of people with migraine to deficient. This study sought to observe the potential benefit of supplementation with ALA in patients with episodic migraine.

This was a randomized, double-blind placebo-controlled trial over the course of 3 months. In this study, 92 female subjects with episodic migraine (defined as experiencing >2 but <15 days of headache per month) were recruited and randomized to receiving 300 mg ALA twice daily or placebo. Patients with chronic migraine, in menopause, pregnant, or lactating were excluded, as were patients with the presence of other chronic medical issues, or patients who had taken antioxidant supplements in the previous 4 months.

The primary outcomes of migraine severity, frequency, and Headache Impact Test (HIT-6) score were found to be significantly improved in the intervention group; duration of headache was not significantly different. Biochemical analysis of the two groups did show a difference in the lactate level of the intervention group, and this was considered a secondary outcome. Relevant side effects were primarily gastrointestinal, including stomach pain (higher in the placebo group), increased appetite, and constipation.

There is a great interest in finding effective non-medical treatments for migraine. These are frequently used as an adjunct to other preventive medications, or potentially as a stand-alone treatment for low frequency migraine. Many patients prefer non-medical options as well, and unfortunately many of the treatments they read about online or in less scientific spaces are unproven or unsafe. Supplementation remains an important part of migraine treatment for many practitioners and patients.

This study argues that ALA can be considered a safe and effective treatment for episodic migraine. When patients ask about non-medical options, ALA can be an additional treatment worth considering. Many patients are already taking multiple supplements before seeing their specialist, and this article  informs us that there may be some treatment benefit for this supplement as well. We may not be recommending this supplement alone as a preventive treatment for migraine, but we can add a new non-medical option to consider to our mix.

Using preventive medication in pediatrics is now more controversial than it had been previously. The well known The Childhood and Adolescent Migraine Prevention (CHAMP) trial² surprised many in the field by revealing that were no significant differences in headache frequency or disability when comparing children with migraine who received preventive medications or placebo. The CHAMP trial spotlighted the effect of non-medical therapies (cognitive behavioral therapy, biofeedback) and education. Many pediatric specialists have altered their practice paradigm in response to these results and have been more reticent to prescribe preventive medications for children with migraine. This is due to concern for potential side effects in light of the absence of direct benefit.

In an observational study of pediatric migraine,³ the investigators followed 186 children with migraine over a 3-year period to determine if the use of a number of preventive medications addresses disability (measured by Pediatric Migraine Disability Assessment [PedMIDAS]) as well as frequency, severity and duration of migraine. Other bothersome features of migraine were followed including the presence of nausea, vomiting, photophobia, analgesic use, and the side effects of the preventive medication.

The preventive medications used were cyproheptadine, flunarazine, propranolol, and topiramate—all at weight based doses. It is important to note that amitriptyline was not used in the study and there was no placebo group. This was a Turkish population, the median age was 14, and 63% were female, all of which are appropriate for a pediatric migraine study. Treatment efficacy was defined as a 50% reduction of symptoms. This was achieved in 90% of subjects in the topiramate group, 75% in the propranolol group, and 52-53% in the flunarazine and cyproheptadine groups.

Medication side effects were divided into minor or significant side effects. The only significant side effect noted was 3% of patient with palpitations; minor side effects were changes in appetite and drowsiness. More than half (57%) of patients taking topiramate experienced some side effect, 51% of the cyproheptadine group did as well, and the propranolol and flunarazine groups were noted to have side effects in 22% and 13%, respectively. Overall, 31.7% of patients had some side effect.  

PedMIDAS scores improved significantly with the use of preventive medications; migraine frequency improved significantly as well, especially in the topiramate group. This study argues for the use of preventive medications in pediatric migraine. One of the most commonly used medications for migraine prevention was not investigated unfortunately. Amitriptyline is widely considered a safe and effective migraine prophylactic medication, especially at low doses. One important takeaway is the frequency of side effects at all, and especially with topiramate. It is unclear how many patients stopped their preventive medications due to a side effect. In light of this study, propranolol, which is often overlooked, might be considered a better choice for children with migraine.

Most of the patients with migraine we see are in their most productive years. Migraine disability can be a major difficulty for our patients, especially as it relates to work. The American Migraine Foundation and American Headache Society have both recently taken on initiatives that relate to migraine in the workplace. Migraine epidemiologic studies have shown that people with migraine are more likely to experience a negative impact on their careers, and migraine disability scores weigh time absent from work as well as lower function at work. Many people with migraine are concerned that having migraine may hold them back from being hired or achieving promotion.

Autio et al performed a retrospective analysis of occupationally active patients treated at a single provider (the Finnish health clinic Terveystalo).⁴ The authors first looked for erenumab responders, who they defined as patients who received two prescriptions for erenumab and no other calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) medication. These patients were followed for 12 months, and their data was compared to the 12-month period prior to initiating erenumab. The authors evaluated headache-related sick days, all-cause sick days, healthcare visits, and prescriptions for all medications based on a registry. This registry also provided an age- and sex-matched control group of patients with migraine not taking any CGRP mAb medication.

A total of 162 patients were included, 82 in the erenumab responder group.  Headache-related sick days decreased by 74%, and headache-related healthcare visits decreased by 44%. Triptan prescription use decreased by 31.5%; all-cause sick days and healthcare visits differences were not statistically significant.

Prevention remains key in improving our patients’ quality of life and a large factor in this is their work life. This study shows that intervention with erenumab significantly decreases migraine-related absenteeism. It could be argued that the other CGRP mAb medications may have the same effect, as can many other preventive therapies. It can also be argued that even with this data we can only assume that patients function better at work with preventive therapies. Further studies will also look at the degree that “presenteeism” plays in the workplace—people who show up to work but are functioning at a lesser extent due to migraine. That said, this is an important step towards recognizing the burden migraine disability has on our patients’ work life, and the extent that prevention can improve their quality of life.

References

1. Kelishadi MR et al. The beneficial effect of Alpha-lipoic acid supplementation as a potential adjunct treatment in episodic migraines. Sci Rep. 2022;12:271 (Jan 7).
2. Powers SW et al. Trial of amitriptyline, topiramate, and placebo for pediatric migraine.  N Engl  J Med. 2017;376(2):115-124. Doi: 10.1056/NEJMoa1610384.
3. Tekin H, Edem P. Effects and side effects of migraine prophylaxis in children. Pediatr Int. 2021 (Dec 14).

1. Autio H et al. Erenumab decreases headache-related sick leave days and health care visits: a retrospective real-world study in working patients with migraine. Neurol Ther. 2021 (Dec 10).

Most practitioners recommend a host of non-medical therapeutic options to their patients with migraine. The best studied and safest, most effective supplements remain magnesium, riboflavin/B₂, and CoQ10. Alpha-lipoic acid (ALA) is a supplement with both antioxidant and anti-inflammatory effects that has showed positive protective effects in a number of medical conditions, including diabetes and episodes of oxidative stress. One migraine study¹ evaluated serum ALA levels and found over 90% of people with migraine to deficient. This study sought to observe the potential benefit of supplementation with ALA in patients with episodic migraine.

This was a randomized, double-blind placebo-controlled trial over the course of 3 months. In this study, 92 female subjects with episodic migraine (defined as experiencing >2 but <15 days of headache per month) were recruited and randomized to receiving 300 mg ALA twice daily or placebo. Patients with chronic migraine, in menopause, pregnant, or lactating were excluded, as were patients with the presence of other chronic medical issues, or patients who had taken antioxidant supplements in the previous 4 months.

The primary outcomes of migraine severity, frequency, and Headache Impact Test (HIT-6) score were found to be significantly improved in the intervention group; duration of headache was not significantly different. Biochemical analysis of the two groups did show a difference in the lactate level of the intervention group, and this was considered a secondary outcome. Relevant side effects were primarily gastrointestinal, including stomach pain (higher in the placebo group), increased appetite, and constipation.

There is a great interest in finding effective non-medical treatments for migraine. These are frequently used as an adjunct to other preventive medications, or potentially as a stand-alone treatment for low frequency migraine. Many patients prefer non-medical options as well, and unfortunately many of the treatments they read about online or in less scientific spaces are unproven or unsafe. Supplementation remains an important part of migraine treatment for many practitioners and patients.

This study argues that ALA can be considered a safe and effective treatment for episodic migraine. When patients ask about non-medical options, ALA can be an additional treatment worth considering. Many patients are already taking multiple supplements before seeing their specialist, and this article  informs us that there may be some treatment benefit for this supplement as well. We may not be recommending this supplement alone as a preventive treatment for migraine, but we can add a new non-medical option to consider to our mix.

Using preventive medication in pediatrics is now more controversial than it had been previously. The well known The Childhood and Adolescent Migraine Prevention (CHAMP) trial² surprised many in the field by revealing that were no significant differences in headache frequency or disability when comparing children with migraine who received preventive medications or placebo. The CHAMP trial spotlighted the effect of non-medical therapies (cognitive behavioral therapy, biofeedback) and education. Many pediatric specialists have altered their practice paradigm in response to these results and have been more reticent to prescribe preventive medications for children with migraine. This is due to concern for potential side effects in light of the absence of direct benefit.

In an observational study of pediatric migraine,³ the investigators followed 186 children with migraine over a 3-year period to determine if the use of a number of preventive medications addresses disability (measured by Pediatric Migraine Disability Assessment [PedMIDAS]) as well as frequency, severity and duration of migraine. Other bothersome features of migraine were followed including the presence of nausea, vomiting, photophobia, analgesic use, and the side effects of the preventive medication.

The preventive medications used were cyproheptadine, flunarazine, propranolol, and topiramate—all at weight based doses. It is important to note that amitriptyline was not used in the study and there was no placebo group. This was a Turkish population, the median age was 14, and 63% were female, all of which are appropriate for a pediatric migraine study. Treatment efficacy was defined as a 50% reduction of symptoms. This was achieved in 90% of subjects in the topiramate group, 75% in the propranolol group, and 52-53% in the flunarazine and cyproheptadine groups.

Medication side effects were divided into minor or significant side effects. The only significant side effect noted was 3% of patient with palpitations; minor side effects were changes in appetite and drowsiness. More than half (57%) of patients taking topiramate experienced some side effect, 51% of the cyproheptadine group did as well, and the propranolol and flunarazine groups were noted to have side effects in 22% and 13%, respectively. Overall, 31.7% of patients had some side effect.  

PedMIDAS scores improved significantly with the use of preventive medications; migraine frequency improved significantly as well, especially in the topiramate group. This study argues for the use of preventive medications in pediatric migraine. One of the most commonly used medications for migraine prevention was not investigated unfortunately. Amitriptyline is widely considered a safe and effective migraine prophylactic medication, especially at low doses. One important takeaway is the frequency of side effects at all, and especially with topiramate. It is unclear how many patients stopped their preventive medications due to a side effect. In light of this study, propranolol, which is often overlooked, might be considered a better choice for children with migraine.

Most of the patients with migraine we see are in their most productive years. Migraine disability can be a major difficulty for our patients, especially as it relates to work. The American Migraine Foundation and American Headache Society have both recently taken on initiatives that relate to migraine in the workplace. Migraine epidemiologic studies have shown that people with migraine are more likely to experience a negative impact on their careers, and migraine disability scores weigh time absent from work as well as lower function at work. Many people with migraine are concerned that having migraine may hold them back from being hired or achieving promotion.

Autio et al performed a retrospective analysis of occupationally active patients treated at a single provider (the Finnish health clinic Terveystalo).⁴ The authors first looked for erenumab responders, who they defined as patients who received two prescriptions for erenumab and no other calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) medication. These patients were followed for 12 months, and their data was compared to the 12-month period prior to initiating erenumab. The authors evaluated headache-related sick days, all-cause sick days, healthcare visits, and prescriptions for all medications based on a registry. This registry also provided an age- and sex-matched control group of patients with migraine not taking any CGRP mAb medication.

A total of 162 patients were included, 82 in the erenumab responder group.  Headache-related sick days decreased by 74%, and headache-related healthcare visits decreased by 44%. Triptan prescription use decreased by 31.5%; all-cause sick days and healthcare visits differences were not statistically significant.

Prevention remains key in improving our patients’ quality of life and a large factor in this is their work life. This study shows that intervention with erenumab significantly decreases migraine-related absenteeism. It could be argued that the other CGRP mAb medications may have the same effect, as can many other preventive therapies. It can also be argued that even with this data we can only assume that patients function better at work with preventive therapies. Further studies will also look at the degree that “presenteeism” plays in the workplace—people who show up to work but are functioning at a lesser extent due to migraine. That said, this is an important step towards recognizing the burden migraine disability has on our patients’ work life, and the extent that prevention can improve their quality of life.

References

1. Kelishadi MR et al. The beneficial effect of Alpha-lipoic acid supplementation as a potential adjunct treatment in episodic migraines. Sci Rep. 2022;12:271 (Jan 7).
2. Powers SW et al. Trial of amitriptyline, topiramate, and placebo for pediatric migraine.  N Engl  J Med. 2017;376(2):115-124. Doi: 10.1056/NEJMoa1610384.
3. Tekin H, Edem P. Effects and side effects of migraine prophylaxis in children. Pediatr Int. 2021 (Dec 14).

1. Autio H et al. Erenumab decreases headache-related sick leave days and health care visits: a retrospective real-world study in working patients with migraine. Neurol Ther. 2021 (Dec 10).

Most practitioners recommend a host of non-medical therapeutic options to their patients with migraine. The best studied and safest, most effective supplements remain magnesium, riboflavin/B₂, and CoQ10. Alpha-lipoic acid (ALA) is a supplement with both antioxidant and anti-inflammatory effects that has showed positive protective effects in a number of medical conditions, including diabetes and episodes of oxidative stress. One migraine study¹ evaluated serum ALA levels and found over 90% of people with migraine to deficient. This study sought to observe the potential benefit of supplementation with ALA in patients with episodic migraine.

This was a randomized, double-blind placebo-controlled trial over the course of 3 months. In this study, 92 female subjects with episodic migraine (defined as experiencing >2 but <15 days of headache per month) were recruited and randomized to receiving 300 mg ALA twice daily or placebo. Patients with chronic migraine, in menopause, pregnant, or lactating were excluded, as were patients with the presence of other chronic medical issues, or patients who had taken antioxidant supplements in the previous 4 months.

The primary outcomes of migraine severity, frequency, and Headache Impact Test (HIT-6) score were found to be significantly improved in the intervention group; duration of headache was not significantly different. Biochemical analysis of the two groups did show a difference in the lactate level of the intervention group, and this was considered a secondary outcome. Relevant side effects were primarily gastrointestinal, including stomach pain (higher in the placebo group), increased appetite, and constipation.

There is a great interest in finding effective non-medical treatments for migraine. These are frequently used as an adjunct to other preventive medications, or potentially as a stand-alone treatment for low frequency migraine. Many patients prefer non-medical options as well, and unfortunately many of the treatments they read about online or in less scientific spaces are unproven or unsafe. Supplementation remains an important part of migraine treatment for many practitioners and patients.

This study argues that ALA can be considered a safe and effective treatment for episodic migraine. When patients ask about non-medical options, ALA can be an additional treatment worth considering. Many patients are already taking multiple supplements before seeing their specialist, and this article  informs us that there may be some treatment benefit for this supplement as well. We may not be recommending this supplement alone as a preventive treatment for migraine, but we can add a new non-medical option to consider to our mix.

Using preventive medication in pediatrics is now more controversial than it had been previously. The well known The Childhood and Adolescent Migraine Prevention (CHAMP) trial² surprised many in the field by revealing that were no significant differences in headache frequency or disability when comparing children with migraine who received preventive medications or placebo. The CHAMP trial spotlighted the effect of non-medical therapies (cognitive behavioral therapy, biofeedback) and education. Many pediatric specialists have altered their practice paradigm in response to these results and have been more reticent to prescribe preventive medications for children with migraine. This is due to concern for potential side effects in light of the absence of direct benefit.

In an observational study of pediatric migraine,³ the investigators followed 186 children with migraine over a 3-year period to determine if the use of a number of preventive medications addresses disability (measured by Pediatric Migraine Disability Assessment [PedMIDAS]) as well as frequency, severity and duration of migraine. Other bothersome features of migraine were followed including the presence of nausea, vomiting, photophobia, analgesic use, and the side effects of the preventive medication.

The preventive medications used were cyproheptadine, flunarazine, propranolol, and topiramate—all at weight based doses. It is important to note that amitriptyline was not used in the study and there was no placebo group. This was a Turkish population, the median age was 14, and 63% were female, all of which are appropriate for a pediatric migraine study. Treatment efficacy was defined as a 50% reduction of symptoms. This was achieved in 90% of subjects in the topiramate group, 75% in the propranolol group, and 52-53% in the flunarazine and cyproheptadine groups.

Medication side effects were divided into minor or significant side effects. The only significant side effect noted was 3% of patient with palpitations; minor side effects were changes in appetite and drowsiness. More than half (57%) of patients taking topiramate experienced some side effect, 51% of the cyproheptadine group did as well, and the propranolol and flunarazine groups were noted to have side effects in 22% and 13%, respectively. Overall, 31.7% of patients had some side effect.  

PedMIDAS scores improved significantly with the use of preventive medications; migraine frequency improved significantly as well, especially in the topiramate group. This study argues for the use of preventive medications in pediatric migraine. One of the most commonly used medications for migraine prevention was not investigated unfortunately. Amitriptyline is widely considered a safe and effective migraine prophylactic medication, especially at low doses. One important takeaway is the frequency of side effects at all, and especially with topiramate. It is unclear how many patients stopped their preventive medications due to a side effect. In light of this study, propranolol, which is often overlooked, might be considered a better choice for children with migraine.

Most of the patients with migraine we see are in their most productive years. Migraine disability can be a major difficulty for our patients, especially as it relates to work. The American Migraine Foundation and American Headache Society have both recently taken on initiatives that relate to migraine in the workplace. Migraine epidemiologic studies have shown that people with migraine are more likely to experience a negative impact on their careers, and migraine disability scores weigh time absent from work as well as lower function at work. Many people with migraine are concerned that having migraine may hold them back from being hired or achieving promotion.

Autio et al performed a retrospective analysis of occupationally active patients treated at a single provider (the Finnish health clinic Terveystalo).⁴ The authors first looked for erenumab responders, who they defined as patients who received two prescriptions for erenumab and no other calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) medication. These patients were followed for 12 months, and their data was compared to the 12-month period prior to initiating erenumab. The authors evaluated headache-related sick days, all-cause sick days, healthcare visits, and prescriptions for all medications based on a registry. This registry also provided an age- and sex-matched control group of patients with migraine not taking any CGRP mAb medication.

A total of 162 patients were included, 82 in the erenumab responder group.  Headache-related sick days decreased by 74%, and headache-related healthcare visits decreased by 44%. Triptan prescription use decreased by 31.5%; all-cause sick days and healthcare visits differences were not statistically significant.

Prevention remains key in improving our patients’ quality of life and a large factor in this is their work life. This study shows that intervention with erenumab significantly decreases migraine-related absenteeism. It could be argued that the other CGRP mAb medications may have the same effect, as can many other preventive therapies. It can also be argued that even with this data we can only assume that patients function better at work with preventive therapies. Further studies will also look at the degree that “presenteeism” plays in the workplace—people who show up to work but are functioning at a lesser extent due to migraine. That said, this is an important step towards recognizing the burden migraine disability has on our patients’ work life, and the extent that prevention can improve their quality of life.

References

1. Kelishadi MR et al. The beneficial effect of Alpha-lipoic acid supplementation as a potential adjunct treatment in episodic migraines. Sci Rep. 2022;12:271 (Jan 7).
2. Powers SW et al. Trial of amitriptyline, topiramate, and placebo for pediatric migraine.  N Engl  J Med. 2017;376(2):115-124. Doi: 10.1056/NEJMoa1610384.
3. Tekin H, Edem P. Effects and side effects of migraine prophylaxis in children. Pediatr Int. 2021 (Dec 14).

1. Autio H et al. Erenumab decreases headache-related sick leave days and health care visits: a retrospective real-world study in working patients with migraine. Neurol Ther. 2021 (Dec 10).

Most practitioners recommend a host of non-medical therapeutic options to their patients with migraine. The best studied and safest, most effective supplements remain magnesium, riboflavin/B₂, and CoQ10. Alpha-lipoic acid (ALA) is a supplement with both antioxidant and anti-inflammatory effects that has showed positive protective effects in a number of medical conditions, including diabetes and episodes of oxidative stress. One migraine study¹ evaluated serum ALA levels and found over 90% of people with migraine to deficient. This study sought to observe the potential benefit of supplementation with ALA in patients with episodic migraine.

This was a randomized, double-blind placebo-controlled trial over the course of 3 months. In this study, 92 female subjects with episodic migraine (defined as experiencing >2 but <15 days of headache per month) were recruited and randomized to receiving 300 mg ALA twice daily or placebo. Patients with chronic migraine, in menopause, pregnant, or lactating were excluded, as were patients with the presence of other chronic medical issues, or patients who had taken antioxidant supplements in the previous 4 months.

The primary outcomes of migraine severity, frequency, and Headache Impact Test (HIT-6) score were found to be significantly improved in the intervention group; duration of headache was not significantly different. Biochemical analysis of the two groups did show a difference in the lactate level of the intervention group, and this was considered a secondary outcome. Relevant side effects were primarily gastrointestinal, including stomach pain (higher in the placebo group), increased appetite, and constipation.

There is a great interest in finding effective non-medical treatments for migraine. These are frequently used as an adjunct to other preventive medications, or potentially as a stand-alone treatment for low frequency migraine. Many patients prefer non-medical options as well, and unfortunately many of the treatments they read about online or in less scientific spaces are unproven or unsafe. Supplementation remains an important part of migraine treatment for many practitioners and patients.

This study argues that ALA can be considered a safe and effective treatment for episodic migraine. When patients ask about non-medical options, ALA can be an additional treatment worth considering. Many patients are already taking multiple supplements before seeing their specialist, and this article  informs us that there may be some treatment benefit for this supplement as well. We may not be recommending this supplement alone as a preventive treatment for migraine, but we can add a new non-medical option to consider to our mix.

Using preventive medication in pediatrics is now more controversial than it had been previously. The well known The Childhood and Adolescent Migraine Prevention (CHAMP) trial² surprised many in the field by revealing that were no significant differences in headache frequency or disability when comparing children with migraine who received preventive medications or placebo. The CHAMP trial spotlighted the effect of non-medical therapies (cognitive behavioral therapy, biofeedback) and education. Many pediatric specialists have altered their practice paradigm in response to these results and have been more reticent to prescribe preventive medications for children with migraine. This is due to concern for potential side effects in light of the absence of direct benefit.

In an observational study of pediatric migraine,³ the investigators followed 186 children with migraine over a 3-year period to determine if the use of a number of preventive medications addresses disability (measured by Pediatric Migraine Disability Assessment [PedMIDAS]) as well as frequency, severity and duration of migraine. Other bothersome features of migraine were followed including the presence of nausea, vomiting, photophobia, analgesic use, and the side effects of the preventive medication.

The preventive medications used were cyproheptadine, flunarazine, propranolol, and topiramate—all at weight based doses. It is important to note that amitriptyline was not used in the study and there was no placebo group. This was a Turkish population, the median age was 14, and 63% were female, all of which are appropriate for a pediatric migraine study. Treatment efficacy was defined as a 50% reduction of symptoms. This was achieved in 90% of subjects in the topiramate group, 75% in the propranolol group, and 52-53% in the flunarazine and cyproheptadine groups.

Medication side effects were divided into minor or significant side effects. The only significant side effect noted was 3% of patient with palpitations; minor side effects were changes in appetite and drowsiness. More than half (57%) of patients taking topiramate experienced some side effect, 51% of the cyproheptadine group did as well, and the propranolol and flunarazine groups were noted to have side effects in 22% and 13%, respectively. Overall, 31.7% of patients had some side effect.  

PedMIDAS scores improved significantly with the use of preventive medications; migraine frequency improved significantly as well, especially in the topiramate group. This study argues for the use of preventive medications in pediatric migraine. One of the most commonly used medications for migraine prevention was not investigated unfortunately. Amitriptyline is widely considered a safe and effective migraine prophylactic medication, especially at low doses. One important takeaway is the frequency of side effects at all, and especially with topiramate. It is unclear how many patients stopped their preventive medications due to a side effect. In light of this study, propranolol, which is often overlooked, might be considered a better choice for children with migraine.

Most of the patients with migraine we see are in their most productive years. Migraine disability can be a major difficulty for our patients, especially as it relates to work. The American Migraine Foundation and American Headache Society have both recently taken on initiatives that relate to migraine in the workplace. Migraine epidemiologic studies have shown that people with migraine are more likely to experience a negative impact on their careers, and migraine disability scores weigh time absent from work as well as lower function at work. Many people with migraine are concerned that having migraine may hold them back from being hired or achieving promotion.

Autio et al performed a retrospective analysis of occupationally active patients treated at a single provider (the Finnish health clinic Terveystalo).⁴ The authors first looked for erenumab responders, who they defined as patients who received two prescriptions for erenumab and no other calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) medication. These patients were followed for 12 months, and their data was compared to the 12-month period prior to initiating erenumab. The authors evaluated headache-related sick days, all-cause sick days, healthcare visits, and prescriptions for all medications based on a registry. This registry also provided an age- and sex-matched control group of patients with migraine not taking any CGRP mAb medication.

A total of 162 patients were included, 82 in the erenumab responder group.  Headache-related sick days decreased by 74%, and headache-related healthcare visits decreased by 44%. Triptan prescription use decreased by 31.5%; all-cause sick days and healthcare visits differences were not statistically significant.

Prevention remains key in improving our patients’ quality of life and a large factor in this is their work life. This study shows that intervention with erenumab significantly decreases migraine-related absenteeism. It could be argued that the other CGRP mAb medications may have the same effect, as can many other preventive therapies. It can also be argued that even with this data we can only assume that patients function better at work with preventive therapies. Further studies will also look at the degree that “presenteeism” plays in the workplace—people who show up to work but are functioning at a lesser extent due to migraine. That said, this is an important step towards recognizing the burden migraine disability has on our patients’ work life, and the extent that prevention can improve their quality of life.

References

1. Kelishadi MR et al. The beneficial effect of Alpha-lipoic acid supplementation as a potential adjunct treatment in episodic migraines. Sci Rep. 2022;12:271 (Jan 7).
2. Powers SW et al. Trial of amitriptyline, topiramate, and placebo for pediatric migraine.  N Engl  J Med. 2017;376(2):115-124. Doi: 10.1056/NEJMoa1610384.
3. Tekin H, Edem P. Effects and side effects of migraine prophylaxis in children. Pediatr Int. 2021 (Dec 14).

1. Autio H et al. Erenumab decreases headache-related sick leave days and health care visits: a retrospective real-world study in working patients with migraine. Neurol Ther. 2021 (Dec 10).

Most practitioners recommend a host of non-medical therapeutic options to their patients with migraine. The best studied and safest, most effective supplements remain magnesium, riboflavin/B₂, and CoQ10. Alpha-lipoic acid (ALA) is a supplement with both antioxidant and anti-inflammatory effects that has showed positive protective effects in a number of medical conditions, including diabetes and episodes of oxidative stress. One migraine study¹ evaluated serum ALA levels and found over 90% of people with migraine to deficient. This study sought to observe the potential benefit of supplementation with ALA in patients with episodic migraine.

This was a randomized, double-blind placebo-controlled trial over the course of 3 months. In this study, 92 female subjects with episodic migraine (defined as experiencing >2 but <15 days of headache per month) were recruited and randomized to receiving 300 mg ALA twice daily or placebo. Patients with chronic migraine, in menopause, pregnant, or lactating were excluded, as were patients with the presence of other chronic medical issues, or patients who had taken antioxidant supplements in the previous 4 months.

The primary outcomes of migraine severity, frequency, and Headache Impact Test (HIT-6) score were found to be significantly improved in the intervention group; duration of headache was not significantly different. Biochemical analysis of the two groups did show a difference in the lactate level of the intervention group, and this was considered a secondary outcome. Relevant side effects were primarily gastrointestinal, including stomach pain (higher in the placebo group), increased appetite, and constipation.

There is a great interest in finding effective non-medical treatments for migraine. These are frequently used as an adjunct to other preventive medications, or potentially as a stand-alone treatment for low frequency migraine. Many patients prefer non-medical options as well, and unfortunately many of the treatments they read about online or in less scientific spaces are unproven or unsafe. Supplementation remains an important part of migraine treatment for many practitioners and patients.

This study argues that ALA can be considered a safe and effective treatment for episodic migraine. When patients ask about non-medical options, ALA can be an additional treatment worth considering. Many patients are already taking multiple supplements before seeing their specialist, and this article  informs us that there may be some treatment benefit for this supplement as well. We may not be recommending this supplement alone as a preventive treatment for migraine, but we can add a new non-medical option to consider to our mix.

Using preventive medication in pediatrics is now more controversial than it had been previously. The well known The Childhood and Adolescent Migraine Prevention (CHAMP) trial² surprised many in the field by revealing that were no significant differences in headache frequency or disability when comparing children with migraine who received preventive medications or placebo. The CHAMP trial spotlighted the effect of non-medical therapies (cognitive behavioral therapy, biofeedback) and education. Many pediatric specialists have altered their practice paradigm in response to these results and have been more reticent to prescribe preventive medications for children with migraine. This is due to concern for potential side effects in light of the absence of direct benefit.

In an observational study of pediatric migraine,³ the investigators followed 186 children with migraine over a 3-year period to determine if the use of a number of preventive medications addresses disability (measured by Pediatric Migraine Disability Assessment [PedMIDAS]) as well as frequency, severity and duration of migraine. Other bothersome features of migraine were followed including the presence of nausea, vomiting, photophobia, analgesic use, and the side effects of the preventive medication.

The preventive medications used were cyproheptadine, flunarazine, propranolol, and topiramate—all at weight based doses. It is important to note that amitriptyline was not used in the study and there was no placebo group. This was a Turkish population, the median age was 14, and 63% were female, all of which are appropriate for a pediatric migraine study. Treatment efficacy was defined as a 50% reduction of symptoms. This was achieved in 90% of subjects in the topiramate group, 75% in the propranolol group, and 52-53% in the flunarazine and cyproheptadine groups.

Medication side effects were divided into minor or significant side effects. The only significant side effect noted was 3% of patient with palpitations; minor side effects were changes in appetite and drowsiness. More than half (57%) of patients taking topiramate experienced some side effect, 51% of the cyproheptadine group did as well, and the propranolol and flunarazine groups were noted to have side effects in 22% and 13%, respectively. Overall, 31.7% of patients had some side effect.  

PedMIDAS scores improved significantly with the use of preventive medications; migraine frequency improved significantly as well, especially in the topiramate group. This study argues for the use of preventive medications in pediatric migraine. One of the most commonly used medications for migraine prevention was not investigated unfortunately. Amitriptyline is widely considered a safe and effective migraine prophylactic medication, especially at low doses. One important takeaway is the frequency of side effects at all, and especially with topiramate. It is unclear how many patients stopped their preventive medications due to a side effect. In light of this study, propranolol, which is often overlooked, might be considered a better choice for children with migraine.

Most of the patients with migraine we see are in their most productive years. Migraine disability can be a major difficulty for our patients, especially as it relates to work. The American Migraine Foundation and American Headache Society have both recently taken on initiatives that relate to migraine in the workplace. Migraine epidemiologic studies have shown that people with migraine are more likely to experience a negative impact on their careers, and migraine disability scores weigh time absent from work as well as lower function at work. Many people with migraine are concerned that having migraine may hold them back from being hired or achieving promotion.

Autio et al performed a retrospective analysis of occupationally active patients treated at a single provider (the Finnish health clinic Terveystalo).⁴ The authors first looked for erenumab responders, who they defined as patients who received two prescriptions for erenumab and no other calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) medication. These patients were followed for 12 months, and their data was compared to the 12-month period prior to initiating erenumab. The authors evaluated headache-related sick days, all-cause sick days, healthcare visits, and prescriptions for all medications based on a registry. This registry also provided an age- and sex-matched control group of patients with migraine not taking any CGRP mAb medication.

A total of 162 patients were included, 82 in the erenumab responder group.  Headache-related sick days decreased by 74%, and headache-related healthcare visits decreased by 44%. Triptan prescription use decreased by 31.5%; all-cause sick days and healthcare visits differences were not statistically significant.

Prevention remains key in improving our patients’ quality of life and a large factor in this is their work life. This study shows that intervention with erenumab significantly decreases migraine-related absenteeism. It could be argued that the other CGRP mAb medications may have the same effect, as can many other preventive therapies. It can also be argued that even with this data we can only assume that patients function better at work with preventive therapies. Further studies will also look at the degree that “presenteeism” plays in the workplace—people who show up to work but are functioning at a lesser extent due to migraine. That said, this is an important step towards recognizing the burden migraine disability has on our patients’ work life, and the extent that prevention can improve their quality of life.

References

1. Kelishadi MR et al. The beneficial effect of Alpha-lipoic acid supplementation as a potential adjunct treatment in episodic migraines. Sci Rep. 2022;12:271 (Jan 7).
2. Powers SW et al. Trial of amitriptyline, topiramate, and placebo for pediatric migraine.  N Engl  J Med. 2017;376(2):115-124. Doi: 10.1056/NEJMoa1610384.
3. Tekin H, Edem P. Effects and side effects of migraine prophylaxis in children. Pediatr Int. 2021 (Dec 14).

1. Autio H et al. Erenumab decreases headache-related sick leave days and health care visits: a retrospective real-world study in working patients with migraine. Neurol Ther. 2021 (Dec 10).

From Hassenfeld Children’s Hospital at NYU Langone Health, New York, NY (Dr Gallagher), T1D Exchange, Boston, MA (Saketh Rompicherla; Drs Ebekozien, Noor, Odugbesan, and Mungmode; Nicole Rioles, Emma Ospelt), University of Mississippi School of Population Health, Jackson, MS (Dr. Ebekozien), Icahn School of Medicine at Mount Sinai, New York, NY (Drs. Wilkes, O’Malley, and Rapaport), Weill Cornell Medicine, New York, NY (Drs. Antal and Feuer), NYU Long Island School of Medicine, Mineola, NY (Dr. Gabriel), NYU Langone Health, New York, NY (Dr. Golden), Barbara Davis Center, Aurora, CO (Dr. Alonso), Texas Children’s Hospital/Baylor College of Medicine, Houston, TX (Dr. Lyons), Stanford University, Stanford, CA (Dr. Prahalad), Children Mercy Kansas City, MO (Dr. Clements), Indiana University School of Medicine, IN (Dr. Neyman), Rady Children’s Hospital, University of California, San Diego, CA (Dr. Demeterco-Berggren).

Background: Patient outcomes of COVID-19 have improved throughout the pandemic. However, because it is not known whether outcomes of COVID-19 in the type 1 diabetes (T1D) population improved over time, we investigated differences in COVID-19 outcomes for patients with T1D in the United States.

Methods: We analyzed data collected via a registry of patients with T1D and COVID-19 from 56 sites between April 2020 and January 2021. We grouped cases into first surge (April 9, 2020, to July 31, 2020, n = 188) and late surge (August 1, 2020, to January 31, 2021, n = 410), and then compared outcomes between both groups using descriptive statistics and logistic regression models.

Results: Adverse outcomes were more frequent during the first surge, including diabetic ketoacidosis (32% vs 15%, P < .001), severe hypoglycemia (4% vs 1%, P = .04), and hospitalization (52% vs 22%, P < .001). Patients in the first surge were older (28 [SD,18.8] years vs 18.0 [SD, 11.1] years, P < .001), had higher median hemoglobin A1c levels (9.3 [interquartile range {IQR}, 4.0] vs 8.4 (IQR, 2.8), P < .001), and were more likely to use public insurance (107 [57%] vs 154 [38%], P < .001). The odds of hospitalization for adults in the first surge were 5 times higher compared to the late surge (odds ratio, 5.01; 95% CI, 2.11-12.63).

Conclusion: Patients with T1D who presented with COVID-19 during the first surge had a higher proportion of adverse outcomes than those who presented in a later surge.

Keywords: TD1, diabetic ketoacidosis, hypoglycemia.

After the World Health Organization declared the disease caused by the novel coronavirus SARS-CoV-2, COVID-19, a pandemic on March 11, 2020, the Centers for Disease Control and Prevention identified patients with diabetes as high risk for severe illness.^1-7 The case-fatality rate for COVID-19 has significantly improved over the past 2 years. Public health measures, less severe COVID-19 variants, increased access to testing, and new treatments for COVID-19 have contributed to improved outcomes.

The T1D Exchange has previously published findings on COVID-19 outcomes for patients with type 1 diabetes (T1D) using data from the T1D COVID-19 Surveillance Registry.^8-12 Given improved outcomes in COVID-19 in the general population, we sought to determine if outcomes for cases of COVID-19 reported to this registry changed over time.

Methods

This study was coordinated by the T1D Exchange and approved as nonhuman subject research by the Western Institutional Review Board. All participating centers also obtained local institutional review board approval. No identifiable patient information was collected as part of this noninterventional, cross-sectional study.

The T1D Exchange Multi-center COVID-19 Surveillance Study collected data from endocrinology clinics that completed a retrospective chart review and submitted information to T1D Exchange via an online questionnaire for all patients with T1D at their sites who tested positive for COVID-19.^13,14 The questionnaire was administered using the Qualtrics survey platform (www.qualtrics.com version XM) and contained 33 pre-coded and free-text response fields to collect patient and clinical attributes.

Each participating center identified 1 team member for reporting to avoid duplicate case submission. Each submitted case was reviewed for potential errors and incomplete information. The coordinating center verified the number of cases per site for data quality assurance.

Quantitative data were represented as mean (standard deviation) or median (interquartile range). Categorical data were described as the number (percentage) of patients. Summary statistics, including frequency and percentage for categorical variables, were calculated for all patient-related and clinical characteristics. The date August 1, 2021, was selected as the end of the first surge based on a review of national COVID-19 surges.

We used the Fisher’s exact test to assess associations between hospitalization and demographics, HbA1c, diabetes duration, symptoms, and adverse outcomes. In addition, multivariate logistic regression was used to calculate odds ratios (OR). Logistic regression models were used to determine the association between time of surge and hospitalization separately for both the pediatric and adult populations. Each model was adjusted for potential sociodemographic confounders, specifically age, sex, race, insurance, and HbA1c.

All tests were 2-sided, with type 1 error set at 5%. Fisher’s exact test and logistic regression were performed using statistical software R, version 3.6.2 (R Foundation for Statistical Computing).

Results

The characteristics of COVID-19 cases in patients with T1D that were reported early in the pandemic, before August 1, 2020 (first surge), compared with those of cases reported on and after August 1, 2020 (later surges) are shown in Table 1.

Patients with T1D who presented with COVID-19 during the first surge as compared to the later surges were older (mean age 28 [SD, 18.0] years vs 18.8 [SD, 11.1] years; P < .001) and had a longer duration of diabetes (P < .001). The first-surge group also had more patients with >20 years’ diabetes duration (20% vs 9%, P < .001). Obesity, hypertension, and chronic kidney disease were also more commonly reported in first-surge cases (all P < .001).

There was a significant difference in race and ethnicity reported in the first surge vs the later surge cases, with fewer patients identifying as non-Hispanic White (39% vs, 63%, P < .001) and more patients identifying as non-Hispanic Black (29% vs 12%, P < .001). The groups also differed significantly in terms of insurance type, with more people on public insurance in the first-surge group (57% vs 38%, P < .001). In addition, median HbA1c was higher (9.3% vs 8.4%, P < .001) and continuous glucose monitor and insulin pump use were less common (P = .02 and <.001, respectively) in the early surge.

All symptoms and adverse outcomes were reported more often in the first surge, including diabetic ketoacidosis (DKA; 32% vs 15%; P < .001) and severe hypoglycemia (4% vs 1%, P = .04). Hospitalization (52% vs 13%, P < .001) and ICU admission (24% vs 9%, P < .001) were reported more often in the first-surge group.

Regression Analyses

Table 2 shows the results of logistic regression analyses for hospitalization in the pediatric (≤19 years of age) and adult (>19 years of age) groups, along with the odds of hospitalization during the first vs late surge among COVID-positive people with T1D. Adult patients who tested positive in the first surge were about 5 times more likely to be hospitalized than adults who tested positive for infection in the late surge after adjusting for age, insurance type, sex, race, and HbA1c levels. Pediatric patients also had an increased odds for hospitalization during the first surge, but this increase was not statistically significant.

Discussion

Our analysis of COVID-19 cases in patients with T1D reported by diabetes providers across the United States found that adverse outcomes were more prevalent early in the pandemic. There may be a number of reasons for this difference in outcomes between patients who presented in the first surge vs a later surge. First, because testing for COVID-19 was extremely limited and reserved for hospitalized patients early in the pandemic, the first-surge patients with confirmed COVID-19 likely represent a skewed population of higher-acuity patients. This may also explain the relative paucity of cases in younger patients reported early in the pandemic. Second, worse outcomes in the early surge may also have been associated with overwhelmed hospitals in New York City at the start of the outbreak. According to Cummings et al, the abrupt surge of critically ill patients hospitalized with severe acute respiratory distress syndrome initially outpaced their capacity to provide prone-positioning ventilation, which has been expanded since then.¹⁵ While there was very little hypertension, cardiovascular disease, or kidney disease reported in the pediatric groups, there was a higher prevalence of obesity in the pediatric group from the mid-Atlantic region. Obesity has been associated with a worse prognosis for COVID-19 illness in children.¹⁶ Finally, there were 5 deaths reported in this study, all of which were reported during the first surge. Older age and increased rates of cardiovascular disease and chronic kidney disease in the first surge cases likely contributed to worse outcomes for adults in mid-Atlantic region relative to the other regions. Minority race and the use of public insurance, risk factors for more severe outcomes in all regions, were also more common in cases reported from the mid-Atlantic region.

This study has several limitations. First, it is a cross-sectional study that relies upon voluntary provider reports. Second, availability of COVID-19 testing was limited in all regions in spring 2020. Third, different regions of the country experienced subsequent surges at different times within the reported timeframes in this analysis. Fourth, this report time period does not include the impact of the newer COVID-19 variants. Finally, trends in COVID-19 outcomes were affected by the evolution of care that developed throughout 2020.

Conclusion

Adult patients with T1D and COVID-19 who reported during the first surge had about 5 times higher hospitalization odds than those who presented in a later surge.

Corresponding author: Osagie Ebekozien, MD, MPH, 11 Avenue de Lafayette, Boston, MA 02111; [email protected]

Disclosures: Dr Ebekozien reports receiving research grants from Medtronic Diabetes, Eli Lilly, and Dexcom, and receiving honoraria from Medtronic Diabetes.

From Hassenfeld Children’s Hospital at NYU Langone Health, New York, NY (Dr Gallagher), T1D Exchange, Boston, MA (Saketh Rompicherla; Drs Ebekozien, Noor, Odugbesan, and Mungmode; Nicole Rioles, Emma Ospelt), University of Mississippi School of Population Health, Jackson, MS (Dr. Ebekozien), Icahn School of Medicine at Mount Sinai, New York, NY (Drs. Wilkes, O’Malley, and Rapaport), Weill Cornell Medicine, New York, NY (Drs. Antal and Feuer), NYU Long Island School of Medicine, Mineola, NY (Dr. Gabriel), NYU Langone Health, New York, NY (Dr. Golden), Barbara Davis Center, Aurora, CO (Dr. Alonso), Texas Children’s Hospital/Baylor College of Medicine, Houston, TX (Dr. Lyons), Stanford University, Stanford, CA (Dr. Prahalad), Children Mercy Kansas City, MO (Dr. Clements), Indiana University School of Medicine, IN (Dr. Neyman), Rady Children’s Hospital, University of California, San Diego, CA (Dr. Demeterco-Berggren).

Background: Patient outcomes of COVID-19 have improved throughout the pandemic. However, because it is not known whether outcomes of COVID-19 in the type 1 diabetes (T1D) population improved over time, we investigated differences in COVID-19 outcomes for patients with T1D in the United States.

Methods: We analyzed data collected via a registry of patients with T1D and COVID-19 from 56 sites between April 2020 and January 2021. We grouped cases into first surge (April 9, 2020, to July 31, 2020, n = 188) and late surge (August 1, 2020, to January 31, 2021, n = 410), and then compared outcomes between both groups using descriptive statistics and logistic regression models.

Results: Adverse outcomes were more frequent during the first surge, including diabetic ketoacidosis (32% vs 15%, P < .001), severe hypoglycemia (4% vs 1%, P = .04), and hospitalization (52% vs 22%, P < .001). Patients in the first surge were older (28 [SD,18.8] years vs 18.0 [SD, 11.1] years, P < .001), had higher median hemoglobin A1c levels (9.3 [interquartile range {IQR}, 4.0] vs 8.4 (IQR, 2.8), P < .001), and were more likely to use public insurance (107 [57%] vs 154 [38%], P < .001). The odds of hospitalization for adults in the first surge were 5 times higher compared to the late surge (odds ratio, 5.01; 95% CI, 2.11-12.63).

Conclusion: Patients with T1D who presented with COVID-19 during the first surge had a higher proportion of adverse outcomes than those who presented in a later surge.

Keywords: TD1, diabetic ketoacidosis, hypoglycemia.

After the World Health Organization declared the disease caused by the novel coronavirus SARS-CoV-2, COVID-19, a pandemic on March 11, 2020, the Centers for Disease Control and Prevention identified patients with diabetes as high risk for severe illness.^1-7 The case-fatality rate for COVID-19 has significantly improved over the past 2 years. Public health measures, less severe COVID-19 variants, increased access to testing, and new treatments for COVID-19 have contributed to improved outcomes.

The T1D Exchange has previously published findings on COVID-19 outcomes for patients with type 1 diabetes (T1D) using data from the T1D COVID-19 Surveillance Registry.^8-12 Given improved outcomes in COVID-19 in the general population, we sought to determine if outcomes for cases of COVID-19 reported to this registry changed over time.

Methods

This study was coordinated by the T1D Exchange and approved as nonhuman subject research by the Western Institutional Review Board. All participating centers also obtained local institutional review board approval. No identifiable patient information was collected as part of this noninterventional, cross-sectional study.

The T1D Exchange Multi-center COVID-19 Surveillance Study collected data from endocrinology clinics that completed a retrospective chart review and submitted information to T1D Exchange via an online questionnaire for all patients with T1D at their sites who tested positive for COVID-19.^13,14 The questionnaire was administered using the Qualtrics survey platform (www.qualtrics.com version XM) and contained 33 pre-coded and free-text response fields to collect patient and clinical attributes.

Each participating center identified 1 team member for reporting to avoid duplicate case submission. Each submitted case was reviewed for potential errors and incomplete information. The coordinating center verified the number of cases per site for data quality assurance.

Quantitative data were represented as mean (standard deviation) or median (interquartile range). Categorical data were described as the number (percentage) of patients. Summary statistics, including frequency and percentage for categorical variables, were calculated for all patient-related and clinical characteristics. The date August 1, 2021, was selected as the end of the first surge based on a review of national COVID-19 surges.

We used the Fisher’s exact test to assess associations between hospitalization and demographics, HbA1c, diabetes duration, symptoms, and adverse outcomes. In addition, multivariate logistic regression was used to calculate odds ratios (OR). Logistic regression models were used to determine the association between time of surge and hospitalization separately for both the pediatric and adult populations. Each model was adjusted for potential sociodemographic confounders, specifically age, sex, race, insurance, and HbA1c.

All tests were 2-sided, with type 1 error set at 5%. Fisher’s exact test and logistic regression were performed using statistical software R, version 3.6.2 (R Foundation for Statistical Computing).

Results

The characteristics of COVID-19 cases in patients with T1D that were reported early in the pandemic, before August 1, 2020 (first surge), compared with those of cases reported on and after August 1, 2020 (later surges) are shown in Table 1.

Patients with T1D who presented with COVID-19 during the first surge as compared to the later surges were older (mean age 28 [SD, 18.0] years vs 18.8 [SD, 11.1] years; P < .001) and had a longer duration of diabetes (P < .001). The first-surge group also had more patients with >20 years’ diabetes duration (20% vs 9%, P < .001). Obesity, hypertension, and chronic kidney disease were also more commonly reported in first-surge cases (all P < .001).

There was a significant difference in race and ethnicity reported in the first surge vs the later surge cases, with fewer patients identifying as non-Hispanic White (39% vs, 63%, P < .001) and more patients identifying as non-Hispanic Black (29% vs 12%, P < .001). The groups also differed significantly in terms of insurance type, with more people on public insurance in the first-surge group (57% vs 38%, P < .001). In addition, median HbA1c was higher (9.3% vs 8.4%, P < .001) and continuous glucose monitor and insulin pump use were less common (P = .02 and <.001, respectively) in the early surge.

All symptoms and adverse outcomes were reported more often in the first surge, including diabetic ketoacidosis (DKA; 32% vs 15%; P < .001) and severe hypoglycemia (4% vs 1%, P = .04). Hospitalization (52% vs 13%, P < .001) and ICU admission (24% vs 9%, P < .001) were reported more often in the first-surge group.

Regression Analyses

Table 2 shows the results of logistic regression analyses for hospitalization in the pediatric (≤19 years of age) and adult (>19 years of age) groups, along with the odds of hospitalization during the first vs late surge among COVID-positive people with T1D. Adult patients who tested positive in the first surge were about 5 times more likely to be hospitalized than adults who tested positive for infection in the late surge after adjusting for age, insurance type, sex, race, and HbA1c levels. Pediatric patients also had an increased odds for hospitalization during the first surge, but this increase was not statistically significant.

Discussion

Our analysis of COVID-19 cases in patients with T1D reported by diabetes providers across the United States found that adverse outcomes were more prevalent early in the pandemic. There may be a number of reasons for this difference in outcomes between patients who presented in the first surge vs a later surge. First, because testing for COVID-19 was extremely limited and reserved for hospitalized patients early in the pandemic, the first-surge patients with confirmed COVID-19 likely represent a skewed population of higher-acuity patients. This may also explain the relative paucity of cases in younger patients reported early in the pandemic. Second, worse outcomes in the early surge may also have been associated with overwhelmed hospitals in New York City at the start of the outbreak. According to Cummings et al, the abrupt surge of critically ill patients hospitalized with severe acute respiratory distress syndrome initially outpaced their capacity to provide prone-positioning ventilation, which has been expanded since then.¹⁵ While there was very little hypertension, cardiovascular disease, or kidney disease reported in the pediatric groups, there was a higher prevalence of obesity in the pediatric group from the mid-Atlantic region. Obesity has been associated with a worse prognosis for COVID-19 illness in children.¹⁶ Finally, there were 5 deaths reported in this study, all of which were reported during the first surge. Older age and increased rates of cardiovascular disease and chronic kidney disease in the first surge cases likely contributed to worse outcomes for adults in mid-Atlantic region relative to the other regions. Minority race and the use of public insurance, risk factors for more severe outcomes in all regions, were also more common in cases reported from the mid-Atlantic region.

This study has several limitations. First, it is a cross-sectional study that relies upon voluntary provider reports. Second, availability of COVID-19 testing was limited in all regions in spring 2020. Third, different regions of the country experienced subsequent surges at different times within the reported timeframes in this analysis. Fourth, this report time period does not include the impact of the newer COVID-19 variants. Finally, trends in COVID-19 outcomes were affected by the evolution of care that developed throughout 2020.

Conclusion

Adult patients with T1D and COVID-19 who reported during the first surge had about 5 times higher hospitalization odds than those who presented in a later surge.

Corresponding author: Osagie Ebekozien, MD, MPH, 11 Avenue de Lafayette, Boston, MA 02111; [email protected]

Disclosures: Dr Ebekozien reports receiving research grants from Medtronic Diabetes, Eli Lilly, and Dexcom, and receiving honoraria from Medtronic Diabetes.

From Hassenfeld Children’s Hospital at NYU Langone Health, New York, NY (Dr Gallagher), T1D Exchange, Boston, MA (Saketh Rompicherla; Drs Ebekozien, Noor, Odugbesan, and Mungmode; Nicole Rioles, Emma Ospelt), University of Mississippi School of Population Health, Jackson, MS (Dr. Ebekozien), Icahn School of Medicine at Mount Sinai, New York, NY (Drs. Wilkes, O’Malley, and Rapaport), Weill Cornell Medicine, New York, NY (Drs. Antal and Feuer), NYU Long Island School of Medicine, Mineola, NY (Dr. Gabriel), NYU Langone Health, New York, NY (Dr. Golden), Barbara Davis Center, Aurora, CO (Dr. Alonso), Texas Children’s Hospital/Baylor College of Medicine, Houston, TX (Dr. Lyons), Stanford University, Stanford, CA (Dr. Prahalad), Children Mercy Kansas City, MO (Dr. Clements), Indiana University School of Medicine, IN (Dr. Neyman), Rady Children’s Hospital, University of California, San Diego, CA (Dr. Demeterco-Berggren).

Background: Patient outcomes of COVID-19 have improved throughout the pandemic. However, because it is not known whether outcomes of COVID-19 in the type 1 diabetes (T1D) population improved over time, we investigated differences in COVID-19 outcomes for patients with T1D in the United States.

Methods: We analyzed data collected via a registry of patients with T1D and COVID-19 from 56 sites between April 2020 and January 2021. We grouped cases into first surge (April 9, 2020, to July 31, 2020, n = 188) and late surge (August 1, 2020, to January 31, 2021, n = 410), and then compared outcomes between both groups using descriptive statistics and logistic regression models.

Results: Adverse outcomes were more frequent during the first surge, including diabetic ketoacidosis (32% vs 15%, P < .001), severe hypoglycemia (4% vs 1%, P = .04), and hospitalization (52% vs 22%, P < .001). Patients in the first surge were older (28 [SD,18.8] years vs 18.0 [SD, 11.1] years, P < .001), had higher median hemoglobin A1c levels (9.3 [interquartile range {IQR}, 4.0] vs 8.4 (IQR, 2.8), P < .001), and were more likely to use public insurance (107 [57%] vs 154 [38%], P < .001). The odds of hospitalization for adults in the first surge were 5 times higher compared to the late surge (odds ratio, 5.01; 95% CI, 2.11-12.63).

Conclusion: Patients with T1D who presented with COVID-19 during the first surge had a higher proportion of adverse outcomes than those who presented in a later surge.

Keywords: TD1, diabetic ketoacidosis, hypoglycemia.

After the World Health Organization declared the disease caused by the novel coronavirus SARS-CoV-2, COVID-19, a pandemic on March 11, 2020, the Centers for Disease Control and Prevention identified patients with diabetes as high risk for severe illness.^1-7 The case-fatality rate for COVID-19 has significantly improved over the past 2 years. Public health measures, less severe COVID-19 variants, increased access to testing, and new treatments for COVID-19 have contributed to improved outcomes.

The T1D Exchange has previously published findings on COVID-19 outcomes for patients with type 1 diabetes (T1D) using data from the T1D COVID-19 Surveillance Registry.^8-12 Given improved outcomes in COVID-19 in the general population, we sought to determine if outcomes for cases of COVID-19 reported to this registry changed over time.

Methods

This study was coordinated by the T1D Exchange and approved as nonhuman subject research by the Western Institutional Review Board. All participating centers also obtained local institutional review board approval. No identifiable patient information was collected as part of this noninterventional, cross-sectional study.

The T1D Exchange Multi-center COVID-19 Surveillance Study collected data from endocrinology clinics that completed a retrospective chart review and submitted information to T1D Exchange via an online questionnaire for all patients with T1D at their sites who tested positive for COVID-19.^13,14 The questionnaire was administered using the Qualtrics survey platform (www.qualtrics.com version XM) and contained 33 pre-coded and free-text response fields to collect patient and clinical attributes.

Each participating center identified 1 team member for reporting to avoid duplicate case submission. Each submitted case was reviewed for potential errors and incomplete information. The coordinating center verified the number of cases per site for data quality assurance.

Quantitative data were represented as mean (standard deviation) or median (interquartile range). Categorical data were described as the number (percentage) of patients. Summary statistics, including frequency and percentage for categorical variables, were calculated for all patient-related and clinical characteristics. The date August 1, 2021, was selected as the end of the first surge based on a review of national COVID-19 surges.

We used the Fisher’s exact test to assess associations between hospitalization and demographics, HbA1c, diabetes duration, symptoms, and adverse outcomes. In addition, multivariate logistic regression was used to calculate odds ratios (OR). Logistic regression models were used to determine the association between time of surge and hospitalization separately for both the pediatric and adult populations. Each model was adjusted for potential sociodemographic confounders, specifically age, sex, race, insurance, and HbA1c.

All tests were 2-sided, with type 1 error set at 5%. Fisher’s exact test and logistic regression were performed using statistical software R, version 3.6.2 (R Foundation for Statistical Computing).

Results

The characteristics of COVID-19 cases in patients with T1D that were reported early in the pandemic, before August 1, 2020 (first surge), compared with those of cases reported on and after August 1, 2020 (later surges) are shown in Table 1.

Patients with T1D who presented with COVID-19 during the first surge as compared to the later surges were older (mean age 28 [SD, 18.0] years vs 18.8 [SD, 11.1] years; P < .001) and had a longer duration of diabetes (P < .001). The first-surge group also had more patients with >20 years’ diabetes duration (20% vs 9%, P < .001). Obesity, hypertension, and chronic kidney disease were also more commonly reported in first-surge cases (all P < .001).

There was a significant difference in race and ethnicity reported in the first surge vs the later surge cases, with fewer patients identifying as non-Hispanic White (39% vs, 63%, P < .001) and more patients identifying as non-Hispanic Black (29% vs 12%, P < .001). The groups also differed significantly in terms of insurance type, with more people on public insurance in the first-surge group (57% vs 38%, P < .001). In addition, median HbA1c was higher (9.3% vs 8.4%, P < .001) and continuous glucose monitor and insulin pump use were less common (P = .02 and <.001, respectively) in the early surge.

All symptoms and adverse outcomes were reported more often in the first surge, including diabetic ketoacidosis (DKA; 32% vs 15%; P < .001) and severe hypoglycemia (4% vs 1%, P = .04). Hospitalization (52% vs 13%, P < .001) and ICU admission (24% vs 9%, P < .001) were reported more often in the first-surge group.

Regression Analyses

Table 2 shows the results of logistic regression analyses for hospitalization in the pediatric (≤19 years of age) and adult (>19 years of age) groups, along with the odds of hospitalization during the first vs late surge among COVID-positive people with T1D. Adult patients who tested positive in the first surge were about 5 times more likely to be hospitalized than adults who tested positive for infection in the late surge after adjusting for age, insurance type, sex, race, and HbA1c levels. Pediatric patients also had an increased odds for hospitalization during the first surge, but this increase was not statistically significant.

Discussion

Our analysis of COVID-19 cases in patients with T1D reported by diabetes providers across the United States found that adverse outcomes were more prevalent early in the pandemic. There may be a number of reasons for this difference in outcomes between patients who presented in the first surge vs a later surge. First, because testing for COVID-19 was extremely limited and reserved for hospitalized patients early in the pandemic, the first-surge patients with confirmed COVID-19 likely represent a skewed population of higher-acuity patients. This may also explain the relative paucity of cases in younger patients reported early in the pandemic. Second, worse outcomes in the early surge may also have been associated with overwhelmed hospitals in New York City at the start of the outbreak. According to Cummings et al, the abrupt surge of critically ill patients hospitalized with severe acute respiratory distress syndrome initially outpaced their capacity to provide prone-positioning ventilation, which has been expanded since then.¹⁵ While there was very little hypertension, cardiovascular disease, or kidney disease reported in the pediatric groups, there was a higher prevalence of obesity in the pediatric group from the mid-Atlantic region. Obesity has been associated with a worse prognosis for COVID-19 illness in children.¹⁶ Finally, there were 5 deaths reported in this study, all of which were reported during the first surge. Older age and increased rates of cardiovascular disease and chronic kidney disease in the first surge cases likely contributed to worse outcomes for adults in mid-Atlantic region relative to the other regions. Minority race and the use of public insurance, risk factors for more severe outcomes in all regions, were also more common in cases reported from the mid-Atlantic region.

This study has several limitations. First, it is a cross-sectional study that relies upon voluntary provider reports. Second, availability of COVID-19 testing was limited in all regions in spring 2020. Third, different regions of the country experienced subsequent surges at different times within the reported timeframes in this analysis. Fourth, this report time period does not include the impact of the newer COVID-19 variants. Finally, trends in COVID-19 outcomes were affected by the evolution of care that developed throughout 2020.

Conclusion

Adult patients with T1D and COVID-19 who reported during the first surge had about 5 times higher hospitalization odds than those who presented in a later surge.

Corresponding author: Osagie Ebekozien, MD, MPH, 11 Avenue de Lafayette, Boston, MA 02111; [email protected]

Disclosures: Dr Ebekozien reports receiving research grants from Medtronic Diabetes, Eli Lilly, and Dexcom, and receiving honoraria from Medtronic Diabetes.

From the Department of Emergency Medicine, Santa Croce e Carle Hospital, Cuneo, Italy (Drs. Abram, Tosello, Emanuele Bernardi, Allione, Cavalot, Dutto, Corsini, Martini, Sciolla, Sara Bernardi, and Lauria). From the School of Emergency Medicine, University of Turin, Turin, Italy (Drs. Paglietta and Giamello).

Objective: This retrospective and prospective cohort study was designed to describe the characteristics, treatments, and outcomes of patients with SARS-CoV-2 infection (COVID-19) admitted to subintensive care units (SICU) and to identify the variables associated with outcomes. SICUs have been extremely stressed during the pandemic, but most data regarding critically ill COVID-19 patients come from intensive care units (ICUs). Studies about COVID-19 patients in SICUs are lacking.

Setting and participants: The study included 88 COVID-19 patients admitted to our SICU in Cuneo, Italy, between March and May 2020.

Measurements: Clinical and ventilatory data were collected, and patients were divided by outcome. Multivariable logistic regression analysis examined the variables associated with negative outcomes (transfer to the ICU, palliation, or death in a SICU).

Results: A total of 60 patients (68%) had a positive outcome, and 28 patients (32%) had a negative outcome; 69 patients (78%) underwent continuous positive airway pressure (CPAP). Pronation (n = 37 [42%]) had been more frequently adopted in patients who had a positive outcome vs a negative outcome (n = 30 [50%] vs n = 7 [25%]; P = .048), and the median (interquartile range) Pao₂/Fio₂ ratio after 6 hours of prone positioning was lower in patients who had a negative outcome vs a positive outcome (144 [140-168] vs 249 [195-268], P = .006). Independent predictors of a negative outcome were diabetes (odds ratio [OR], 8.22; 95% CI, 1.50-44.70; P = .015), higher D-dimer (OR, 1.28; 95% CI, 1.04-1.57; P = .019), higher lactate dehydrogenase level (OR, 1.003; 95% CI, 1.000-1.006; P = .039), and lower lymphocytes count (OR, 0.996; 95% CI, 0.993-0.999; P = .004).

Conclusion: SICUs have a fundamental role in the treatment of critically ill patients with COVID-19, who require long-term CPAP and pronation cycles. Diabetes, lymphopenia, and high D-dimer and LDH levels are associated with negative outcomes.

Keywords: emergency medicine, noninvasive ventilation, prone position, continuous positive airway pressure.

The COVID-19 pandemic has led to large increases in hospital admissions. Subintensive care units (SICUs) are among the wards most under pressure worldwide,¹ dealing with the increased number of critically ill patients who need noninvasive ventilation, as well as serving as the best alternative to overfilled intensive care units (ICUs). In Italy, SICUs are playing a fundamental role in the management of COVID-19 patients, providing early treatment of respiratory failure by continuous noninvasive ventilation in order to reduce the need for intubation.^2-5 Nevertheless, the great majority of available data about critically ill COVID-19 patients comes from ICUs. Full studies about outcomes of patients in SICUs are lacking and need to be conducted.

We sought to evaluate the characteristics and outcomes of patients admitted to our SICU for COVID-19 to describe the treatments they needed and their impact on prognosis, and to identify the variables associated with patient outcomes.

Methods

Study Design

This cohort study used data from patients who were admitted in the very first weeks of the pandemic. Data were collected retrospectively as well as prospectively, since the ethical committee approved our project. The quality and quantity of data in the 2 groups were comparable.

Data were collected from electronic and written medical records gathered during the patient’s entire stay in our SICU. Data were entered in a database with limited and controlled access. This study complied with the Declaration of Helsinki and was approved by the local ethics committees (ID: MEDURG10).

Study Population

We studied 88 consecutive patients admitted to the SICU of the Santa Croce e Carle Teaching Hospital, Cuneo, Italy, for COVID-19, from March 8 to May 1, 2020. The diagnosis was based on acute respiratory failure associated with SARS-CoV-2 RNA detection on nasopharyngeal swab or tracheal aspirate and/or typical COVID-19 features on a pulmonary computed tomography (CT) scan.⁶ Exclusion criteria were age younger than 18 years and patient denial of permission to use their data for research purposes (the great majority of patients could actively give consent; for patients who were too sick to do so, family members were asked whether they were aware of any reason why the patient would deny consent).

The past medical history and recent symptoms description were obtained by manually reviewing medical records. Epidemiological exposure was defined as contact with SARS-CoV-2–positive people or staying in an epidemic outbreak area. Initial vital parameters, venous blood tests, arterial blood gas analysis, chest x-ray, as well as the result of the nasopharyngeal swab were gathered from the emergency department (ED) examination. (Additional swabs could be requested when the first one was negative but clinical suspicion for COVID-19 was high.) Upon admission to the SICU, a standardized panel of blood tests was performed, which was repeated the next day and then every 48 hours. Arterial blood gas analysis was performed when clinically indicated, at least twice a day, or following a scheduled time in patients undergoing pronation. Charlson Comorbidity Index⁷ and MuLBSTA score⁸ were calculated based on the collected data.

Imaging

Chest ultrasonography was performed in the ED at the time of hospitalization and once a day in the SICU. Pulmonary high-resolution computed tomography (HRCT) was performed when clinically indicated or when the results of nasopharyngeal swabs and/or x-ray results were discordant with COVID-19 clinical suspicion. Contrast CT was performed when pulmonary embolism was suspected.

Medical Therapy

Hydroxychloroquine, antiviral agents, tocilizumab, and ruxolitinib were used in the early phase of the pandemic, then were dismissed after evidence of no efficacy.^9-11 Steroids and low-molecular-weight heparin were used afterward. Enoxaparin was used at the standard prophylactic dosage, and 70% of the anticoagulant dosage was also adopted in patients with moderate-to-severe COVID-19 and D-dimer values >3 times the normal value.^12-14 Antibiotics were given when a bacterial superinfection was suspected.

Oxygen and Ventilatory Therapy

Oxygen support or noninvasive ventilation were started based on patients’ respiratory efficacy, estimated by respiratory rate and the ratio of partial pressure of arterial oxygen and fraction of inspired oxygen (P/F ratio).^15,16 Oxygen support was delivered through nasal cannula, Venturi mask, or reservoir mask. Noninvasive ventilation was performed by continuous positive airway pressure (CPAP) when the P/F ratio was <250 or the respiratory rate was >25 breaths per minute, using the helmet interface.^5,17 Prone positioning during CPAP^18-20 was adopted in patients meeting the acute respiratory distress syndrome (ARDS) criteria²¹ and having persistence of respiratory distress and P/F <300 after a 1-hour trial of CPAP.

The prone position was maintained based on patient tolerance. P/F ratio was measured before pronation (T0), after 1 hour of prone position (T1), before resupination (T2), and 6 hours after resupination (T3). With the same timing, the patient was asked to rate their comfort in each position, from 0 (lack of comfort) to 10 (optimal comfort). Delta P/F was defined as the difference between P/F at T3 and basal P/F at T0.

Outcomes

Positive outcomes were defined as patient discharge from the SICU or transfer to a lower-intensity care ward for treatment continuation. Negative outcomes were defined as need for transfer to the ICU, transfer to another ward for palliation, or death in the SICU.

Statistical Analysis

Continuous data are reported as median and interquartile range (IQR); normal distribution of variables was tested using the Shapiro-Wilk test. Categorical variables were reported as absolute number and percentage. The Mann-Whitney test was used to compare continuous variables between groups, and chi-square test with continuity correction was used for categorical variables. The variables that were most significantly associated with a negative outcome on the univariate analysis were included in a stepwise logistic regression analysis, in order to identify independent predictors of patient outcome. Statistical analysis was performed using JASP (JASP Team) software.

Study Population

Of the 88 patients included in the study, 70% were male; the median age was 66 years (IQR, 60-77). In most patients, the diagnosis of COVID-19 was derived from a positive SARS-CoV-2 nasopharyngeal swab. Six patients, however, maintained a negative swab at all determinations but had clinical and imaging features strongly suggesting COVID-19. No patients met the exclusion criteria. Most patients came from the ED (n = 58 [66%]) or general wards (n = 22 [25%]), while few were transferred from the ICU (n = 8 [9%]). The median length of stay in the SICU was 4 days (IQR, 2-7). An epidemiological link to affected persons or a known virus exposure was identifiable in 37 patients (42%).

Clinical, Laboratory, and Imaging Data

The clinical and anthropometric characteristics of patients are shown in Table 1. Hypertension and smoking habits were prevalent in our population, and the median Charlson Comorbidity Index was 3. Most patients experienced fever, dyspnea, and cough during the days before hospitalization.

Laboratory data showed a marked inflammatory milieu in all studied patients, both at baseline and after 24 and 72 hours. Lymphopenia was observed, along with a significant increase of lactate dehydrogenase (LDH), C-reactive protein (CPR), and D-dimer, and a mild increase of procalcitonin. N-terminal pro-brain natriuretic peptide (NT-proBNP) values were also increased, with normal troponin I values (Table 2).

Medical Therapy

Most patients (89%) received hydroxychloroquine, whereas steroids were used in one-third of the population (36%). Immunomodulators (tocilizumab and ruxolitinib) were restricted to 12 patients (14%). Empirical antiviral therapy was introduced in the first 41 patients (47%). Enoxaparin was the default agent for thromboembolism prophylaxis, and 6 patients (7%) received 70% of the anticoagulating dose.

Oxygen and Ventilatory Therapy

Basal median P/F ratio was 253 (IQR, 218-291), and respiratory rate at triage was 20 breaths/min (IQR, 16-28), underlining a moderate-to-severe respiratory insufficiency at presentation. A total of 69 patients (78%) underwent CPAP, with a median positive end-expiratory pressure (PEEP) of 10.0 cm H₂O (IQR, 7.5-10.0) and fraction of inspired oxygen (Fio₂) of 0.40 (IQR, 0.40-0.50). In 37 patients (42%) who received ongoing CPAP, prone positioning was adopted. In this subgroup, respiratory rate was not significantly different from baseline to resupination (24 vs 25 breaths/min). The median P/F improved from 197 (IQR, 154-236) at baseline to 217 (IQR, 180-262) after pronation (the duration of the prone position was variable, depending on patients’ tolerance: 1 to 6 hours or every pronation cycle). The median delta P/F ratio was 39.4 (IQR, –17.0 to 78.0).

Outcomes

A total of 28 patients (32%) had a negative outcome in the SICU: 8 patients (9%) died, having no clinical indication for higher-intensity care; 6 patients (7%) were transferred to general wards for palliation; and 14 patients (16%) needed an upgrade of cure intensity and were transferred to the ICU. Of these 14 patients, 9 died in the ICU. The total in-hospital mortality of COVID-19 patients, including patients transferred from the SICU to general wards in fair condition, was 27% (n = 24). Clinical, laboratory, and therapeutic characteristics between the 2 groups are shown in Table 4.

Patients who had a negative outcome were significantly older and had more comorbidities, as suggested by a significantly higher prevalence of diabetes and higher Charlson Comorbidity scores (reflecting the mortality risk based on age and comorbidities). The median MuLBSTA score, which estimates the 90-day mortality risk from viral pneumonia, was also higher in patients who had a negative outcome (9.33%). Symptom occurrence was not different in patients with a negative outcome (apart from cough, which was less frequent), but these patients underwent hospitalization earlier—since the appearance of their first COVID-19 symptoms—compared to patients who had a positive outcome. No difference was found in antihypertensive therapy with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers among outcome groups.

More pronounced laboratory abnormalities were found in patients who had a negative outcome, compared to patients who had a positive outcome: lower lymphocytes and higher C-reactive protein (CRP), procalcitonin, D-dimer, LDH, and NT-proBNP. We found no differences in the radiological distribution of pulmonary involvement in patients who had negative or positive outcomes, nor in the adopted medical treatment.

Data showed no difference in CPAP implementation in the 2 groups. However, prone positioning had been more frequently adopted in the group of patients who had a positive outcome, compared with patients who had a negative outcome. No differences of basal P/F were found in patients who had a negative or positive outcome, but the median P/F after 6 hours of prone position was significantly lower in patients who had a negative outcome. The delta P/F ratio did not differ in the 2 groups of patients.

Multivariate Analysis

A logistic regression model was created, including the variables significantly associated with outcomes in the univariate analysis (age, sex, history of diabetes, lymphocytes, CRP, procalcitonin, LDH, NT-proBNP, and D-dimer). In the multivariate analysis, independent predictors of a negative outcome were history of diabetes (odds ratio [OR], 8.22; 95% CI, 1.50-44.70; P =.015), high D-dimer values (OR, 1.28; CI, 1.04-1.57; P = .019), high LDH values (OR, 1.003; CI, 1.000-1.006; P = .039), and low lymphocytes count (OR, 0.996; CI, 0.993-0.999; P = .004).

Discussion

Role of Subintensive Units and Mortality

The novelty of our report is its attempt to investigate the specific group of COVID-19 patients admitted to a SICU. In Italy, SICUs receive acutely ill, spontaneously breathing patients who need (invasive) hemodynamic monitoring, vasoactive medication, renal replacement therapy, chest- tube placement, thrombolysis, and respiratory noninvasive support. The nurse-to-patient ratio is higher than for general wards (usually 1 nurse to every 4 or 5 patients), though lower than for ICUs. In northern Italy, a great number of COVID-19 patients have required this kind of high-intensity care during the pandemic: Noninvasive ventilation support had to be maintained for several days, pronation maneuvers required a high number of people 2 or 3 times a day, and strict monitoring had to be assured. The SICU setting allows patients to buy time as a bridge to progressive reduction of pulmonary involvement, sometimes preventing the need for intubation.

The high prevalence of negative outcomes in the SICU underlines the complexity of COVID-19 patients in this setting. In fact, published data about mortality for patients with severe COVID-19 pneumonia are similar to ours.^22,23

Clinical, Laboratory, and Imaging Data

Our analysis confirmed a high rate of comorbidities in COVID-19 patients²⁴ and their prognostic role with age.^25,26 A marked inflammatory milieu was a negative prognostic indicator, and associated concomitant bacterial superinfection could have led to a worse prognosis (procalcitonin was associated with negative outcomes).²⁷ The cardiovascular system was nevertheless stressed, as suggested by higher values of NT-proBNP in patients with negative outcomes, which could reflect sepsis-related systemic involvement.²⁸

It is known that the pulmonary damage caused by SARS-CoV-2 has a dynamic radiological and clinical course, with early areas of subsegmental consolidation, and bilateral ground-glass opacities predominating later in the course of the disease.²⁹ This could explain why in our population we found no specific radiological pattern leading to a worse outcome.

Medical Therapy

No specific pharmacological therapy was found to be associated with a positive outcome in our study, just like antiviral and immunomodulator therapies failed to demonstrate effectiveness in subsequent pandemic surges. The low statistical power of our study did not allow us to give insight into the effectiveness of steroids and heparin at any dosage.

PEEP Support and Prone Positioning

Continuous positive airway pressure was initiated in the majority of patients and maintained for several days. This was an absolute novelty, because we rarely had to keep patients in helmets for long. This was feasible thanks to the SICU’s high nurse-to-patient ratio and the possibility of providing monitored sedation. Patients who could no longer tolerate CPAP helmets or did not improve with CPAP support were evaluated with anesthetists for programming further management. No initial data on respiratory rate, level of hypoxemia, or oxygen support need (level of PEEP and Fio₂) could discriminate between outcomes.

Prone positioning during CPAP was implemented in 42% of our study population: P/F ratio amelioration after prone positioning was highly variable, ranging from very good P/F ratio improvements to few responses or no response. No significantly greater delta P/F ratio was seen after the first prone positioning cycle in patients who had a positive outcome, probably due to the small size of our population, but we observed a clear positive trend. Interestingly, patients showing a negative outcome had a lower percentage of long-term responses to prone positioning: 6 hours after resupination, they lost the benefit of prone positioning in terms of P/F ratio amelioration. Similarly, a greater number of patients tolerating prone positioning had a positive outcome. These data give insight on the possible benefits of prone positioning in a noninvasively supported cohort of patients, which has been mentioned in previous studies.^30,31

Outcomes and Variables Associated With Negative Outcomes

After correction for age and sex, we found in multiple regression analysis that higher D-dimer and LDH values, lymphopenia, and history of diabetes were independently associated with a worse outcome. Although our results had low statistical significance, we consider the trend of the obtained odds ratios important from a clinical point of view. These results could lead to greater attention being placed on COVID-19 patients who present with these characteristics upon their arrival to the ED because they have increased risk of death or intensive care need. Clinicians should consider SICU admission for these patients in order to guarantee closer monitoring and possibly more aggressive ventilatory treatments, earlier pronation, or earlier transfer to the ICU.

Limitations

The major limitation to our study is undoubtedly its statistical power, due to its relatively low patient population. Particularly, the small number of patients who underwent pronation did not allow speculation about the efficacy of this technique, although preliminary data seem promising. However, ours is among the first studies regarding patients with COVID-19 admitted to a SICU, and these preliminary data truthfully describe the Italian, and perhaps international, experience with the first surge of the pandemic.

Conclusions

Our data highlight the primary role of the SICU in COVID-19 in adequately treating critically ill patients who have high care needs different from intubation, and who require noninvasive ventilation for prolonged times as well as frequent pronation cycles. This setting of care may represent a valid, reliable, and effective option for critically ill respiratory patients. History of diabetes, lymphopenia, and high D-dimer and LDH values are independently associated with negative outcomes, and patients presenting with these characteristics should be strictly monitored.

Acknowledgments: The authors thank the Informatica System S.R.L., as well as Allessando Mendolia for the pro bono creation of the ISCovidCollect data collecting app.

Corresponding author: Sara Abram, MD, via Coppino, 12100 Cuneo, Italy; [email protected].

Disclosures: None.

From the Department of Emergency Medicine, Santa Croce e Carle Hospital, Cuneo, Italy (Drs. Abram, Tosello, Emanuele Bernardi, Allione, Cavalot, Dutto, Corsini, Martini, Sciolla, Sara Bernardi, and Lauria). From the School of Emergency Medicine, University of Turin, Turin, Italy (Drs. Paglietta and Giamello).

Objective: This retrospective and prospective cohort study was designed to describe the characteristics, treatments, and outcomes of patients with SARS-CoV-2 infection (COVID-19) admitted to subintensive care units (SICU) and to identify the variables associated with outcomes. SICUs have been extremely stressed during the pandemic, but most data regarding critically ill COVID-19 patients come from intensive care units (ICUs). Studies about COVID-19 patients in SICUs are lacking.

Setting and participants: The study included 88 COVID-19 patients admitted to our SICU in Cuneo, Italy, between March and May 2020.

Measurements: Clinical and ventilatory data were collected, and patients were divided by outcome. Multivariable logistic regression analysis examined the variables associated with negative outcomes (transfer to the ICU, palliation, or death in a SICU).

Results: A total of 60 patients (68%) had a positive outcome, and 28 patients (32%) had a negative outcome; 69 patients (78%) underwent continuous positive airway pressure (CPAP). Pronation (n = 37 [42%]) had been more frequently adopted in patients who had a positive outcome vs a negative outcome (n = 30 [50%] vs n = 7 [25%]; P = .048), and the median (interquartile range) Pao₂/Fio₂ ratio after 6 hours of prone positioning was lower in patients who had a negative outcome vs a positive outcome (144 [140-168] vs 249 [195-268], P = .006). Independent predictors of a negative outcome were diabetes (odds ratio [OR], 8.22; 95% CI, 1.50-44.70; P = .015), higher D-dimer (OR, 1.28; 95% CI, 1.04-1.57; P = .019), higher lactate dehydrogenase level (OR, 1.003; 95% CI, 1.000-1.006; P = .039), and lower lymphocytes count (OR, 0.996; 95% CI, 0.993-0.999; P = .004).

Conclusion: SICUs have a fundamental role in the treatment of critically ill patients with COVID-19, who require long-term CPAP and pronation cycles. Diabetes, lymphopenia, and high D-dimer and LDH levels are associated with negative outcomes.

Keywords: emergency medicine, noninvasive ventilation, prone position, continuous positive airway pressure.

The COVID-19 pandemic has led to large increases in hospital admissions. Subintensive care units (SICUs) are among the wards most under pressure worldwide,¹ dealing with the increased number of critically ill patients who need noninvasive ventilation, as well as serving as the best alternative to overfilled intensive care units (ICUs). In Italy, SICUs are playing a fundamental role in the management of COVID-19 patients, providing early treatment of respiratory failure by continuous noninvasive ventilation in order to reduce the need for intubation.^2-5 Nevertheless, the great majority of available data about critically ill COVID-19 patients comes from ICUs. Full studies about outcomes of patients in SICUs are lacking and need to be conducted.

We sought to evaluate the characteristics and outcomes of patients admitted to our SICU for COVID-19 to describe the treatments they needed and their impact on prognosis, and to identify the variables associated with patient outcomes.

Methods

Study Design

This cohort study used data from patients who were admitted in the very first weeks of the pandemic. Data were collected retrospectively as well as prospectively, since the ethical committee approved our project. The quality and quantity of data in the 2 groups were comparable.

Data were collected from electronic and written medical records gathered during the patient’s entire stay in our SICU. Data were entered in a database with limited and controlled access. This study complied with the Declaration of Helsinki and was approved by the local ethics committees (ID: MEDURG10).

Study Population

We studied 88 consecutive patients admitted to the SICU of the Santa Croce e Carle Teaching Hospital, Cuneo, Italy, for COVID-19, from March 8 to May 1, 2020. The diagnosis was based on acute respiratory failure associated with SARS-CoV-2 RNA detection on nasopharyngeal swab or tracheal aspirate and/or typical COVID-19 features on a pulmonary computed tomography (CT) scan.⁶ Exclusion criteria were age younger than 18 years and patient denial of permission to use their data for research purposes (the great majority of patients could actively give consent; for patients who were too sick to do so, family members were asked whether they were aware of any reason why the patient would deny consent).

The past medical history and recent symptoms description were obtained by manually reviewing medical records. Epidemiological exposure was defined as contact with SARS-CoV-2–positive people or staying in an epidemic outbreak area. Initial vital parameters, venous blood tests, arterial blood gas analysis, chest x-ray, as well as the result of the nasopharyngeal swab were gathered from the emergency department (ED) examination. (Additional swabs could be requested when the first one was negative but clinical suspicion for COVID-19 was high.) Upon admission to the SICU, a standardized panel of blood tests was performed, which was repeated the next day and then every 48 hours. Arterial blood gas analysis was performed when clinically indicated, at least twice a day, or following a scheduled time in patients undergoing pronation. Charlson Comorbidity Index⁷ and MuLBSTA score⁸ were calculated based on the collected data.

Imaging

Chest ultrasonography was performed in the ED at the time of hospitalization and once a day in the SICU. Pulmonary high-resolution computed tomography (HRCT) was performed when clinically indicated or when the results of nasopharyngeal swabs and/or x-ray results were discordant with COVID-19 clinical suspicion. Contrast CT was performed when pulmonary embolism was suspected.

Medical Therapy

Hydroxychloroquine, antiviral agents, tocilizumab, and ruxolitinib were used in the early phase of the pandemic, then were dismissed after evidence of no efficacy.^9-11 Steroids and low-molecular-weight heparin were used afterward. Enoxaparin was used at the standard prophylactic dosage, and 70% of the anticoagulant dosage was also adopted in patients with moderate-to-severe COVID-19 and D-dimer values >3 times the normal value.^12-14 Antibiotics were given when a bacterial superinfection was suspected.

Oxygen and Ventilatory Therapy

Oxygen support or noninvasive ventilation were started based on patients’ respiratory efficacy, estimated by respiratory rate and the ratio of partial pressure of arterial oxygen and fraction of inspired oxygen (P/F ratio).^15,16 Oxygen support was delivered through nasal cannula, Venturi mask, or reservoir mask. Noninvasive ventilation was performed by continuous positive airway pressure (CPAP) when the P/F ratio was <250 or the respiratory rate was >25 breaths per minute, using the helmet interface.^5,17 Prone positioning during CPAP^18-20 was adopted in patients meeting the acute respiratory distress syndrome (ARDS) criteria²¹ and having persistence of respiratory distress and P/F <300 after a 1-hour trial of CPAP.

The prone position was maintained based on patient tolerance. P/F ratio was measured before pronation (T0), after 1 hour of prone position (T1), before resupination (T2), and 6 hours after resupination (T3). With the same timing, the patient was asked to rate their comfort in each position, from 0 (lack of comfort) to 10 (optimal comfort). Delta P/F was defined as the difference between P/F at T3 and basal P/F at T0.

Outcomes

Positive outcomes were defined as patient discharge from the SICU or transfer to a lower-intensity care ward for treatment continuation. Negative outcomes were defined as need for transfer to the ICU, transfer to another ward for palliation, or death in the SICU.

Statistical Analysis

Continuous data are reported as median and interquartile range (IQR); normal distribution of variables was tested using the Shapiro-Wilk test. Categorical variables were reported as absolute number and percentage. The Mann-Whitney test was used to compare continuous variables between groups, and chi-square test with continuity correction was used for categorical variables. The variables that were most significantly associated with a negative outcome on the univariate analysis were included in a stepwise logistic regression analysis, in order to identify independent predictors of patient outcome. Statistical analysis was performed using JASP (JASP Team) software.

Study Population

Of the 88 patients included in the study, 70% were male; the median age was 66 years (IQR, 60-77). In most patients, the diagnosis of COVID-19 was derived from a positive SARS-CoV-2 nasopharyngeal swab. Six patients, however, maintained a negative swab at all determinations but had clinical and imaging features strongly suggesting COVID-19. No patients met the exclusion criteria. Most patients came from the ED (n = 58 [66%]) or general wards (n = 22 [25%]), while few were transferred from the ICU (n = 8 [9%]). The median length of stay in the SICU was 4 days (IQR, 2-7). An epidemiological link to affected persons or a known virus exposure was identifiable in 37 patients (42%).

Clinical, Laboratory, and Imaging Data

The clinical and anthropometric characteristics of patients are shown in Table 1. Hypertension and smoking habits were prevalent in our population, and the median Charlson Comorbidity Index was 3. Most patients experienced fever, dyspnea, and cough during the days before hospitalization.

Laboratory data showed a marked inflammatory milieu in all studied patients, both at baseline and after 24 and 72 hours. Lymphopenia was observed, along with a significant increase of lactate dehydrogenase (LDH), C-reactive protein (CPR), and D-dimer, and a mild increase of procalcitonin. N-terminal pro-brain natriuretic peptide (NT-proBNP) values were also increased, with normal troponin I values (Table 2).

Medical Therapy

Most patients (89%) received hydroxychloroquine, whereas steroids were used in one-third of the population (36%). Immunomodulators (tocilizumab and ruxolitinib) were restricted to 12 patients (14%). Empirical antiviral therapy was introduced in the first 41 patients (47%). Enoxaparin was the default agent for thromboembolism prophylaxis, and 6 patients (7%) received 70% of the anticoagulating dose.

Oxygen and Ventilatory Therapy

Basal median P/F ratio was 253 (IQR, 218-291), and respiratory rate at triage was 20 breaths/min (IQR, 16-28), underlining a moderate-to-severe respiratory insufficiency at presentation. A total of 69 patients (78%) underwent CPAP, with a median positive end-expiratory pressure (PEEP) of 10.0 cm H₂O (IQR, 7.5-10.0) and fraction of inspired oxygen (Fio₂) of 0.40 (IQR, 0.40-0.50). In 37 patients (42%) who received ongoing CPAP, prone positioning was adopted. In this subgroup, respiratory rate was not significantly different from baseline to resupination (24 vs 25 breaths/min). The median P/F improved from 197 (IQR, 154-236) at baseline to 217 (IQR, 180-262) after pronation (the duration of the prone position was variable, depending on patients’ tolerance: 1 to 6 hours or every pronation cycle). The median delta P/F ratio was 39.4 (IQR, –17.0 to 78.0).

Outcomes

A total of 28 patients (32%) had a negative outcome in the SICU: 8 patients (9%) died, having no clinical indication for higher-intensity care; 6 patients (7%) were transferred to general wards for palliation; and 14 patients (16%) needed an upgrade of cure intensity and were transferred to the ICU. Of these 14 patients, 9 died in the ICU. The total in-hospital mortality of COVID-19 patients, including patients transferred from the SICU to general wards in fair condition, was 27% (n = 24). Clinical, laboratory, and therapeutic characteristics between the 2 groups are shown in Table 4.

Patients who had a negative outcome were significantly older and had more comorbidities, as suggested by a significantly higher prevalence of diabetes and higher Charlson Comorbidity scores (reflecting the mortality risk based on age and comorbidities). The median MuLBSTA score, which estimates the 90-day mortality risk from viral pneumonia, was also higher in patients who had a negative outcome (9.33%). Symptom occurrence was not different in patients with a negative outcome (apart from cough, which was less frequent), but these patients underwent hospitalization earlier—since the appearance of their first COVID-19 symptoms—compared to patients who had a positive outcome. No difference was found in antihypertensive therapy with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers among outcome groups.

More pronounced laboratory abnormalities were found in patients who had a negative outcome, compared to patients who had a positive outcome: lower lymphocytes and higher C-reactive protein (CRP), procalcitonin, D-dimer, LDH, and NT-proBNP. We found no differences in the radiological distribution of pulmonary involvement in patients who had negative or positive outcomes, nor in the adopted medical treatment.

Data showed no difference in CPAP implementation in the 2 groups. However, prone positioning had been more frequently adopted in the group of patients who had a positive outcome, compared with patients who had a negative outcome. No differences of basal P/F were found in patients who had a negative or positive outcome, but the median P/F after 6 hours of prone position was significantly lower in patients who had a negative outcome. The delta P/F ratio did not differ in the 2 groups of patients.

Multivariate Analysis

A logistic regression model was created, including the variables significantly associated with outcomes in the univariate analysis (age, sex, history of diabetes, lymphocytes, CRP, procalcitonin, LDH, NT-proBNP, and D-dimer). In the multivariate analysis, independent predictors of a negative outcome were history of diabetes (odds ratio [OR], 8.22; 95% CI, 1.50-44.70; P =.015), high D-dimer values (OR, 1.28; CI, 1.04-1.57; P = .019), high LDH values (OR, 1.003; CI, 1.000-1.006; P = .039), and low lymphocytes count (OR, 0.996; CI, 0.993-0.999; P = .004).

Discussion

Role of Subintensive Units and Mortality

The novelty of our report is its attempt to investigate the specific group of COVID-19 patients admitted to a SICU. In Italy, SICUs receive acutely ill, spontaneously breathing patients who need (invasive) hemodynamic monitoring, vasoactive medication, renal replacement therapy, chest- tube placement, thrombolysis, and respiratory noninvasive support. The nurse-to-patient ratio is higher than for general wards (usually 1 nurse to every 4 or 5 patients), though lower than for ICUs. In northern Italy, a great number of COVID-19 patients have required this kind of high-intensity care during the pandemic: Noninvasive ventilation support had to be maintained for several days, pronation maneuvers required a high number of people 2 or 3 times a day, and strict monitoring had to be assured. The SICU setting allows patients to buy time as a bridge to progressive reduction of pulmonary involvement, sometimes preventing the need for intubation.

The high prevalence of negative outcomes in the SICU underlines the complexity of COVID-19 patients in this setting. In fact, published data about mortality for patients with severe COVID-19 pneumonia are similar to ours.^22,23

Clinical, Laboratory, and Imaging Data

Our analysis confirmed a high rate of comorbidities in COVID-19 patients²⁴ and their prognostic role with age.^25,26 A marked inflammatory milieu was a negative prognostic indicator, and associated concomitant bacterial superinfection could have led to a worse prognosis (procalcitonin was associated with negative outcomes).²⁷ The cardiovascular system was nevertheless stressed, as suggested by higher values of NT-proBNP in patients with negative outcomes, which could reflect sepsis-related systemic involvement.²⁸

It is known that the pulmonary damage caused by SARS-CoV-2 has a dynamic radiological and clinical course, with early areas of subsegmental consolidation, and bilateral ground-glass opacities predominating later in the course of the disease.²⁹ This could explain why in our population we found no specific radiological pattern leading to a worse outcome.

Medical Therapy

No specific pharmacological therapy was found to be associated with a positive outcome in our study, just like antiviral and immunomodulator therapies failed to demonstrate effectiveness in subsequent pandemic surges. The low statistical power of our study did not allow us to give insight into the effectiveness of steroids and heparin at any dosage.

PEEP Support and Prone Positioning

Continuous positive airway pressure was initiated in the majority of patients and maintained for several days. This was an absolute novelty, because we rarely had to keep patients in helmets for long. This was feasible thanks to the SICU’s high nurse-to-patient ratio and the possibility of providing monitored sedation. Patients who could no longer tolerate CPAP helmets or did not improve with CPAP support were evaluated with anesthetists for programming further management. No initial data on respiratory rate, level of hypoxemia, or oxygen support need (level of PEEP and Fio₂) could discriminate between outcomes.

Prone positioning during CPAP was implemented in 42% of our study population: P/F ratio amelioration after prone positioning was highly variable, ranging from very good P/F ratio improvements to few responses or no response. No significantly greater delta P/F ratio was seen after the first prone positioning cycle in patients who had a positive outcome, probably due to the small size of our population, but we observed a clear positive trend. Interestingly, patients showing a negative outcome had a lower percentage of long-term responses to prone positioning: 6 hours after resupination, they lost the benefit of prone positioning in terms of P/F ratio amelioration. Similarly, a greater number of patients tolerating prone positioning had a positive outcome. These data give insight on the possible benefits of prone positioning in a noninvasively supported cohort of patients, which has been mentioned in previous studies.^30,31

Outcomes and Variables Associated With Negative Outcomes

After correction for age and sex, we found in multiple regression analysis that higher D-dimer and LDH values, lymphopenia, and history of diabetes were independently associated with a worse outcome. Although our results had low statistical significance, we consider the trend of the obtained odds ratios important from a clinical point of view. These results could lead to greater attention being placed on COVID-19 patients who present with these characteristics upon their arrival to the ED because they have increased risk of death or intensive care need. Clinicians should consider SICU admission for these patients in order to guarantee closer monitoring and possibly more aggressive ventilatory treatments, earlier pronation, or earlier transfer to the ICU.

Limitations

The major limitation to our study is undoubtedly its statistical power, due to its relatively low patient population. Particularly, the small number of patients who underwent pronation did not allow speculation about the efficacy of this technique, although preliminary data seem promising. However, ours is among the first studies regarding patients with COVID-19 admitted to a SICU, and these preliminary data truthfully describe the Italian, and perhaps international, experience with the first surge of the pandemic.

Conclusions

Our data highlight the primary role of the SICU in COVID-19 in adequately treating critically ill patients who have high care needs different from intubation, and who require noninvasive ventilation for prolonged times as well as frequent pronation cycles. This setting of care may represent a valid, reliable, and effective option for critically ill respiratory patients. History of diabetes, lymphopenia, and high D-dimer and LDH values are independently associated with negative outcomes, and patients presenting with these characteristics should be strictly monitored.

Acknowledgments: The authors thank the Informatica System S.R.L., as well as Allessando Mendolia for the pro bono creation of the ISCovidCollect data collecting app.

Corresponding author: Sara Abram, MD, via Coppino, 12100 Cuneo, Italy; [email protected].

Disclosures: None.

From the Department of Emergency Medicine, Santa Croce e Carle Hospital, Cuneo, Italy (Drs. Abram, Tosello, Emanuele Bernardi, Allione, Cavalot, Dutto, Corsini, Martini, Sciolla, Sara Bernardi, and Lauria). From the School of Emergency Medicine, University of Turin, Turin, Italy (Drs. Paglietta and Giamello).

Objective: This retrospective and prospective cohort study was designed to describe the characteristics, treatments, and outcomes of patients with SARS-CoV-2 infection (COVID-19) admitted to subintensive care units (SICU) and to identify the variables associated with outcomes. SICUs have been extremely stressed during the pandemic, but most data regarding critically ill COVID-19 patients come from intensive care units (ICUs). Studies about COVID-19 patients in SICUs are lacking.

Setting and participants: The study included 88 COVID-19 patients admitted to our SICU in Cuneo, Italy, between March and May 2020.

Measurements: Clinical and ventilatory data were collected, and patients were divided by outcome. Multivariable logistic regression analysis examined the variables associated with negative outcomes (transfer to the ICU, palliation, or death in a SICU).

Results: A total of 60 patients (68%) had a positive outcome, and 28 patients (32%) had a negative outcome; 69 patients (78%) underwent continuous positive airway pressure (CPAP). Pronation (n = 37 [42%]) had been more frequently adopted in patients who had a positive outcome vs a negative outcome (n = 30 [50%] vs n = 7 [25%]; P = .048), and the median (interquartile range) Pao₂/Fio₂ ratio after 6 hours of prone positioning was lower in patients who had a negative outcome vs a positive outcome (144 [140-168] vs 249 [195-268], P = .006). Independent predictors of a negative outcome were diabetes (odds ratio [OR], 8.22; 95% CI, 1.50-44.70; P = .015), higher D-dimer (OR, 1.28; 95% CI, 1.04-1.57; P = .019), higher lactate dehydrogenase level (OR, 1.003; 95% CI, 1.000-1.006; P = .039), and lower lymphocytes count (OR, 0.996; 95% CI, 0.993-0.999; P = .004).

Conclusion: SICUs have a fundamental role in the treatment of critically ill patients with COVID-19, who require long-term CPAP and pronation cycles. Diabetes, lymphopenia, and high D-dimer and LDH levels are associated with negative outcomes.

Keywords: emergency medicine, noninvasive ventilation, prone position, continuous positive airway pressure.

The COVID-19 pandemic has led to large increases in hospital admissions. Subintensive care units (SICUs) are among the wards most under pressure worldwide,¹ dealing with the increased number of critically ill patients who need noninvasive ventilation, as well as serving as the best alternative to overfilled intensive care units (ICUs). In Italy, SICUs are playing a fundamental role in the management of COVID-19 patients, providing early treatment of respiratory failure by continuous noninvasive ventilation in order to reduce the need for intubation.^2-5 Nevertheless, the great majority of available data about critically ill COVID-19 patients comes from ICUs. Full studies about outcomes of patients in SICUs are lacking and need to be conducted.

We sought to evaluate the characteristics and outcomes of patients admitted to our SICU for COVID-19 to describe the treatments they needed and their impact on prognosis, and to identify the variables associated with patient outcomes.

Methods

Study Design

This cohort study used data from patients who were admitted in the very first weeks of the pandemic. Data were collected retrospectively as well as prospectively, since the ethical committee approved our project. The quality and quantity of data in the 2 groups were comparable.

Data were collected from electronic and written medical records gathered during the patient’s entire stay in our SICU. Data were entered in a database with limited and controlled access. This study complied with the Declaration of Helsinki and was approved by the local ethics committees (ID: MEDURG10).

Study Population

We studied 88 consecutive patients admitted to the SICU of the Santa Croce e Carle Teaching Hospital, Cuneo, Italy, for COVID-19, from March 8 to May 1, 2020. The diagnosis was based on acute respiratory failure associated with SARS-CoV-2 RNA detection on nasopharyngeal swab or tracheal aspirate and/or typical COVID-19 features on a pulmonary computed tomography (CT) scan.⁶ Exclusion criteria were age younger than 18 years and patient denial of permission to use their data for research purposes (the great majority of patients could actively give consent; for patients who were too sick to do so, family members were asked whether they were aware of any reason why the patient would deny consent).

The past medical history and recent symptoms description were obtained by manually reviewing medical records. Epidemiological exposure was defined as contact with SARS-CoV-2–positive people or staying in an epidemic outbreak area. Initial vital parameters, venous blood tests, arterial blood gas analysis, chest x-ray, as well as the result of the nasopharyngeal swab were gathered from the emergency department (ED) examination. (Additional swabs could be requested when the first one was negative but clinical suspicion for COVID-19 was high.) Upon admission to the SICU, a standardized panel of blood tests was performed, which was repeated the next day and then every 48 hours. Arterial blood gas analysis was performed when clinically indicated, at least twice a day, or following a scheduled time in patients undergoing pronation. Charlson Comorbidity Index⁷ and MuLBSTA score⁸ were calculated based on the collected data.

Imaging

Chest ultrasonography was performed in the ED at the time of hospitalization and once a day in the SICU. Pulmonary high-resolution computed tomography (HRCT) was performed when clinically indicated or when the results of nasopharyngeal swabs and/or x-ray results were discordant with COVID-19 clinical suspicion. Contrast CT was performed when pulmonary embolism was suspected.

Medical Therapy

Hydroxychloroquine, antiviral agents, tocilizumab, and ruxolitinib were used in the early phase of the pandemic, then were dismissed after evidence of no efficacy.^9-11 Steroids and low-molecular-weight heparin were used afterward. Enoxaparin was used at the standard prophylactic dosage, and 70% of the anticoagulant dosage was also adopted in patients with moderate-to-severe COVID-19 and D-dimer values >3 times the normal value.^12-14 Antibiotics were given when a bacterial superinfection was suspected.

Oxygen and Ventilatory Therapy

Oxygen support or noninvasive ventilation were started based on patients’ respiratory efficacy, estimated by respiratory rate and the ratio of partial pressure of arterial oxygen and fraction of inspired oxygen (P/F ratio).^15,16 Oxygen support was delivered through nasal cannula, Venturi mask, or reservoir mask. Noninvasive ventilation was performed by continuous positive airway pressure (CPAP) when the P/F ratio was <250 or the respiratory rate was >25 breaths per minute, using the helmet interface.^5,17 Prone positioning during CPAP^18-20 was adopted in patients meeting the acute respiratory distress syndrome (ARDS) criteria²¹ and having persistence of respiratory distress and P/F <300 after a 1-hour trial of CPAP.

The prone position was maintained based on patient tolerance. P/F ratio was measured before pronation (T0), after 1 hour of prone position (T1), before resupination (T2), and 6 hours after resupination (T3). With the same timing, the patient was asked to rate their comfort in each position, from 0 (lack of comfort) to 10 (optimal comfort). Delta P/F was defined as the difference between P/F at T3 and basal P/F at T0.

Outcomes

Positive outcomes were defined as patient discharge from the SICU or transfer to a lower-intensity care ward for treatment continuation. Negative outcomes were defined as need for transfer to the ICU, transfer to another ward for palliation, or death in the SICU.

Statistical Analysis

Continuous data are reported as median and interquartile range (IQR); normal distribution of variables was tested using the Shapiro-Wilk test. Categorical variables were reported as absolute number and percentage. The Mann-Whitney test was used to compare continuous variables between groups, and chi-square test with continuity correction was used for categorical variables. The variables that were most significantly associated with a negative outcome on the univariate analysis were included in a stepwise logistic regression analysis, in order to identify independent predictors of patient outcome. Statistical analysis was performed using JASP (JASP Team) software.

Study Population

Of the 88 patients included in the study, 70% were male; the median age was 66 years (IQR, 60-77). In most patients, the diagnosis of COVID-19 was derived from a positive SARS-CoV-2 nasopharyngeal swab. Six patients, however, maintained a negative swab at all determinations but had clinical and imaging features strongly suggesting COVID-19. No patients met the exclusion criteria. Most patients came from the ED (n = 58 [66%]) or general wards (n = 22 [25%]), while few were transferred from the ICU (n = 8 [9%]). The median length of stay in the SICU was 4 days (IQR, 2-7). An epidemiological link to affected persons or a known virus exposure was identifiable in 37 patients (42%).

Clinical, Laboratory, and Imaging Data

The clinical and anthropometric characteristics of patients are shown in Table 1. Hypertension and smoking habits were prevalent in our population, and the median Charlson Comorbidity Index was 3. Most patients experienced fever, dyspnea, and cough during the days before hospitalization.

Laboratory data showed a marked inflammatory milieu in all studied patients, both at baseline and after 24 and 72 hours. Lymphopenia was observed, along with a significant increase of lactate dehydrogenase (LDH), C-reactive protein (CPR), and D-dimer, and a mild increase of procalcitonin. N-terminal pro-brain natriuretic peptide (NT-proBNP) values were also increased, with normal troponin I values (Table 2).

Medical Therapy

Most patients (89%) received hydroxychloroquine, whereas steroids were used in one-third of the population (36%). Immunomodulators (tocilizumab and ruxolitinib) were restricted to 12 patients (14%). Empirical antiviral therapy was introduced in the first 41 patients (47%). Enoxaparin was the default agent for thromboembolism prophylaxis, and 6 patients (7%) received 70% of the anticoagulating dose.

Oxygen and Ventilatory Therapy

Basal median P/F ratio was 253 (IQR, 218-291), and respiratory rate at triage was 20 breaths/min (IQR, 16-28), underlining a moderate-to-severe respiratory insufficiency at presentation. A total of 69 patients (78%) underwent CPAP, with a median positive end-expiratory pressure (PEEP) of 10.0 cm H₂O (IQR, 7.5-10.0) and fraction of inspired oxygen (Fio₂) of 0.40 (IQR, 0.40-0.50). In 37 patients (42%) who received ongoing CPAP, prone positioning was adopted. In this subgroup, respiratory rate was not significantly different from baseline to resupination (24 vs 25 breaths/min). The median P/F improved from 197 (IQR, 154-236) at baseline to 217 (IQR, 180-262) after pronation (the duration of the prone position was variable, depending on patients’ tolerance: 1 to 6 hours or every pronation cycle). The median delta P/F ratio was 39.4 (IQR, –17.0 to 78.0).

Outcomes

A total of 28 patients (32%) had a negative outcome in the SICU: 8 patients (9%) died, having no clinical indication for higher-intensity care; 6 patients (7%) were transferred to general wards for palliation; and 14 patients (16%) needed an upgrade of cure intensity and were transferred to the ICU. Of these 14 patients, 9 died in the ICU. The total in-hospital mortality of COVID-19 patients, including patients transferred from the SICU to general wards in fair condition, was 27% (n = 24). Clinical, laboratory, and therapeutic characteristics between the 2 groups are shown in Table 4.

Patients who had a negative outcome were significantly older and had more comorbidities, as suggested by a significantly higher prevalence of diabetes and higher Charlson Comorbidity scores (reflecting the mortality risk based on age and comorbidities). The median MuLBSTA score, which estimates the 90-day mortality risk from viral pneumonia, was also higher in patients who had a negative outcome (9.33%). Symptom occurrence was not different in patients with a negative outcome (apart from cough, which was less frequent), but these patients underwent hospitalization earlier—since the appearance of their first COVID-19 symptoms—compared to patients who had a positive outcome. No difference was found in antihypertensive therapy with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers among outcome groups.

More pronounced laboratory abnormalities were found in patients who had a negative outcome, compared to patients who had a positive outcome: lower lymphocytes and higher C-reactive protein (CRP), procalcitonin, D-dimer, LDH, and NT-proBNP. We found no differences in the radiological distribution of pulmonary involvement in patients who had negative or positive outcomes, nor in the adopted medical treatment.

Data showed no difference in CPAP implementation in the 2 groups. However, prone positioning had been more frequently adopted in the group of patients who had a positive outcome, compared with patients who had a negative outcome. No differences of basal P/F were found in patients who had a negative or positive outcome, but the median P/F after 6 hours of prone position was significantly lower in patients who had a negative outcome. The delta P/F ratio did not differ in the 2 groups of patients.

Multivariate Analysis

A logistic regression model was created, including the variables significantly associated with outcomes in the univariate analysis (age, sex, history of diabetes, lymphocytes, CRP, procalcitonin, LDH, NT-proBNP, and D-dimer). In the multivariate analysis, independent predictors of a negative outcome were history of diabetes (odds ratio [OR], 8.22; 95% CI, 1.50-44.70; P =.015), high D-dimer values (OR, 1.28; CI, 1.04-1.57; P = .019), high LDH values (OR, 1.003; CI, 1.000-1.006; P = .039), and low lymphocytes count (OR, 0.996; CI, 0.993-0.999; P = .004).

Discussion

Role of Subintensive Units and Mortality

The novelty of our report is its attempt to investigate the specific group of COVID-19 patients admitted to a SICU. In Italy, SICUs receive acutely ill, spontaneously breathing patients who need (invasive) hemodynamic monitoring, vasoactive medication, renal replacement therapy, chest- tube placement, thrombolysis, and respiratory noninvasive support. The nurse-to-patient ratio is higher than for general wards (usually 1 nurse to every 4 or 5 patients), though lower than for ICUs. In northern Italy, a great number of COVID-19 patients have required this kind of high-intensity care during the pandemic: Noninvasive ventilation support had to be maintained for several days, pronation maneuvers required a high number of people 2 or 3 times a day, and strict monitoring had to be assured. The SICU setting allows patients to buy time as a bridge to progressive reduction of pulmonary involvement, sometimes preventing the need for intubation.

The high prevalence of negative outcomes in the SICU underlines the complexity of COVID-19 patients in this setting. In fact, published data about mortality for patients with severe COVID-19 pneumonia are similar to ours.^22,23

Clinical, Laboratory, and Imaging Data

Our analysis confirmed a high rate of comorbidities in COVID-19 patients²⁴ and their prognostic role with age.^25,26 A marked inflammatory milieu was a negative prognostic indicator, and associated concomitant bacterial superinfection could have led to a worse prognosis (procalcitonin was associated with negative outcomes).²⁷ The cardiovascular system was nevertheless stressed, as suggested by higher values of NT-proBNP in patients with negative outcomes, which could reflect sepsis-related systemic involvement.²⁸

It is known that the pulmonary damage caused by SARS-CoV-2 has a dynamic radiological and clinical course, with early areas of subsegmental consolidation, and bilateral ground-glass opacities predominating later in the course of the disease.²⁹ This could explain why in our population we found no specific radiological pattern leading to a worse outcome.

Medical Therapy

No specific pharmacological therapy was found to be associated with a positive outcome in our study, just like antiviral and immunomodulator therapies failed to demonstrate effectiveness in subsequent pandemic surges. The low statistical power of our study did not allow us to give insight into the effectiveness of steroids and heparin at any dosage.

PEEP Support and Prone Positioning

Continuous positive airway pressure was initiated in the majority of patients and maintained for several days. This was an absolute novelty, because we rarely had to keep patients in helmets for long. This was feasible thanks to the SICU’s high nurse-to-patient ratio and the possibility of providing monitored sedation. Patients who could no longer tolerate CPAP helmets or did not improve with CPAP support were evaluated with anesthetists for programming further management. No initial data on respiratory rate, level of hypoxemia, or oxygen support need (level of PEEP and Fio₂) could discriminate between outcomes.

Prone positioning during CPAP was implemented in 42% of our study population: P/F ratio amelioration after prone positioning was highly variable, ranging from very good P/F ratio improvements to few responses or no response. No significantly greater delta P/F ratio was seen after the first prone positioning cycle in patients who had a positive outcome, probably due to the small size of our population, but we observed a clear positive trend. Interestingly, patients showing a negative outcome had a lower percentage of long-term responses to prone positioning: 6 hours after resupination, they lost the benefit of prone positioning in terms of P/F ratio amelioration. Similarly, a greater number of patients tolerating prone positioning had a positive outcome. These data give insight on the possible benefits of prone positioning in a noninvasively supported cohort of patients, which has been mentioned in previous studies.^30,31

Outcomes and Variables Associated With Negative Outcomes

After correction for age and sex, we found in multiple regression analysis that higher D-dimer and LDH values, lymphopenia, and history of diabetes were independently associated with a worse outcome. Although our results had low statistical significance, we consider the trend of the obtained odds ratios important from a clinical point of view. These results could lead to greater attention being placed on COVID-19 patients who present with these characteristics upon their arrival to the ED because they have increased risk of death or intensive care need. Clinicians should consider SICU admission for these patients in order to guarantee closer monitoring and possibly more aggressive ventilatory treatments, earlier pronation, or earlier transfer to the ICU.

Limitations

The major limitation to our study is undoubtedly its statistical power, due to its relatively low patient population. Particularly, the small number of patients who underwent pronation did not allow speculation about the efficacy of this technique, although preliminary data seem promising. However, ours is among the first studies regarding patients with COVID-19 admitted to a SICU, and these preliminary data truthfully describe the Italian, and perhaps international, experience with the first surge of the pandemic.

Conclusions

Our data highlight the primary role of the SICU in COVID-19 in adequately treating critically ill patients who have high care needs different from intubation, and who require noninvasive ventilation for prolonged times as well as frequent pronation cycles. This setting of care may represent a valid, reliable, and effective option for critically ill respiratory patients. History of diabetes, lymphopenia, and high D-dimer and LDH values are independently associated with negative outcomes, and patients presenting with these characteristics should be strictly monitored.

Acknowledgments: The authors thank the Informatica System S.R.L., as well as Allessando Mendolia for the pro bono creation of the ISCovidCollect data collecting app.

Corresponding author: Sara Abram, MD, via Coppino, 12100 Cuneo, Italy; [email protected].

Disclosures: None.

Equitable Standards for All Patients in a Crisis

Health care delivered during a pandemic instantiates medicine’s perspectives on the value of human life in clinical scenarios where resource allocation is limited. The COVID-19 pandemic has fostered dialogue and debate around the ethical principles that underly such resource allocation, which generally balance (1) utilitarian optimization of resources, (2) equality or equity in health access, (3) the instrumental value of individuals as agents in society, and (4) prioritizing the “worst off” in their natural history of disease.^1,2 State legislatures and health systems have responded to the challeges posed by COVID-19 by considering both the scarcity of intensive care resources, such as mechanical ventilation and hemodialysis, and the clinical criteria to be used for determining which patients should receive said resources. These crisis guidelines have yielded several concerning themes vis-à-vis equitable distribution of health care resources, particularly when the disability status of patients is considered alongside life-expectancy or quality of life.³

Crisis standards of care (CSC) prioritize population-level health under a utilitarian paradigm, explicitly maximizing “life-years” within a population of patients rather than the life of any individual patient.⁴ Debated during initial COVID surges, these CSC guidelines have recently been enacted at the state level in several settings, including Alaska and Idaho.⁵ In a setting with scarce intensive care resources, balancing health equity in access to these resources against population-based survival metrics has been a challenge for commissions considering CSC.^6,7 This need for balance has further promoted systemic views of “disability,” raising concern for structural “ableism” and highlighting the need for greater “ability awareness” in clinicians’ continued professional learning.

Structural Ableism: Defining Perspectives to Address Health Equity

Ableism has been defined as “a system that places value on people’s bodies and minds, based on societally constructed ideas of normalcy, intelligence, excellence, and productivity…[and] leads to people and society determining who is valuable and worthy based on their appearance and/or their ability to satisfactorily [re]produce, excel, and ‘behave.’”⁸ Regarding CSC, concerns about systemic bias in guideline design were raised early by disability advocacy groups during comment periods.^9,10 More broadly, concerns about ableism sit alongside many deeply rooted societal perspectives of disabled individuals as pitiable or, conversely, heroic for having “overcome” their disability in some way. As a physician who sits in a manual wheelchair with paraplegia and mobility impairment, I have equally been subject to inappropriate bias and inappropriate praise for living in a wheelchair. I have also wondered, alongside my patients living with different levels of mobility or ability, why others often view us as “worse off.” Addressing directly whether disabled individuals are “worse off,” disability rights attorney and advocate Harriet McBryde Johnson has articulated a predominant sentiment among persons living with unique or different abilities:

Are we “worse off”? I don’t think so. Not in any meaningful way. There are too many variables. For those of us with congenital conditions, disability shapes all we are. Those disabled later in life adapt. We take constraints that no one would choose and build rich and satisfying lives within them. We enjoy pleasures other people enjoy and pleasures peculiarly our own. We have something the world needs.¹¹

Many physician colleagues have common, invisible diseases such as diabetes and heart disease; fewer colleagues share conditions that are as visible as my spinal cord injury, as readily apparent to patients upon my entry to their hospital rooms. This simultaneous and inescapable identity as both patient and provider has afforded me wonderful doctor-patient interactions, particularly with those patients who appreciate how my patient experience impacts my ability to partially understand theirs. However, this simultaneous identity as doctor and patient also informed my personal and professional concerns regarding structural ableism as I considered scoring my own acutely ill hospital medicine patients with CSC triage scores in April 2020.

As a practicing hospital medicine physician, I have been emboldened by the efforts of my fellow clinicians amid COVID-19; their efforts have reaffirmed all the reasons I pursued a career in medicine. However, when I heard my clinical colleagues’ first explanation of the Massachusetts CSC guidelines in April 2020, I raised my hand to ask whether the “life-years” to which the guidelines referred were quality-adjusted. My concern regarding the implicit use of quality-adjusted life years (QALY) or disability-adjusted life years in clinical decision-making and implementation of these guidelines was validated when no clinical leaders could address this question directly. Sitting on the CSC committee for my hospital during this time was an honor. However, it was disconcerting to hear many clinicians’ unease when estimating mean survival for common chronic diseases, ranging from end-stage renal disease to advanced heart failure. If my expert colleagues, clinical specialists in kidney and heart disease, could not confidently apply mean survival estimates to multimorbid hospital patients, then idiosyncratic clinical judgment was sure to have a heavy hand in any calculation of “life-years.” Thus, my primary concern was that clinicians using triage heuristics would be subject to bias, regardless of their intention, and negatively adjust for the quality of a disabled life in their CSC triage scoring. My secondary concern was that the CSC guidelines themselves included systemic bias against disabled individuals.

According to CSC schema, triage scores index heavily on Sequential Organ Failure Assessment (SOFA) scores to define short-term survival; SOFA scores are partially driven by the Glasgow Coma Scale (GCS). Following professional and public comment periods, CSC guidelines in Massachusetts were revised to, among other critical points of revision, change prognostic estimation via “life years” in favor of generic estimation of short-term survival (Table). I wondered, if I presented to an emergency department with severe COVID-19 and was scored with the GCS for the purpose of making a CSC ventilator triage decision, how would my complete paraplegia and lower-extremity motor impairment be accounted for by a clinician assessing “best motor response” in the GCS? The purpose of these scores is to act algorithmically, to guide clinicians whose cognitive load and time limitations may not allow for adjustment of these algorithms based on the individual patient in front of them. Individualization of clinical decisions is part of medicine’s art, but is difficult in the best of times and no easier during a crisis in care delivery. As CSC triage scores were amended and addended throughout 2020, I returned to the COVID wards, time and again wondering, “What have we learned about systemic bias and health inequity in the CSC process and the pandemic broadly, with specific regard to disability?”

Ability Awareness: Room for Our Improvement

Unfortunately, there is reason to believe that clinical judgment is impaired by structural ableism. In seminal work on this topic, Gerhart et al¹² demonstrated that clinicians considered spinal cord injury (SCI) survivors to have low self-perceptions of worthiness, overall negative attitudes, and low self-esteem as compared to able-bodied individuals. However, surveyed SCI survivors generally had similar self-perceptions of worth and positivity as compared to ”able-bodied” clinicians.¹² For providers who care for persons with disabilities, the majority (82.4%) have rated their disabled patients’ quality of life as worse.¹³ It is no wonder that patients with disabilities are more likely to feel that their doctor-patient relationship is impacted by lack of understanding, negative sentiment, or simple lack of listening.¹⁴ Generally, this poor doctor-patient relationship with disabled patients is exacerbated by poor exposure of medical trainees to disability education; only 34.2% of internal medicine residents recall any form of disability education in medical school, while only 52% of medical school deans report having disability educational content in their curricula.^15,16 There is a similar lack of disability representation in the population of medical trainees themselves. While approximately 20% of the American population lives with a disability, less than 2% of American medical students have a disability.^17-19

While representation of disabled populations in medical practice remains poor, disabled patients are generally less likely to receive age-appropriate prevention, appropriate access to care, and equal access to treatment.^20-22 “Diagnostic overshadowing” refers to clinicians’ attribution of nonspecific signs or symptoms to a patient’s chronic disability as opposed to acute illness.²³ This phenomenon has led to higher rates of preventable malignancy in disabled patients and misattribution of common somatic symptoms to intellectual disability.^24,25 With this disparity in place as status quo for health care delivery to disabled populations, it is no surprise that certain portions of the disabled population have accounted for disproportionate mortality due to COVID-19.^26,27Disability advocates have called for “nothing about us without us,” a phrase associated with the United Nations Convention on the Rights of Persons with Disabilities. Understanding the profound neurodiversity among several forms of sensory and cognitive disabilities, as well as the functional difference between cognitive disabilities, mobility impairment, and inability to meet one’s instrumental activities of daily living independently, others have proposed a unique approach to certain disabled populations in COVID care.²⁸ My own perspective is that definite progress may require a more general understanding of the prevalence of disability by clinicians, both via medical training and by directly addressing health equity for disabled populations in such calculations as the CSC. Systemic ableism is apparent in our most common clinical scoring systems, ranging from the GCS and Functional Assessment Staging Table to the Eastern Cooperative Oncology Group and Karnofsky Performance Status scales. I have reexamined these scoring systems in my own understanding given their general equation of ambulation with ability or normalcy. As a doctor in a manual wheelchair who values greatly my personal quality of life and professional contribution to patient care, I worry that these scoring systems inherently discount my own equitable access to care. Individualization of patients’ particular abilities in the context of these scales must occur alongside evidence-based, guideline-directed management via these scoring systems.

Conclusion: Future Orientation

Updated CSC guidelines have accounted for the unique considerations of disabled patients by effectively caveating their scoring algorithms, directing clinicians via disclaimers to uniquely consider their disabled patients in clinical judgement. This is a first step, but it is also one that erodes the value of algorithms, which generally obviate more deliberative thinking and individualization. For our patients who lack certain abilities, as CSC continue to be activated in several states, we have an opportunity to pursue more inherently equitable solutions before further suffering accrues.²⁹ By way of example, adaptations to scoring systems that leverage QALYs for value-based drug pricing indices have been proposed by organizations like the Institute for Clinical and Economic Review, which proposed the Equal-Value-of Life-Years-Gained framework to inform QALY-based arbitration of drug pricing.³⁰ This is not a perfect rubric but instead represents an attempt to balance consideration of drugs, as has been done with ventilators during the pandemic, as a scare and expensive resource while addressing the just concerns of advocacy groups in structural ableism.

Resource stewardship during a crisis should not discount those states of human life that are perceived to be less desirable, particularly if they are not experienced as less desirable but are experienced uniquely. Instead, we should consider equitably measuring our intervention to match a patient’s needs, as we would dose-adjust a medication for renal function or consider minimally invasive procedures for multimorbid patients. COVID-19 has reflected our profession’s ethical adaptation during crisis as resources have become scarce; there is no better time to define solutions for health equity. We should now be concerned equally by the influence our personal biases have on our clinical practice and by the way in which these crisis standards will influence patients’ perception of and trust in their care providers during periods of perceived plentiful resources in the future. Health care resources are always limited, allocated according to societal values; if we value health equity for people of all abilities, then we will consider these abilities equitably as we pursue new standards for health care delivery.

Corresponding author: Gregory D. Snyder, MD, MBA, 2014 Washington Street, Newton, MA 02462; [email protected].

Disclosures: None.
 

Equitable Standards for All Patients in a Crisis

Health care delivered during a pandemic instantiates medicine’s perspectives on the value of human life in clinical scenarios where resource allocation is limited. The COVID-19 pandemic has fostered dialogue and debate around the ethical principles that underly such resource allocation, which generally balance (1) utilitarian optimization of resources, (2) equality or equity in health access, (3) the instrumental value of individuals as agents in society, and (4) prioritizing the “worst off” in their natural history of disease.^1,2 State legislatures and health systems have responded to the challeges posed by COVID-19 by considering both the scarcity of intensive care resources, such as mechanical ventilation and hemodialysis, and the clinical criteria to be used for determining which patients should receive said resources. These crisis guidelines have yielded several concerning themes vis-à-vis equitable distribution of health care resources, particularly when the disability status of patients is considered alongside life-expectancy or quality of life.³

Crisis standards of care (CSC) prioritize population-level health under a utilitarian paradigm, explicitly maximizing “life-years” within a population of patients rather than the life of any individual patient.⁴ Debated during initial COVID surges, these CSC guidelines have recently been enacted at the state level in several settings, including Alaska and Idaho.⁵ In a setting with scarce intensive care resources, balancing health equity in access to these resources against population-based survival metrics has been a challenge for commissions considering CSC.^6,7 This need for balance has further promoted systemic views of “disability,” raising concern for structural “ableism” and highlighting the need for greater “ability awareness” in clinicians’ continued professional learning.

Structural Ableism: Defining Perspectives to Address Health Equity

Ableism has been defined as “a system that places value on people’s bodies and minds, based on societally constructed ideas of normalcy, intelligence, excellence, and productivity…[and] leads to people and society determining who is valuable and worthy based on their appearance and/or their ability to satisfactorily [re]produce, excel, and ‘behave.’”⁸ Regarding CSC, concerns about systemic bias in guideline design were raised early by disability advocacy groups during comment periods.^9,10 More broadly, concerns about ableism sit alongside many deeply rooted societal perspectives of disabled individuals as pitiable or, conversely, heroic for having “overcome” their disability in some way. As a physician who sits in a manual wheelchair with paraplegia and mobility impairment, I have equally been subject to inappropriate bias and inappropriate praise for living in a wheelchair. I have also wondered, alongside my patients living with different levels of mobility or ability, why others often view us as “worse off.” Addressing directly whether disabled individuals are “worse off,” disability rights attorney and advocate Harriet McBryde Johnson has articulated a predominant sentiment among persons living with unique or different abilities:

Are we “worse off”? I don’t think so. Not in any meaningful way. There are too many variables. For those of us with congenital conditions, disability shapes all we are. Those disabled later in life adapt. We take constraints that no one would choose and build rich and satisfying lives within them. We enjoy pleasures other people enjoy and pleasures peculiarly our own. We have something the world needs.¹¹

Many physician colleagues have common, invisible diseases such as diabetes and heart disease; fewer colleagues share conditions that are as visible as my spinal cord injury, as readily apparent to patients upon my entry to their hospital rooms. This simultaneous and inescapable identity as both patient and provider has afforded me wonderful doctor-patient interactions, particularly with those patients who appreciate how my patient experience impacts my ability to partially understand theirs. However, this simultaneous identity as doctor and patient also informed my personal and professional concerns regarding structural ableism as I considered scoring my own acutely ill hospital medicine patients with CSC triage scores in April 2020.

As a practicing hospital medicine physician, I have been emboldened by the efforts of my fellow clinicians amid COVID-19; their efforts have reaffirmed all the reasons I pursued a career in medicine. However, when I heard my clinical colleagues’ first explanation of the Massachusetts CSC guidelines in April 2020, I raised my hand to ask whether the “life-years” to which the guidelines referred were quality-adjusted. My concern regarding the implicit use of quality-adjusted life years (QALY) or disability-adjusted life years in clinical decision-making and implementation of these guidelines was validated when no clinical leaders could address this question directly. Sitting on the CSC committee for my hospital during this time was an honor. However, it was disconcerting to hear many clinicians’ unease when estimating mean survival for common chronic diseases, ranging from end-stage renal disease to advanced heart failure. If my expert colleagues, clinical specialists in kidney and heart disease, could not confidently apply mean survival estimates to multimorbid hospital patients, then idiosyncratic clinical judgment was sure to have a heavy hand in any calculation of “life-years.” Thus, my primary concern was that clinicians using triage heuristics would be subject to bias, regardless of their intention, and negatively adjust for the quality of a disabled life in their CSC triage scoring. My secondary concern was that the CSC guidelines themselves included systemic bias against disabled individuals.

According to CSC schema, triage scores index heavily on Sequential Organ Failure Assessment (SOFA) scores to define short-term survival; SOFA scores are partially driven by the Glasgow Coma Scale (GCS). Following professional and public comment periods, CSC guidelines in Massachusetts were revised to, among other critical points of revision, change prognostic estimation via “life years” in favor of generic estimation of short-term survival (Table). I wondered, if I presented to an emergency department with severe COVID-19 and was scored with the GCS for the purpose of making a CSC ventilator triage decision, how would my complete paraplegia and lower-extremity motor impairment be accounted for by a clinician assessing “best motor response” in the GCS? The purpose of these scores is to act algorithmically, to guide clinicians whose cognitive load and time limitations may not allow for adjustment of these algorithms based on the individual patient in front of them. Individualization of clinical decisions is part of medicine’s art, but is difficult in the best of times and no easier during a crisis in care delivery. As CSC triage scores were amended and addended throughout 2020, I returned to the COVID wards, time and again wondering, “What have we learned about systemic bias and health inequity in the CSC process and the pandemic broadly, with specific regard to disability?”

Ability Awareness: Room for Our Improvement

Unfortunately, there is reason to believe that clinical judgment is impaired by structural ableism. In seminal work on this topic, Gerhart et al¹² demonstrated that clinicians considered spinal cord injury (SCI) survivors to have low self-perceptions of worthiness, overall negative attitudes, and low self-esteem as compared to able-bodied individuals. However, surveyed SCI survivors generally had similar self-perceptions of worth and positivity as compared to ”able-bodied” clinicians.¹² For providers who care for persons with disabilities, the majority (82.4%) have rated their disabled patients’ quality of life as worse.¹³ It is no wonder that patients with disabilities are more likely to feel that their doctor-patient relationship is impacted by lack of understanding, negative sentiment, or simple lack of listening.¹⁴ Generally, this poor doctor-patient relationship with disabled patients is exacerbated by poor exposure of medical trainees to disability education; only 34.2% of internal medicine residents recall any form of disability education in medical school, while only 52% of medical school deans report having disability educational content in their curricula.^15,16 There is a similar lack of disability representation in the population of medical trainees themselves. While approximately 20% of the American population lives with a disability, less than 2% of American medical students have a disability.^17-19

While representation of disabled populations in medical practice remains poor, disabled patients are generally less likely to receive age-appropriate prevention, appropriate access to care, and equal access to treatment.^20-22 “Diagnostic overshadowing” refers to clinicians’ attribution of nonspecific signs or symptoms to a patient’s chronic disability as opposed to acute illness.²³ This phenomenon has led to higher rates of preventable malignancy in disabled patients and misattribution of common somatic symptoms to intellectual disability.^24,25 With this disparity in place as status quo for health care delivery to disabled populations, it is no surprise that certain portions of the disabled population have accounted for disproportionate mortality due to COVID-19.^26,27Disability advocates have called for “nothing about us without us,” a phrase associated with the United Nations Convention on the Rights of Persons with Disabilities. Understanding the profound neurodiversity among several forms of sensory and cognitive disabilities, as well as the functional difference between cognitive disabilities, mobility impairment, and inability to meet one’s instrumental activities of daily living independently, others have proposed a unique approach to certain disabled populations in COVID care.²⁸ My own perspective is that definite progress may require a more general understanding of the prevalence of disability by clinicians, both via medical training and by directly addressing health equity for disabled populations in such calculations as the CSC. Systemic ableism is apparent in our most common clinical scoring systems, ranging from the GCS and Functional Assessment Staging Table to the Eastern Cooperative Oncology Group and Karnofsky Performance Status scales. I have reexamined these scoring systems in my own understanding given their general equation of ambulation with ability or normalcy. As a doctor in a manual wheelchair who values greatly my personal quality of life and professional contribution to patient care, I worry that these scoring systems inherently discount my own equitable access to care. Individualization of patients’ particular abilities in the context of these scales must occur alongside evidence-based, guideline-directed management via these scoring systems.

Conclusion: Future Orientation

Updated CSC guidelines have accounted for the unique considerations of disabled patients by effectively caveating their scoring algorithms, directing clinicians via disclaimers to uniquely consider their disabled patients in clinical judgement. This is a first step, but it is also one that erodes the value of algorithms, which generally obviate more deliberative thinking and individualization. For our patients who lack certain abilities, as CSC continue to be activated in several states, we have an opportunity to pursue more inherently equitable solutions before further suffering accrues.²⁹ By way of example, adaptations to scoring systems that leverage QALYs for value-based drug pricing indices have been proposed by organizations like the Institute for Clinical and Economic Review, which proposed the Equal-Value-of Life-Years-Gained framework to inform QALY-based arbitration of drug pricing.³⁰ This is not a perfect rubric but instead represents an attempt to balance consideration of drugs, as has been done with ventilators during the pandemic, as a scare and expensive resource while addressing the just concerns of advocacy groups in structural ableism.

Resource stewardship during a crisis should not discount those states of human life that are perceived to be less desirable, particularly if they are not experienced as less desirable but are experienced uniquely. Instead, we should consider equitably measuring our intervention to match a patient’s needs, as we would dose-adjust a medication for renal function or consider minimally invasive procedures for multimorbid patients. COVID-19 has reflected our profession’s ethical adaptation during crisis as resources have become scarce; there is no better time to define solutions for health equity. We should now be concerned equally by the influence our personal biases have on our clinical practice and by the way in which these crisis standards will influence patients’ perception of and trust in their care providers during periods of perceived plentiful resources in the future. Health care resources are always limited, allocated according to societal values; if we value health equity for people of all abilities, then we will consider these abilities equitably as we pursue new standards for health care delivery.

Corresponding author: Gregory D. Snyder, MD, MBA, 2014 Washington Street, Newton, MA 02462; [email protected].

Disclosures: None.
 

Equitable Standards for All Patients in a Crisis

Health care delivered during a pandemic instantiates medicine’s perspectives on the value of human life in clinical scenarios where resource allocation is limited. The COVID-19 pandemic has fostered dialogue and debate around the ethical principles that underly such resource allocation, which generally balance (1) utilitarian optimization of resources, (2) equality or equity in health access, (3) the instrumental value of individuals as agents in society, and (4) prioritizing the “worst off” in their natural history of disease.^1,2 State legislatures and health systems have responded to the challeges posed by COVID-19 by considering both the scarcity of intensive care resources, such as mechanical ventilation and hemodialysis, and the clinical criteria to be used for determining which patients should receive said resources. These crisis guidelines have yielded several concerning themes vis-à-vis equitable distribution of health care resources, particularly when the disability status of patients is considered alongside life-expectancy or quality of life.³

Crisis standards of care (CSC) prioritize population-level health under a utilitarian paradigm, explicitly maximizing “life-years” within a population of patients rather than the life of any individual patient.⁴ Debated during initial COVID surges, these CSC guidelines have recently been enacted at the state level in several settings, including Alaska and Idaho.⁵ In a setting with scarce intensive care resources, balancing health equity in access to these resources against population-based survival metrics has been a challenge for commissions considering CSC.^6,7 This need for balance has further promoted systemic views of “disability,” raising concern for structural “ableism” and highlighting the need for greater “ability awareness” in clinicians’ continued professional learning.

Structural Ableism: Defining Perspectives to Address Health Equity

Ableism has been defined as “a system that places value on people’s bodies and minds, based on societally constructed ideas of normalcy, intelligence, excellence, and productivity…[and] leads to people and society determining who is valuable and worthy based on their appearance and/or their ability to satisfactorily [re]produce, excel, and ‘behave.’”⁸ Regarding CSC, concerns about systemic bias in guideline design were raised early by disability advocacy groups during comment periods.^9,10 More broadly, concerns about ableism sit alongside many deeply rooted societal perspectives of disabled individuals as pitiable or, conversely, heroic for having “overcome” their disability in some way. As a physician who sits in a manual wheelchair with paraplegia and mobility impairment, I have equally been subject to inappropriate bias and inappropriate praise for living in a wheelchair. I have also wondered, alongside my patients living with different levels of mobility or ability, why others often view us as “worse off.” Addressing directly whether disabled individuals are “worse off,” disability rights attorney and advocate Harriet McBryde Johnson has articulated a predominant sentiment among persons living with unique or different abilities:

Are we “worse off”? I don’t think so. Not in any meaningful way. There are too many variables. For those of us with congenital conditions, disability shapes all we are. Those disabled later in life adapt. We take constraints that no one would choose and build rich and satisfying lives within them. We enjoy pleasures other people enjoy and pleasures peculiarly our own. We have something the world needs.¹¹

Many physician colleagues have common, invisible diseases such as diabetes and heart disease; fewer colleagues share conditions that are as visible as my spinal cord injury, as readily apparent to patients upon my entry to their hospital rooms. This simultaneous and inescapable identity as both patient and provider has afforded me wonderful doctor-patient interactions, particularly with those patients who appreciate how my patient experience impacts my ability to partially understand theirs. However, this simultaneous identity as doctor and patient also informed my personal and professional concerns regarding structural ableism as I considered scoring my own acutely ill hospital medicine patients with CSC triage scores in April 2020.

As a practicing hospital medicine physician, I have been emboldened by the efforts of my fellow clinicians amid COVID-19; their efforts have reaffirmed all the reasons I pursued a career in medicine. However, when I heard my clinical colleagues’ first explanation of the Massachusetts CSC guidelines in April 2020, I raised my hand to ask whether the “life-years” to which the guidelines referred were quality-adjusted. My concern regarding the implicit use of quality-adjusted life years (QALY) or disability-adjusted life years in clinical decision-making and implementation of these guidelines was validated when no clinical leaders could address this question directly. Sitting on the CSC committee for my hospital during this time was an honor. However, it was disconcerting to hear many clinicians’ unease when estimating mean survival for common chronic diseases, ranging from end-stage renal disease to advanced heart failure. If my expert colleagues, clinical specialists in kidney and heart disease, could not confidently apply mean survival estimates to multimorbid hospital patients, then idiosyncratic clinical judgment was sure to have a heavy hand in any calculation of “life-years.” Thus, my primary concern was that clinicians using triage heuristics would be subject to bias, regardless of their intention, and negatively adjust for the quality of a disabled life in their CSC triage scoring. My secondary concern was that the CSC guidelines themselves included systemic bias against disabled individuals.

According to CSC schema, triage scores index heavily on Sequential Organ Failure Assessment (SOFA) scores to define short-term survival; SOFA scores are partially driven by the Glasgow Coma Scale (GCS). Following professional and public comment periods, CSC guidelines in Massachusetts were revised to, among other critical points of revision, change prognostic estimation via “life years” in favor of generic estimation of short-term survival (Table). I wondered, if I presented to an emergency department with severe COVID-19 and was scored with the GCS for the purpose of making a CSC ventilator triage decision, how would my complete paraplegia and lower-extremity motor impairment be accounted for by a clinician assessing “best motor response” in the GCS? The purpose of these scores is to act algorithmically, to guide clinicians whose cognitive load and time limitations may not allow for adjustment of these algorithms based on the individual patient in front of them. Individualization of clinical decisions is part of medicine’s art, but is difficult in the best of times and no easier during a crisis in care delivery. As CSC triage scores were amended and addended throughout 2020, I returned to the COVID wards, time and again wondering, “What have we learned about systemic bias and health inequity in the CSC process and the pandemic broadly, with specific regard to disability?”

Ability Awareness: Room for Our Improvement

Unfortunately, there is reason to believe that clinical judgment is impaired by structural ableism. In seminal work on this topic, Gerhart et al¹² demonstrated that clinicians considered spinal cord injury (SCI) survivors to have low self-perceptions of worthiness, overall negative attitudes, and low self-esteem as compared to able-bodied individuals. However, surveyed SCI survivors generally had similar self-perceptions of worth and positivity as compared to ”able-bodied” clinicians.¹² For providers who care for persons with disabilities, the majority (82.4%) have rated their disabled patients’ quality of life as worse.¹³ It is no wonder that patients with disabilities are more likely to feel that their doctor-patient relationship is impacted by lack of understanding, negative sentiment, or simple lack of listening.¹⁴ Generally, this poor doctor-patient relationship with disabled patients is exacerbated by poor exposure of medical trainees to disability education; only 34.2% of internal medicine residents recall any form of disability education in medical school, while only 52% of medical school deans report having disability educational content in their curricula.^15,16 There is a similar lack of disability representation in the population of medical trainees themselves. While approximately 20% of the American population lives with a disability, less than 2% of American medical students have a disability.^17-19

While representation of disabled populations in medical practice remains poor, disabled patients are generally less likely to receive age-appropriate prevention, appropriate access to care, and equal access to treatment.^20-22 “Diagnostic overshadowing” refers to clinicians’ attribution of nonspecific signs or symptoms to a patient’s chronic disability as opposed to acute illness.²³ This phenomenon has led to higher rates of preventable malignancy in disabled patients and misattribution of common somatic symptoms to intellectual disability.^24,25 With this disparity in place as status quo for health care delivery to disabled populations, it is no surprise that certain portions of the disabled population have accounted for disproportionate mortality due to COVID-19.^26,27Disability advocates have called for “nothing about us without us,” a phrase associated with the United Nations Convention on the Rights of Persons with Disabilities. Understanding the profound neurodiversity among several forms of sensory and cognitive disabilities, as well as the functional difference between cognitive disabilities, mobility impairment, and inability to meet one’s instrumental activities of daily living independently, others have proposed a unique approach to certain disabled populations in COVID care.²⁸ My own perspective is that definite progress may require a more general understanding of the prevalence of disability by clinicians, both via medical training and by directly addressing health equity for disabled populations in such calculations as the CSC. Systemic ableism is apparent in our most common clinical scoring systems, ranging from the GCS and Functional Assessment Staging Table to the Eastern Cooperative Oncology Group and Karnofsky Performance Status scales. I have reexamined these scoring systems in my own understanding given their general equation of ambulation with ability or normalcy. As a doctor in a manual wheelchair who values greatly my personal quality of life and professional contribution to patient care, I worry that these scoring systems inherently discount my own equitable access to care. Individualization of patients’ particular abilities in the context of these scales must occur alongside evidence-based, guideline-directed management via these scoring systems.

Conclusion: Future Orientation

Updated CSC guidelines have accounted for the unique considerations of disabled patients by effectively caveating their scoring algorithms, directing clinicians via disclaimers to uniquely consider their disabled patients in clinical judgement. This is a first step, but it is also one that erodes the value of algorithms, which generally obviate more deliberative thinking and individualization. For our patients who lack certain abilities, as CSC continue to be activated in several states, we have an opportunity to pursue more inherently equitable solutions before further suffering accrues.²⁹ By way of example, adaptations to scoring systems that leverage QALYs for value-based drug pricing indices have been proposed by organizations like the Institute for Clinical and Economic Review, which proposed the Equal-Value-of Life-Years-Gained framework to inform QALY-based arbitration of drug pricing.³⁰ This is not a perfect rubric but instead represents an attempt to balance consideration of drugs, as has been done with ventilators during the pandemic, as a scare and expensive resource while addressing the just concerns of advocacy groups in structural ableism.

Resource stewardship during a crisis should not discount those states of human life that are perceived to be less desirable, particularly if they are not experienced as less desirable but are experienced uniquely. Instead, we should consider equitably measuring our intervention to match a patient’s needs, as we would dose-adjust a medication for renal function or consider minimally invasive procedures for multimorbid patients. COVID-19 has reflected our profession’s ethical adaptation during crisis as resources have become scarce; there is no better time to define solutions for health equity. We should now be concerned equally by the influence our personal biases have on our clinical practice and by the way in which these crisis standards will influence patients’ perception of and trust in their care providers during periods of perceived plentiful resources in the future. Health care resources are always limited, allocated according to societal values; if we value health equity for people of all abilities, then we will consider these abilities equitably as we pursue new standards for health care delivery.

Corresponding author: Gregory D. Snyder, MD, MBA, 2014 Washington Street, Newton, MA 02462; [email protected].

Disclosures: None.
 

Atopic dermatitis can really mess with patients’ lives

Atopic dermatitis (AD) is a multi-faceted disease that can cause major burden to the lives of patients. Chronic itch is the most common and burdensome symptom of AD and can be very distressing and debilitating for patients.¹Visible skin lesions of AD can be embarrassing and contribute to decreased self-esteem and psychosocial distress (ref). Recent studies uncovered many additional impacts and sequelae of AD.

• While itch has been long recognized as a burdensome symptom in AD, skin pain was recently shown to be an important symptom of AD. Cheng et al² performed a cross-sectional national survey of 240 children with AD and their parents, of which 200 had moderate-to-very severe disease. They found that skin pain intensity was associated with increased skin bleeding (adjusted β [95% CI]: 1.47 [0.61-2.33]), weeping/oozing (adjusted β [95% CI]: 1.18 [0.47-1.90]), and cracking (adjusted β [95% CI]: 1.00 [0.27-1.73]). These relationships may be indirectly related to scratching of the skin leading to open sores that hurt but also bleed, weep/ooze, and crack. On the other hand, patients may experience cracking of skin on hands and feet secondary to dryness and inflammation that can cause skin pain. The authors also found that parent-reported pain intensity was associated with impaired quality of life in infants aged 1-4 years (adjusted β [95% CI]: 1.16 [0.18-2.14]) and children aged 5-17 years (adjusted β [95% CI]: 1.68 [1.00-2.36]). These results show that skin pain is a burdensome symptom in children and adolescents with AD.

• Sleep disturbance is a major problem in patients with AD, especially in those with moderate-to-severe AD. Zhou et al³ conducted a cross-sectional study of 60 children aged 1-4 years with mild-to-severe AD. They found that eczema caused sleep disturbance on 5 or more nights in the past week in 76% of children with severe AD, 24% children with moderate AD, but none with mild AD. Children with more severe AD had greater attention dysregulation (correlation coefficient 0.65). AD severity was a significant predictor of both poor sleep health (β = 0.79) and attention dysregulation (β = 1.22). These results have important ramifications for pediatric health. Previous studies found associations of AD with attention-deficit disorder and attention-deficit hyperactivity disorder. The results of Zhou et al. suggest that AD is associated with symptoms of attention dysregulation, likely secondary to distraction from itch, chronic sleep deprivation, skin pain, etc.

• AD can affect individuals of all age groups, though there may be distinct ramifications when this debilitating disease occurs in childhood during the formative years of life. Manjunath et al⁴ examined data from the Fragile Families and Child Wellbeing Study, which is a prospective, longitudinal birth cohort including 4,898 children aged 1, 3, 5, 9, or 15 years. They found that AD in children aged 5 years (adjusted odds ratio [aOR] [95% CI]: 1.31 [1.04-1.64]) or 9 years (aOR [95% CI]: 1.38 [1.14-1.67]) was associated with ≥75th percentile of mean delinquent behavior scores at age 9 or 15 years. At 9 years of age, a 1-year history of AD was associated with smoking at age 15 years (aOR [95% CI]: 1.46 [1.00-2.13]), damaging property (aOR [95% CI]: 1.38 [1.08-1.77]), cheating on a test (aOR [95% CI]: 1.62 [1.17-2.26]), and school suspension (aOR [95% CI]: 1.36 [1.08-1.71]). These results are provocative and suggest that AD negatively impacts children’s behavior. This study was not able to examine specific clinical aspects of AD that led to delinquent behaviors. However, it is likely that multiple factors contribute to this association, including chronic itch, skin pain, sleep deprivation, attention dysregulation, psychosocial distress, teasing, and bullying.

• A major question on everyone’s mind these days is which individuals have a higher risk of developing COVID-19 infections. There have been many studies since the pandemic began on whether specific immune-mediated disorders are associated with higher risk of COVID-19 or worse outcomes from COVID-19 infections. Previous studies found mixed results about whether individuals with AD have higher risk of COVID-19. Fan et al⁵ performed a case-control study from a large healthcare system database, including 11,752 patients with AD and 47,008 age, sex and race matched healthy controls. They found that patients with AD were more likely to have a diagnosis of COVID-19 compared to those without AD (4.2% vs. 2.8%; P < .001). This association remained significant even after adjusting for demographic factors and comorbidities (odds ratio 1.29; P < .001). Of note, the effect-size was relatively modest in multivariable models. Residual confounding always remains a possibility, ie, that there are other unexplained factors in common with COVID-19 and AD that explain the association. Nevertheless, the results raise important questions about whether immune dysregulation or different treatments used in AD increase risk of COVID-19. Future studies are certainly warranted. Better yet, I look forward to the end of the pandemic when we will no longer have to worry about the potential harms of COVID-19 on AD patients.

References

1. Kim BS. Atopic Dermatitis Clinical Presentation. Medscape (Jan 10, 2022). https://emedicine.medscape.com/article/1049085-clinical (accessed Jan 28, 2022).
2. Cheng BT et al. Burden and characteristics of skin pain among children with atopic dermatitis. J Allergy Clin Immunol Pract. 2021 (Dec 23).
3. Zhou et al. Parent report of sleep health and attention regulation in a cross-sectional study of infants and preschool-aged children with atopic dermatitis. Pediatr Dermatol. 2021 (Dec 21).
4. Manjunath et al. Association of atopic dermatitis with delinquent behaviors in US children and adolescents. Arch Dermatol Res. 2022 (Jan 10).
5. Fan et al. Association between atopic dermatitis and COVID-19 infection: A case-control study in the All of Us research program. JAAD Int. 2021;6:P77-81 (Dec 27).

Atopic dermatitis can really mess with patients’ lives

Atopic dermatitis (AD) is a multi-faceted disease that can cause major burden to the lives of patients. Chronic itch is the most common and burdensome symptom of AD and can be very distressing and debilitating for patients.¹Visible skin lesions of AD can be embarrassing and contribute to decreased self-esteem and psychosocial distress (ref). Recent studies uncovered many additional impacts and sequelae of AD.

• While itch has been long recognized as a burdensome symptom in AD, skin pain was recently shown to be an important symptom of AD. Cheng et al² performed a cross-sectional national survey of 240 children with AD and their parents, of which 200 had moderate-to-very severe disease. They found that skin pain intensity was associated with increased skin bleeding (adjusted β [95% CI]: 1.47 [0.61-2.33]), weeping/oozing (adjusted β [95% CI]: 1.18 [0.47-1.90]), and cracking (adjusted β [95% CI]: 1.00 [0.27-1.73]). These relationships may be indirectly related to scratching of the skin leading to open sores that hurt but also bleed, weep/ooze, and crack. On the other hand, patients may experience cracking of skin on hands and feet secondary to dryness and inflammation that can cause skin pain. The authors also found that parent-reported pain intensity was associated with impaired quality of life in infants aged 1-4 years (adjusted β [95% CI]: 1.16 [0.18-2.14]) and children aged 5-17 years (adjusted β [95% CI]: 1.68 [1.00-2.36]). These results show that skin pain is a burdensome symptom in children and adolescents with AD.

• Sleep disturbance is a major problem in patients with AD, especially in those with moderate-to-severe AD. Zhou et al³ conducted a cross-sectional study of 60 children aged 1-4 years with mild-to-severe AD. They found that eczema caused sleep disturbance on 5 or more nights in the past week in 76% of children with severe AD, 24% children with moderate AD, but none with mild AD. Children with more severe AD had greater attention dysregulation (correlation coefficient 0.65). AD severity was a significant predictor of both poor sleep health (β = 0.79) and attention dysregulation (β = 1.22). These results have important ramifications for pediatric health. Previous studies found associations of AD with attention-deficit disorder and attention-deficit hyperactivity disorder. The results of Zhou et al. suggest that AD is associated with symptoms of attention dysregulation, likely secondary to distraction from itch, chronic sleep deprivation, skin pain, etc.

• AD can affect individuals of all age groups, though there may be distinct ramifications when this debilitating disease occurs in childhood during the formative years of life. Manjunath et al⁴ examined data from the Fragile Families and Child Wellbeing Study, which is a prospective, longitudinal birth cohort including 4,898 children aged 1, 3, 5, 9, or 15 years. They found that AD in children aged 5 years (adjusted odds ratio [aOR] [95% CI]: 1.31 [1.04-1.64]) or 9 years (aOR [95% CI]: 1.38 [1.14-1.67]) was associated with ≥75th percentile of mean delinquent behavior scores at age 9 or 15 years. At 9 years of age, a 1-year history of AD was associated with smoking at age 15 years (aOR [95% CI]: 1.46 [1.00-2.13]), damaging property (aOR [95% CI]: 1.38 [1.08-1.77]), cheating on a test (aOR [95% CI]: 1.62 [1.17-2.26]), and school suspension (aOR [95% CI]: 1.36 [1.08-1.71]). These results are provocative and suggest that AD negatively impacts children’s behavior. This study was not able to examine specific clinical aspects of AD that led to delinquent behaviors. However, it is likely that multiple factors contribute to this association, including chronic itch, skin pain, sleep deprivation, attention dysregulation, psychosocial distress, teasing, and bullying.

• A major question on everyone’s mind these days is which individuals have a higher risk of developing COVID-19 infections. There have been many studies since the pandemic began on whether specific immune-mediated disorders are associated with higher risk of COVID-19 or worse outcomes from COVID-19 infections. Previous studies found mixed results about whether individuals with AD have higher risk of COVID-19. Fan et al⁵ performed a case-control study from a large healthcare system database, including 11,752 patients with AD and 47,008 age, sex and race matched healthy controls. They found that patients with AD were more likely to have a diagnosis of COVID-19 compared to those without AD (4.2% vs. 2.8%; P < .001). This association remained significant even after adjusting for demographic factors and comorbidities (odds ratio 1.29; P < .001). Of note, the effect-size was relatively modest in multivariable models. Residual confounding always remains a possibility, ie, that there are other unexplained factors in common with COVID-19 and AD that explain the association. Nevertheless, the results raise important questions about whether immune dysregulation or different treatments used in AD increase risk of COVID-19. Future studies are certainly warranted. Better yet, I look forward to the end of the pandemic when we will no longer have to worry about the potential harms of COVID-19 on AD patients.

References

1. Kim BS. Atopic Dermatitis Clinical Presentation. Medscape (Jan 10, 2022). https://emedicine.medscape.com/article/1049085-clinical (accessed Jan 28, 2022).
2. Cheng BT et al. Burden and characteristics of skin pain among children with atopic dermatitis. J Allergy Clin Immunol Pract. 2021 (Dec 23).
3. Zhou et al. Parent report of sleep health and attention regulation in a cross-sectional study of infants and preschool-aged children with atopic dermatitis. Pediatr Dermatol. 2021 (Dec 21).
4. Manjunath et al. Association of atopic dermatitis with delinquent behaviors in US children and adolescents. Arch Dermatol Res. 2022 (Jan 10).
5. Fan et al. Association between atopic dermatitis and COVID-19 infection: A case-control study in the All of Us research program. JAAD Int. 2021;6:P77-81 (Dec 27).

Atopic dermatitis can really mess with patients’ lives

Atopic dermatitis (AD) is a multi-faceted disease that can cause major burden to the lives of patients. Chronic itch is the most common and burdensome symptom of AD and can be very distressing and debilitating for patients.¹Visible skin lesions of AD can be embarrassing and contribute to decreased self-esteem and psychosocial distress (ref). Recent studies uncovered many additional impacts and sequelae of AD.

• While itch has been long recognized as a burdensome symptom in AD, skin pain was recently shown to be an important symptom of AD. Cheng et al² performed a cross-sectional national survey of 240 children with AD and their parents, of which 200 had moderate-to-very severe disease. They found that skin pain intensity was associated with increased skin bleeding (adjusted β [95% CI]: 1.47 [0.61-2.33]), weeping/oozing (adjusted β [95% CI]: 1.18 [0.47-1.90]), and cracking (adjusted β [95% CI]: 1.00 [0.27-1.73]). These relationships may be indirectly related to scratching of the skin leading to open sores that hurt but also bleed, weep/ooze, and crack. On the other hand, patients may experience cracking of skin on hands and feet secondary to dryness and inflammation that can cause skin pain. The authors also found that parent-reported pain intensity was associated with impaired quality of life in infants aged 1-4 years (adjusted β [95% CI]: 1.16 [0.18-2.14]) and children aged 5-17 years (adjusted β [95% CI]: 1.68 [1.00-2.36]). These results show that skin pain is a burdensome symptom in children and adolescents with AD.

• Sleep disturbance is a major problem in patients with AD, especially in those with moderate-to-severe AD. Zhou et al³ conducted a cross-sectional study of 60 children aged 1-4 years with mild-to-severe AD. They found that eczema caused sleep disturbance on 5 or more nights in the past week in 76% of children with severe AD, 24% children with moderate AD, but none with mild AD. Children with more severe AD had greater attention dysregulation (correlation coefficient 0.65). AD severity was a significant predictor of both poor sleep health (β = 0.79) and attention dysregulation (β = 1.22). These results have important ramifications for pediatric health. Previous studies found associations of AD with attention-deficit disorder and attention-deficit hyperactivity disorder. The results of Zhou et al. suggest that AD is associated with symptoms of attention dysregulation, likely secondary to distraction from itch, chronic sleep deprivation, skin pain, etc.

• AD can affect individuals of all age groups, though there may be distinct ramifications when this debilitating disease occurs in childhood during the formative years of life. Manjunath et al⁴ examined data from the Fragile Families and Child Wellbeing Study, which is a prospective, longitudinal birth cohort including 4,898 children aged 1, 3, 5, 9, or 15 years. They found that AD in children aged 5 years (adjusted odds ratio [aOR] [95% CI]: 1.31 [1.04-1.64]) or 9 years (aOR [95% CI]: 1.38 [1.14-1.67]) was associated with ≥75th percentile of mean delinquent behavior scores at age 9 or 15 years. At 9 years of age, a 1-year history of AD was associated with smoking at age 15 years (aOR [95% CI]: 1.46 [1.00-2.13]), damaging property (aOR [95% CI]: 1.38 [1.08-1.77]), cheating on a test (aOR [95% CI]: 1.62 [1.17-2.26]), and school suspension (aOR [95% CI]: 1.36 [1.08-1.71]). These results are provocative and suggest that AD negatively impacts children’s behavior. This study was not able to examine specific clinical aspects of AD that led to delinquent behaviors. However, it is likely that multiple factors contribute to this association, including chronic itch, skin pain, sleep deprivation, attention dysregulation, psychosocial distress, teasing, and bullying.

• A major question on everyone’s mind these days is which individuals have a higher risk of developing COVID-19 infections. There have been many studies since the pandemic began on whether specific immune-mediated disorders are associated with higher risk of COVID-19 or worse outcomes from COVID-19 infections. Previous studies found mixed results about whether individuals with AD have higher risk of COVID-19. Fan et al⁵ performed a case-control study from a large healthcare system database, including 11,752 patients with AD and 47,008 age, sex and race matched healthy controls. They found that patients with AD were more likely to have a diagnosis of COVID-19 compared to those without AD (4.2% vs. 2.8%; P < .001). This association remained significant even after adjusting for demographic factors and comorbidities (odds ratio 1.29; P < .001). Of note, the effect-size was relatively modest in multivariable models. Residual confounding always remains a possibility, ie, that there are other unexplained factors in common with COVID-19 and AD that explain the association. Nevertheless, the results raise important questions about whether immune dysregulation or different treatments used in AD increase risk of COVID-19. Future studies are certainly warranted. Better yet, I look forward to the end of the pandemic when we will no longer have to worry about the potential harms of COVID-19 on AD patients.

References

1. Kim BS. Atopic Dermatitis Clinical Presentation. Medscape (Jan 10, 2022). https://emedicine.medscape.com/article/1049085-clinical (accessed Jan 28, 2022).
2. Cheng BT et al. Burden and characteristics of skin pain among children with atopic dermatitis. J Allergy Clin Immunol Pract. 2021 (Dec 23).
3. Zhou et al. Parent report of sleep health and attention regulation in a cross-sectional study of infants and preschool-aged children with atopic dermatitis. Pediatr Dermatol. 2021 (Dec 21).
4. Manjunath et al. Association of atopic dermatitis with delinquent behaviors in US children and adolescents. Arch Dermatol Res. 2022 (Jan 10).
5. Fan et al. Association between atopic dermatitis and COVID-19 infection: A case-control study in the All of Us research program. JAAD Int. 2021;6:P77-81 (Dec 27).

Study Overview

Objective: To examine the effect of the intervention “Eat Walk Engage,” a program that is designed to more consistently deliver age-friendly principles of care to older individuals in acute medical and surgical wards.

Design: This cluster randomized trial to examine the effect of an intervention in acute medical and surgical wards on older adults was conducted in 8 acute medical and surgical wards in 4 public hospitals in Australia from 2016 to 2017. To be eligible to participate in this trial, wards had to have the following: a patient population with 50% of patients aged 65 years and older; perceived alignment with hospital priorities; and nurse manager agreement to participation. Randomization was stratified by hospital, resulting in 4 wards with the intervention (a general medicine ward, an orthopedic ward, a general surgery ward, and a respiratory medicine ward) and 4 control wards (2 general medicine wards, a respiratory medicine ward, and a general surgery ward). Participants were consecutive inpatients aged 65 years or older who were admitted to the ward for at least 3 consecutive days during the study time period. Exclusion criteria included terminal or critical illness, severe cognitive impairment without a surrogate decision-maker, non-English speaking, or previously enrolled in the trial. Of a total of 453 patients who were eligible from the intervention wards, 188 were excluded and 6 died, yielding 259 participants in the intervention group. There were 413 patients eligible from the control wards, with 139 excluded and 3 deaths, yielding 271 participants in the control group.

Intervention: The intervention, called “Eat Walk Engage,” was developed to target older adults at risk for hospital-associated complications of delirium, functional decline, pressure injuries, falls, and incontinence, and aimed to improve care practices, environment, and culture to support age-friendly principles. This ward-based program delivered a structured improvement intervention through a site facilitator who is a nurse or allied health professional. The site facilitator identified opportunities for improvement using structured assessments of context, patient-experience interviews, and audits of care processes, and engaged an interdisciplinary working group from the intervention wards to participate in an hour-per-month meeting to develop plans for iterative improvements. Each site developed their own intervention plan; examples of interventions include shifting priorities to enable staff to increase the proportion of patients sitting in a chair for meals; designating the patient lounge as a walking destination to increase the proportion of time patients spend mobile; and using orientation boards and small groups to engage older patients in meaningful activities.

Main outcome measures: Study outcome measures included hospital-associated complications for older people, which is a composite of hospital-associated delirium, hospital-associated disability, hospital-associated incontinence, and fall or pressure injury during hospitalization. Delirium was assessed using the 3-minute diagnostic interview for Confusion Assessment Method (3D-CAM); hospital-associated disability was defined as new disability at discharge compared to 2 weeks prior to hospitalization. The primary outcome was defined as incidence of any complications and hospital length of stay. Secondary outcomes included incidence of individual complications, hospital discharge to facility, mortality at 6 months, and readmission for any cause at 6 months.

Main results: Patient characteristics for the intervention and control groups, respectively, were: 47% women with a mean age of 75.9 years (SD, 7.3), and 53% women with a mean age of 78.0 years (SD, 8.2). For the primary outcome, 46.4% of participants in the intervention group experienced any hospital complications compared with 51.8% in the control group (odds ratio [OR], 1.07; 95% CI, 0.71-1.61). The incidence of delirium was lower in the intervention group as compared with the control group (15.9% vs 31.4%; OR, 0.53; 95% CI, 0.31-0.90), while there were no other differences in the incidence rates of other complications. There was also no difference in hospital length of stay; median length of stay in the intervention group was 6 days (interquartile range [IQR], 4-9 days) compared with 7 days in the control group (IQR, 5-10), with an estimated mean difference in length of stay of 0.16 days (95% CI, –0.43 to 0.78 days). There was also no significant difference in mortality or all-cause readmission at 6 months.

Conclusion: The intervention “Eat Walk Engage” did not reduce hospital-associated complications overall or hospital length of stay, but it did reduce the incidence of hospital-associated delirium.

Older adults, often with reduced physiologic reserve, when admitted to the hospital with an acute illness may be vulnerable to potential hazards of hospitalization, such as complications from prolonged periods of immobility, pressure injury, and delirium.¹ Models of care in the inpatient setting to reduce these hazards, including the Acute Care for the Elderly model and the Mobile Acute Care for the Elderly Team model, have been examined in clinical trials.^2,3 Specifically, models of care to prevent and treat delirium have been developed and tested over the past decade.⁴ The effect of these models in improving function, reducing complications, and reducing delirium incidence has been well documented. The present study adds to the literature by testing a model that utilizes implementation science methods to take into account real-world settings. In contrast with prior models-of-care studies, the implementation of the intervention at each ward was not prescriptive, but rather was developed in each ward in an iterative manner with stakeholder input. The advantage of this approach is that engagement of stakeholders at each intervention ward obtains buy-in from staff, mobilizing staff in a way that a prescriptive model of care may not; this ultimately may lead to longer-lasting change. The iterative approach also allows for the intervention to be adapted to conditions and settings over time. Other studies have taken this approach of using implementation science to drive change.⁵ Although the intervention in the present study failed to improve the primary outcome, it did reduce the incidence of delirium, which is a significant outcome and one that may confer considerable benefits to older adults under the model’s care.

A limitation of the intervention’s nonprescriptive approach is that, because of the variation of the interventions across sites, it is difficult to discern what elements drove the clinical outcomes. In addition, it would be challenging to consider what aspects of the intervention did not work should refinement or changes be needed. How one may measure fidelity to the intervention or how well a site implements the intervention and its relationship with clinical outcomes will need to be examined further.

Application for Clinical Practice

Clinicians look to effective models of care to improve clinical outcomes for older adults in the hospital. The intervention described in this study offers a real-world approach that may need less upfront investment than other recently studied models, such as the Acute Care for the Elderly model, which requires structural and staffing enhancements. Clinicians and health system leaders may consider implementing this model to improve the care delivered to older adults in the hospital as it may help reduce the incidence of delirium among the older adults they serve.

–William W. Hung, MD, MPH

Disclosures: None.

 

Study Overview

Objective: To examine the effect of the intervention “Eat Walk Engage,” a program that is designed to more consistently deliver age-friendly principles of care to older individuals in acute medical and surgical wards.

Design: This cluster randomized trial to examine the effect of an intervention in acute medical and surgical wards on older adults was conducted in 8 acute medical and surgical wards in 4 public hospitals in Australia from 2016 to 2017. To be eligible to participate in this trial, wards had to have the following: a patient population with 50% of patients aged 65 years and older; perceived alignment with hospital priorities; and nurse manager agreement to participation. Randomization was stratified by hospital, resulting in 4 wards with the intervention (a general medicine ward, an orthopedic ward, a general surgery ward, and a respiratory medicine ward) and 4 control wards (2 general medicine wards, a respiratory medicine ward, and a general surgery ward). Participants were consecutive inpatients aged 65 years or older who were admitted to the ward for at least 3 consecutive days during the study time period. Exclusion criteria included terminal or critical illness, severe cognitive impairment without a surrogate decision-maker, non-English speaking, or previously enrolled in the trial. Of a total of 453 patients who were eligible from the intervention wards, 188 were excluded and 6 died, yielding 259 participants in the intervention group. There were 413 patients eligible from the control wards, with 139 excluded and 3 deaths, yielding 271 participants in the control group.

Intervention: The intervention, called “Eat Walk Engage,” was developed to target older adults at risk for hospital-associated complications of delirium, functional decline, pressure injuries, falls, and incontinence, and aimed to improve care practices, environment, and culture to support age-friendly principles. This ward-based program delivered a structured improvement intervention through a site facilitator who is a nurse or allied health professional. The site facilitator identified opportunities for improvement using structured assessments of context, patient-experience interviews, and audits of care processes, and engaged an interdisciplinary working group from the intervention wards to participate in an hour-per-month meeting to develop plans for iterative improvements. Each site developed their own intervention plan; examples of interventions include shifting priorities to enable staff to increase the proportion of patients sitting in a chair for meals; designating the patient lounge as a walking destination to increase the proportion of time patients spend mobile; and using orientation boards and small groups to engage older patients in meaningful activities.

Main outcome measures: Study outcome measures included hospital-associated complications for older people, which is a composite of hospital-associated delirium, hospital-associated disability, hospital-associated incontinence, and fall or pressure injury during hospitalization. Delirium was assessed using the 3-minute diagnostic interview for Confusion Assessment Method (3D-CAM); hospital-associated disability was defined as new disability at discharge compared to 2 weeks prior to hospitalization. The primary outcome was defined as incidence of any complications and hospital length of stay. Secondary outcomes included incidence of individual complications, hospital discharge to facility, mortality at 6 months, and readmission for any cause at 6 months.

Main results: Patient characteristics for the intervention and control groups, respectively, were: 47% women with a mean age of 75.9 years (SD, 7.3), and 53% women with a mean age of 78.0 years (SD, 8.2). For the primary outcome, 46.4% of participants in the intervention group experienced any hospital complications compared with 51.8% in the control group (odds ratio [OR], 1.07; 95% CI, 0.71-1.61). The incidence of delirium was lower in the intervention group as compared with the control group (15.9% vs 31.4%; OR, 0.53; 95% CI, 0.31-0.90), while there were no other differences in the incidence rates of other complications. There was also no difference in hospital length of stay; median length of stay in the intervention group was 6 days (interquartile range [IQR], 4-9 days) compared with 7 days in the control group (IQR, 5-10), with an estimated mean difference in length of stay of 0.16 days (95% CI, –0.43 to 0.78 days). There was also no significant difference in mortality or all-cause readmission at 6 months.

Conclusion: The intervention “Eat Walk Engage” did not reduce hospital-associated complications overall or hospital length of stay, but it did reduce the incidence of hospital-associated delirium.

Older adults, often with reduced physiologic reserve, when admitted to the hospital with an acute illness may be vulnerable to potential hazards of hospitalization, such as complications from prolonged periods of immobility, pressure injury, and delirium.¹ Models of care in the inpatient setting to reduce these hazards, including the Acute Care for the Elderly model and the Mobile Acute Care for the Elderly Team model, have been examined in clinical trials.^2,3 Specifically, models of care to prevent and treat delirium have been developed and tested over the past decade.⁴ The effect of these models in improving function, reducing complications, and reducing delirium incidence has been well documented. The present study adds to the literature by testing a model that utilizes implementation science methods to take into account real-world settings. In contrast with prior models-of-care studies, the implementation of the intervention at each ward was not prescriptive, but rather was developed in each ward in an iterative manner with stakeholder input. The advantage of this approach is that engagement of stakeholders at each intervention ward obtains buy-in from staff, mobilizing staff in a way that a prescriptive model of care may not; this ultimately may lead to longer-lasting change. The iterative approach also allows for the intervention to be adapted to conditions and settings over time. Other studies have taken this approach of using implementation science to drive change.⁵ Although the intervention in the present study failed to improve the primary outcome, it did reduce the incidence of delirium, which is a significant outcome and one that may confer considerable benefits to older adults under the model’s care.

A limitation of the intervention’s nonprescriptive approach is that, because of the variation of the interventions across sites, it is difficult to discern what elements drove the clinical outcomes. In addition, it would be challenging to consider what aspects of the intervention did not work should refinement or changes be needed. How one may measure fidelity to the intervention or how well a site implements the intervention and its relationship with clinical outcomes will need to be examined further.

Application for Clinical Practice

Clinicians look to effective models of care to improve clinical outcomes for older adults in the hospital. The intervention described in this study offers a real-world approach that may need less upfront investment than other recently studied models, such as the Acute Care for the Elderly model, which requires structural and staffing enhancements. Clinicians and health system leaders may consider implementing this model to improve the care delivered to older adults in the hospital as it may help reduce the incidence of delirium among the older adults they serve.

–William W. Hung, MD, MPH

Disclosures: None.

 

Study Overview

Objective: To examine the effect of the intervention “Eat Walk Engage,” a program that is designed to more consistently deliver age-friendly principles of care to older individuals in acute medical and surgical wards.

Design: This cluster randomized trial to examine the effect of an intervention in acute medical and surgical wards on older adults was conducted in 8 acute medical and surgical wards in 4 public hospitals in Australia from 2016 to 2017. To be eligible to participate in this trial, wards had to have the following: a patient population with 50% of patients aged 65 years and older; perceived alignment with hospital priorities; and nurse manager agreement to participation. Randomization was stratified by hospital, resulting in 4 wards with the intervention (a general medicine ward, an orthopedic ward, a general surgery ward, and a respiratory medicine ward) and 4 control wards (2 general medicine wards, a respiratory medicine ward, and a general surgery ward). Participants were consecutive inpatients aged 65 years or older who were admitted to the ward for at least 3 consecutive days during the study time period. Exclusion criteria included terminal or critical illness, severe cognitive impairment without a surrogate decision-maker, non-English speaking, or previously enrolled in the trial. Of a total of 453 patients who were eligible from the intervention wards, 188 were excluded and 6 died, yielding 259 participants in the intervention group. There were 413 patients eligible from the control wards, with 139 excluded and 3 deaths, yielding 271 participants in the control group.

Intervention: The intervention, called “Eat Walk Engage,” was developed to target older adults at risk for hospital-associated complications of delirium, functional decline, pressure injuries, falls, and incontinence, and aimed to improve care practices, environment, and culture to support age-friendly principles. This ward-based program delivered a structured improvement intervention through a site facilitator who is a nurse or allied health professional. The site facilitator identified opportunities for improvement using structured assessments of context, patient-experience interviews, and audits of care processes, and engaged an interdisciplinary working group from the intervention wards to participate in an hour-per-month meeting to develop plans for iterative improvements. Each site developed their own intervention plan; examples of interventions include shifting priorities to enable staff to increase the proportion of patients sitting in a chair for meals; designating the patient lounge as a walking destination to increase the proportion of time patients spend mobile; and using orientation boards and small groups to engage older patients in meaningful activities.

Main outcome measures: Study outcome measures included hospital-associated complications for older people, which is a composite of hospital-associated delirium, hospital-associated disability, hospital-associated incontinence, and fall or pressure injury during hospitalization. Delirium was assessed using the 3-minute diagnostic interview for Confusion Assessment Method (3D-CAM); hospital-associated disability was defined as new disability at discharge compared to 2 weeks prior to hospitalization. The primary outcome was defined as incidence of any complications and hospital length of stay. Secondary outcomes included incidence of individual complications, hospital discharge to facility, mortality at 6 months, and readmission for any cause at 6 months.

Main results: Patient characteristics for the intervention and control groups, respectively, were: 47% women with a mean age of 75.9 years (SD, 7.3), and 53% women with a mean age of 78.0 years (SD, 8.2). For the primary outcome, 46.4% of participants in the intervention group experienced any hospital complications compared with 51.8% in the control group (odds ratio [OR], 1.07; 95% CI, 0.71-1.61). The incidence of delirium was lower in the intervention group as compared with the control group (15.9% vs 31.4%; OR, 0.53; 95% CI, 0.31-0.90), while there were no other differences in the incidence rates of other complications. There was also no difference in hospital length of stay; median length of stay in the intervention group was 6 days (interquartile range [IQR], 4-9 days) compared with 7 days in the control group (IQR, 5-10), with an estimated mean difference in length of stay of 0.16 days (95% CI, –0.43 to 0.78 days). There was also no significant difference in mortality or all-cause readmission at 6 months.

Conclusion: The intervention “Eat Walk Engage” did not reduce hospital-associated complications overall or hospital length of stay, but it did reduce the incidence of hospital-associated delirium.

Older adults, often with reduced physiologic reserve, when admitted to the hospital with an acute illness may be vulnerable to potential hazards of hospitalization, such as complications from prolonged periods of immobility, pressure injury, and delirium.¹ Models of care in the inpatient setting to reduce these hazards, including the Acute Care for the Elderly model and the Mobile Acute Care for the Elderly Team model, have been examined in clinical trials.^2,3 Specifically, models of care to prevent and treat delirium have been developed and tested over the past decade.⁴ The effect of these models in improving function, reducing complications, and reducing delirium incidence has been well documented. The present study adds to the literature by testing a model that utilizes implementation science methods to take into account real-world settings. In contrast with prior models-of-care studies, the implementation of the intervention at each ward was not prescriptive, but rather was developed in each ward in an iterative manner with stakeholder input. The advantage of this approach is that engagement of stakeholders at each intervention ward obtains buy-in from staff, mobilizing staff in a way that a prescriptive model of care may not; this ultimately may lead to longer-lasting change. The iterative approach also allows for the intervention to be adapted to conditions and settings over time. Other studies have taken this approach of using implementation science to drive change.⁵ Although the intervention in the present study failed to improve the primary outcome, it did reduce the incidence of delirium, which is a significant outcome and one that may confer considerable benefits to older adults under the model’s care.

A limitation of the intervention’s nonprescriptive approach is that, because of the variation of the interventions across sites, it is difficult to discern what elements drove the clinical outcomes. In addition, it would be challenging to consider what aspects of the intervention did not work should refinement or changes be needed. How one may measure fidelity to the intervention or how well a site implements the intervention and its relationship with clinical outcomes will need to be examined further.

Application for Clinical Practice

Clinicians look to effective models of care to improve clinical outcomes for older adults in the hospital. The intervention described in this study offers a real-world approach that may need less upfront investment than other recently studied models, such as the Acute Care for the Elderly model, which requires structural and staffing enhancements. Clinicians and health system leaders may consider implementing this model to improve the care delivered to older adults in the hospital as it may help reduce the incidence of delirium among the older adults they serve.

–William W. Hung, MD, MPH

Disclosures: None.

 

Study Overview

Objective: To determine whether fractional flow reserve (FFR)–guided percutaneous coronary intervention (PCI) is noninferior to coronary-artery bypass grafting (CABG) in patients with 3-vessel coronary artery disease (CAD).

Design: Investigator-initiated, multicenter, international, randomized, controlled trial conducted at 48 sites.

Setting and participants: A total of 1500 patients with angiographically identified 3-vessel CAD not involving the left main coronary artery were randomly assigned to receive FFR-guided PCI with zotarolimus-eluting stents or CABG in a 1:1 ratio. Randomization was stratified according to trial site and diabetes status.

Main outcome measures: The primary end point was major adverse cardiac or cerebrovascular event, defined as death from any cause, myocardial infarction (MI), stroke, or repeat revascularization. The secondary end point was defined as a composite of death, MI, or stroke.

Results: At 1 year, the incidence of the composite primary end point was 10.6% for patients with FFR-guided PCI and 6.9% for patients with CABG (hazard ratio [HR], 1.5; 95% CI, 1.1-2.2; P = .35 for noninferiority), which was not consistent with noninferiority of FFR-guided PCI compared to CABG. The secondary end point occurred in 7.3% of patients in the FFR-guided PCI group compared with 5.2% in the CABG group (HR, 1.4; 95% CI, 0.9-2.1). Individual findings for the outcomes comprising the primary end point for the FFR-guided PCI group vs the CABG group were as follows: death, 1.6% vs 0.9%; MI, 5.2% vs 3.5%; stroke, 0.9% vs 1.1%; and repeat revascularization, 5.9% vs 3.9%. The CABG group had more extended hospital stays and higher incidences of major bleeding, arrhythmia, acute kidney injury, and rehospitalization within 30 days than the FFR-guided PCI group.

Conclusion: FFR-guided PCI was not found to be noninferior to CABG with respect to the incidence of a composite of death, MI, stroke, or repeat revascularization at 1 year.

Commentary

Revascularization for multivessel CAD can be performed by CABG or PCI. Previous studies have shown superior outcomes in patients with multivessel CAD who were treated with CABG compared to PCI.^1-3 The Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial, which compared CABG to PCI in patients with multivessel disease or unprotected left main CAD, stratified the anatomic complexity based on SYNTAX score and found that patients with higher anatomic complexity with a high SYNTAX score derive larger benefit from CABG compared to PCI.⁴ Therefore, the current guidelines favor CABG over PCI in patients with severe 3-vessel disease, except for patients with a lower SYNTAX score (<22) without diabetes.^5,6 However, except for a smaller size study,³ the previous trials that led to this recommendation used mostly first-generation drug-eluting stents and have not evaluated second-generation stents that have lower rates of in-stent restenosis and stent thrombosis. In addition, there have been significant improvements in PCI techniques since the study period, including the adoption of a radial approach and superior adjunct pharmacologic therapy. Furthermore, previous studies have not systematically investigated the use of FFR-guided PCI, which has been shown to be superior to angiography-guided PCI or medical treatment alone.^7-9

In this context, Fearon and the FAME-3 trial investigators studied the use of FFR-guided PCI with second-generation zotarolimus drug-eluting stents compared to CABG in patients with 3-vessel CAD. They randomized patients with angiographically identified 3-vessel CAD in a 1:1 ratio to receive FFR-guided PCI or CABG at 48 sites internationally. Patients with left main CAD, recent ST-elevation MI, cardiogenic shock, and left-ventricular ejection fraction <30% were excluded. The study results (composite primary end point incidence of 10.6% for patients with FFR-guided PCI vs 6.9% in the CABG group [HR, 1.5; 95% CI, 1.1-2.2; P = 0.35 for noninferiority]) showed that FFR-guided PCI did not meet the noninferiority criterion.

Although the FAME-3 study is an important study, there are a few points to consider. First, 24% of the lesions had a FFR measured at >0.80. The benefit of FFR-guided PCI lies in the number of lesions that are safely deferred compared to angiography-guided PCI. The small number of deferred lesions could have limited the benefit of FFR guidance compared with angiography. Second, this study did not include all comers who had angiographic 3-vessel disease. Patients who had FFR assessment of moderate lesions at the time of diagnostic angiogram and were found to have FFR >0.80 or were deemed single- or 2-vessel disease were likely treated with PCI. Therefore, as the authors point out, the patients included in this study may have been skewed to a higher-risk population compared to previous studies.

Third, the study may not reflect contemporary interventional practice, as the use of intravascular ultrasound was very low (12%). Intravascular ultrasound–guided PCI has been associated with increased luminal gain and improved outcomes compared to angiography-guided PCI.¹⁰ Although 20% of the patients in each arm were found to have chronic total occlusions, the completeness of revascularization has not yet been reported. It is possible that the PCI arm had fewer complete revascularizations, which has been shown in previous observational studies to be associated with worse clinical outcomes.^11,12

Although the current guidelines favor CABG over PCI in patients with multivessel disease, this recommendation is stratified by anatomic complexity.⁶ In fact, in the European guidelines, CABG and PCI are both class I recommendations for the treatment of 3-vessel disease with low SYNTAX score in patients without diabetes.⁵ Although the FAME-3 study failed to show noninferiority in the overall population, when stratified by the SYNTAX score, the major adverse cardiac event rate for the PCI group was numerically lower than that of the CABG group. The results from the FAME-3 study are overall in line with the previous studies and the current guidelines. Future studies are necessary to assess the outcomes of multivessel PCI compared to CABG using the most contemporary interventional practice and achieving complete revascularization in the PCI arm.

Applications for Clinical Practice

In patients with 3-vessel disease, FFR-guided PCI was not found to be noninferior to CABG; this finding is consistent with previous studies.

—Shubham Kanake, BS, Chirag Bavishi, MD, MPH, and Taishi Hirai, MD, University of Missouri, Columbia, MO

Disclosures: None.

Study Overview

Objective: To determine whether fractional flow reserve (FFR)–guided percutaneous coronary intervention (PCI) is noninferior to coronary-artery bypass grafting (CABG) in patients with 3-vessel coronary artery disease (CAD).

Design: Investigator-initiated, multicenter, international, randomized, controlled trial conducted at 48 sites.

Setting and participants: A total of 1500 patients with angiographically identified 3-vessel CAD not involving the left main coronary artery were randomly assigned to receive FFR-guided PCI with zotarolimus-eluting stents or CABG in a 1:1 ratio. Randomization was stratified according to trial site and diabetes status.

Main outcome measures: The primary end point was major adverse cardiac or cerebrovascular event, defined as death from any cause, myocardial infarction (MI), stroke, or repeat revascularization. The secondary end point was defined as a composite of death, MI, or stroke.

Results: At 1 year, the incidence of the composite primary end point was 10.6% for patients with FFR-guided PCI and 6.9% for patients with CABG (hazard ratio [HR], 1.5; 95% CI, 1.1-2.2; P = .35 for noninferiority), which was not consistent with noninferiority of FFR-guided PCI compared to CABG. The secondary end point occurred in 7.3% of patients in the FFR-guided PCI group compared with 5.2% in the CABG group (HR, 1.4; 95% CI, 0.9-2.1). Individual findings for the outcomes comprising the primary end point for the FFR-guided PCI group vs the CABG group were as follows: death, 1.6% vs 0.9%; MI, 5.2% vs 3.5%; stroke, 0.9% vs 1.1%; and repeat revascularization, 5.9% vs 3.9%. The CABG group had more extended hospital stays and higher incidences of major bleeding, arrhythmia, acute kidney injury, and rehospitalization within 30 days than the FFR-guided PCI group.

Conclusion: FFR-guided PCI was not found to be noninferior to CABG with respect to the incidence of a composite of death, MI, stroke, or repeat revascularization at 1 year.

Commentary

Revascularization for multivessel CAD can be performed by CABG or PCI. Previous studies have shown superior outcomes in patients with multivessel CAD who were treated with CABG compared to PCI.^1-3 The Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial, which compared CABG to PCI in patients with multivessel disease or unprotected left main CAD, stratified the anatomic complexity based on SYNTAX score and found that patients with higher anatomic complexity with a high SYNTAX score derive larger benefit from CABG compared to PCI.⁴ Therefore, the current guidelines favor CABG over PCI in patients with severe 3-vessel disease, except for patients with a lower SYNTAX score (<22) without diabetes.^5,6 However, except for a smaller size study,³ the previous trials that led to this recommendation used mostly first-generation drug-eluting stents and have not evaluated second-generation stents that have lower rates of in-stent restenosis and stent thrombosis. In addition, there have been significant improvements in PCI techniques since the study period, including the adoption of a radial approach and superior adjunct pharmacologic therapy. Furthermore, previous studies have not systematically investigated the use of FFR-guided PCI, which has been shown to be superior to angiography-guided PCI or medical treatment alone.^7-9

In this context, Fearon and the FAME-3 trial investigators studied the use of FFR-guided PCI with second-generation zotarolimus drug-eluting stents compared to CABG in patients with 3-vessel CAD. They randomized patients with angiographically identified 3-vessel CAD in a 1:1 ratio to receive FFR-guided PCI or CABG at 48 sites internationally. Patients with left main CAD, recent ST-elevation MI, cardiogenic shock, and left-ventricular ejection fraction <30% were excluded. The study results (composite primary end point incidence of 10.6% for patients with FFR-guided PCI vs 6.9% in the CABG group [HR, 1.5; 95% CI, 1.1-2.2; P = 0.35 for noninferiority]) showed that FFR-guided PCI did not meet the noninferiority criterion.

Although the FAME-3 study is an important study, there are a few points to consider. First, 24% of the lesions had a FFR measured at >0.80. The benefit of FFR-guided PCI lies in the number of lesions that are safely deferred compared to angiography-guided PCI. The small number of deferred lesions could have limited the benefit of FFR guidance compared with angiography. Second, this study did not include all comers who had angiographic 3-vessel disease. Patients who had FFR assessment of moderate lesions at the time of diagnostic angiogram and were found to have FFR >0.80 or were deemed single- or 2-vessel disease were likely treated with PCI. Therefore, as the authors point out, the patients included in this study may have been skewed to a higher-risk population compared to previous studies.

Third, the study may not reflect contemporary interventional practice, as the use of intravascular ultrasound was very low (12%). Intravascular ultrasound–guided PCI has been associated with increased luminal gain and improved outcomes compared to angiography-guided PCI.¹⁰ Although 20% of the patients in each arm were found to have chronic total occlusions, the completeness of revascularization has not yet been reported. It is possible that the PCI arm had fewer complete revascularizations, which has been shown in previous observational studies to be associated with worse clinical outcomes.^11,12

Although the current guidelines favor CABG over PCI in patients with multivessel disease, this recommendation is stratified by anatomic complexity.⁶ In fact, in the European guidelines, CABG and PCI are both class I recommendations for the treatment of 3-vessel disease with low SYNTAX score in patients without diabetes.⁵ Although the FAME-3 study failed to show noninferiority in the overall population, when stratified by the SYNTAX score, the major adverse cardiac event rate for the PCI group was numerically lower than that of the CABG group. The results from the FAME-3 study are overall in line with the previous studies and the current guidelines. Future studies are necessary to assess the outcomes of multivessel PCI compared to CABG using the most contemporary interventional practice and achieving complete revascularization in the PCI arm.

Applications for Clinical Practice

In patients with 3-vessel disease, FFR-guided PCI was not found to be noninferior to CABG; this finding is consistent with previous studies.

—Shubham Kanake, BS, Chirag Bavishi, MD, MPH, and Taishi Hirai, MD, University of Missouri, Columbia, MO

Disclosures: None.

Study Overview

Objective: To determine whether fractional flow reserve (FFR)–guided percutaneous coronary intervention (PCI) is noninferior to coronary-artery bypass grafting (CABG) in patients with 3-vessel coronary artery disease (CAD).

Design: Investigator-initiated, multicenter, international, randomized, controlled trial conducted at 48 sites.

Setting and participants: A total of 1500 patients with angiographically identified 3-vessel CAD not involving the left main coronary artery were randomly assigned to receive FFR-guided PCI with zotarolimus-eluting stents or CABG in a 1:1 ratio. Randomization was stratified according to trial site and diabetes status.

Main outcome measures: The primary end point was major adverse cardiac or cerebrovascular event, defined as death from any cause, myocardial infarction (MI), stroke, or repeat revascularization. The secondary end point was defined as a composite of death, MI, or stroke.

Results: At 1 year, the incidence of the composite primary end point was 10.6% for patients with FFR-guided PCI and 6.9% for patients with CABG (hazard ratio [HR], 1.5; 95% CI, 1.1-2.2; P = .35 for noninferiority), which was not consistent with noninferiority of FFR-guided PCI compared to CABG. The secondary end point occurred in 7.3% of patients in the FFR-guided PCI group compared with 5.2% in the CABG group (HR, 1.4; 95% CI, 0.9-2.1). Individual findings for the outcomes comprising the primary end point for the FFR-guided PCI group vs the CABG group were as follows: death, 1.6% vs 0.9%; MI, 5.2% vs 3.5%; stroke, 0.9% vs 1.1%; and repeat revascularization, 5.9% vs 3.9%. The CABG group had more extended hospital stays and higher incidences of major bleeding, arrhythmia, acute kidney injury, and rehospitalization within 30 days than the FFR-guided PCI group.

Conclusion: FFR-guided PCI was not found to be noninferior to CABG with respect to the incidence of a composite of death, MI, stroke, or repeat revascularization at 1 year.

Commentary

Revascularization for multivessel CAD can be performed by CABG or PCI. Previous studies have shown superior outcomes in patients with multivessel CAD who were treated with CABG compared to PCI.^1-3 The Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial, which compared CABG to PCI in patients with multivessel disease or unprotected left main CAD, stratified the anatomic complexity based on SYNTAX score and found that patients with higher anatomic complexity with a high SYNTAX score derive larger benefit from CABG compared to PCI.⁴ Therefore, the current guidelines favor CABG over PCI in patients with severe 3-vessel disease, except for patients with a lower SYNTAX score (<22) without diabetes.^5,6 However, except for a smaller size study,³ the previous trials that led to this recommendation used mostly first-generation drug-eluting stents and have not evaluated second-generation stents that have lower rates of in-stent restenosis and stent thrombosis. In addition, there have been significant improvements in PCI techniques since the study period, including the adoption of a radial approach and superior adjunct pharmacologic therapy. Furthermore, previous studies have not systematically investigated the use of FFR-guided PCI, which has been shown to be superior to angiography-guided PCI or medical treatment alone.^7-9

In this context, Fearon and the FAME-3 trial investigators studied the use of FFR-guided PCI with second-generation zotarolimus drug-eluting stents compared to CABG in patients with 3-vessel CAD. They randomized patients with angiographically identified 3-vessel CAD in a 1:1 ratio to receive FFR-guided PCI or CABG at 48 sites internationally. Patients with left main CAD, recent ST-elevation MI, cardiogenic shock, and left-ventricular ejection fraction <30% were excluded. The study results (composite primary end point incidence of 10.6% for patients with FFR-guided PCI vs 6.9% in the CABG group [HR, 1.5; 95% CI, 1.1-2.2; P = 0.35 for noninferiority]) showed that FFR-guided PCI did not meet the noninferiority criterion.

Although the FAME-3 study is an important study, there are a few points to consider. First, 24% of the lesions had a FFR measured at >0.80. The benefit of FFR-guided PCI lies in the number of lesions that are safely deferred compared to angiography-guided PCI. The small number of deferred lesions could have limited the benefit of FFR guidance compared with angiography. Second, this study did not include all comers who had angiographic 3-vessel disease. Patients who had FFR assessment of moderate lesions at the time of diagnostic angiogram and were found to have FFR >0.80 or were deemed single- or 2-vessel disease were likely treated with PCI. Therefore, as the authors point out, the patients included in this study may have been skewed to a higher-risk population compared to previous studies.

Third, the study may not reflect contemporary interventional practice, as the use of intravascular ultrasound was very low (12%). Intravascular ultrasound–guided PCI has been associated with increased luminal gain and improved outcomes compared to angiography-guided PCI.¹⁰ Although 20% of the patients in each arm were found to have chronic total occlusions, the completeness of revascularization has not yet been reported. It is possible that the PCI arm had fewer complete revascularizations, which has been shown in previous observational studies to be associated with worse clinical outcomes.^11,12

Although the current guidelines favor CABG over PCI in patients with multivessel disease, this recommendation is stratified by anatomic complexity.⁶ In fact, in the European guidelines, CABG and PCI are both class I recommendations for the treatment of 3-vessel disease with low SYNTAX score in patients without diabetes.⁵ Although the FAME-3 study failed to show noninferiority in the overall population, when stratified by the SYNTAX score, the major adverse cardiac event rate for the PCI group was numerically lower than that of the CABG group. The results from the FAME-3 study are overall in line with the previous studies and the current guidelines. Future studies are necessary to assess the outcomes of multivessel PCI compared to CABG using the most contemporary interventional practice and achieving complete revascularization in the PCI arm.

Applications for Clinical Practice

In patients with 3-vessel disease, FFR-guided PCI was not found to be noninferior to CABG; this finding is consistent with previous studies.

—Shubham Kanake, BS, Chirag Bavishi, MD, MPH, and Taishi Hirai, MD, University of Missouri, Columbia, MO

Disclosures: None.

The Diagnosis: Pemphigoid Gestationis

A lesional biopsy showed a subepidermal split with eosinophils and neutrophils. Perilesional biopsy for direct immunofluorescence (DIF) showed linear deposition of 3+ C3 along the basement membrane zone. The clinical, histopathologic, and immunofluorescent findings were consistent with pemphigoid gestationis (PG). Prednisone 1 mg/kg daily was initiated. Her condition continued to worsen, and cyclosporine 250 mg daily was added while prednisone was tapered, with remission of disease.

Pemphigoid gestationis is an autoimmune bullous dermatosis that occurs in the second or third trimester of pregnancy, with an incidence of 1 in 50,000 to 60,000 pregnancies.¹ In terms of pathogenesis, aberrant expression of major histocompatibility complex class II molecules on placental tissues causes the loss of immune tolerance of the placenta, which leads to the production of antibodies against the placental protein bullous pemphigoid 180.² Bullous pemphigoid 180 also is a hemidesmosomal protein found in the skin of the mother; therefore, the presence of the circulating antibodies leads to separation at the dermoepidermal junction and vesiculation.

Pemphigoid gestationis is characterized by the sudden eruption of intensely pruritic urticarial papules and plaques, classically with periumbilical involvement. Tense vesicles and bullae can develop. Women with PG have an increased risk for development of Graves disease. Histopathology shows subepidermal vesiculation with a predominance of eosinophils. Direct immunofluorescence classically shows linear deposition of C3 along the basement membrane zone. Fetal complications include prematurity and small size for gestational age. Additionally, blisters can be seen in 5% to 10% of neonates due to placental transmission of autoantibodies.³

Frequently PG flares shortly postpartum. Pemphigoid gestationis resolves within 6 months postdelivery but frequently reoccurs in subsequent pregnancies. Mild disease can be treated with mid- to high-potency topical corticosteroids. Severe disease is managed with oral corticosteroids, most commonly prednisone. Refractory disease is managed with azathioprine, cyclosporine, intravenous immunoglobulin, or plasmapheresis.

The differential diagnosis of PG includes other pregnancy-associated dermatoses such as atopic eruption of pregnancy, impetigo herpetiformis, intrahepatic cholestasis of pregnancy, and polymorphous eruption of pregnancy. Atopic eruption of pregnancy is the most common dermatosis of pregnancy and is characterized by an eczematous eruption in patients with an atopic history, typically in the first trimester. Blisters are not seen, and DIF is negative. Impetigo herpetiformis, or pustular psoriasis of pregnancy, is a variant of generalized pustular psoriasis that occurs during pregnancy. Diffuse erythematous patches studded with pustules, rather than vesicles, are seen; DIF is negative. Intrahepatic cholestasis of pregnancy presents without primary skin findings and severe pruritus predominantly on the palms and soles, often with secondary excoriations. Polymorphous eruption of pregnancy presents as a polymorphous eruption of urticarial to erythematous papules and plaques commonly originating in striae. In contrast to PG, there is periumbilical sparing, vesiculation is rare, and DIF is negative.

The Diagnosis: Pemphigoid Gestationis

A lesional biopsy showed a subepidermal split with eosinophils and neutrophils. Perilesional biopsy for direct immunofluorescence (DIF) showed linear deposition of 3+ C3 along the basement membrane zone. The clinical, histopathologic, and immunofluorescent findings were consistent with pemphigoid gestationis (PG). Prednisone 1 mg/kg daily was initiated. Her condition continued to worsen, and cyclosporine 250 mg daily was added while prednisone was tapered, with remission of disease.

Pemphigoid gestationis is an autoimmune bullous dermatosis that occurs in the second or third trimester of pregnancy, with an incidence of 1 in 50,000 to 60,000 pregnancies.¹ In terms of pathogenesis, aberrant expression of major histocompatibility complex class II molecules on placental tissues causes the loss of immune tolerance of the placenta, which leads to the production of antibodies against the placental protein bullous pemphigoid 180.² Bullous pemphigoid 180 also is a hemidesmosomal protein found in the skin of the mother; therefore, the presence of the circulating antibodies leads to separation at the dermoepidermal junction and vesiculation.

Pemphigoid gestationis is characterized by the sudden eruption of intensely pruritic urticarial papules and plaques, classically with periumbilical involvement. Tense vesicles and bullae can develop. Women with PG have an increased risk for development of Graves disease. Histopathology shows subepidermal vesiculation with a predominance of eosinophils. Direct immunofluorescence classically shows linear deposition of C3 along the basement membrane zone. Fetal complications include prematurity and small size for gestational age. Additionally, blisters can be seen in 5% to 10% of neonates due to placental transmission of autoantibodies.³

Frequently PG flares shortly postpartum. Pemphigoid gestationis resolves within 6 months postdelivery but frequently reoccurs in subsequent pregnancies. Mild disease can be treated with mid- to high-potency topical corticosteroids. Severe disease is managed with oral corticosteroids, most commonly prednisone. Refractory disease is managed with azathioprine, cyclosporine, intravenous immunoglobulin, or plasmapheresis.

The differential diagnosis of PG includes other pregnancy-associated dermatoses such as atopic eruption of pregnancy, impetigo herpetiformis, intrahepatic cholestasis of pregnancy, and polymorphous eruption of pregnancy. Atopic eruption of pregnancy is the most common dermatosis of pregnancy and is characterized by an eczematous eruption in patients with an atopic history, typically in the first trimester. Blisters are not seen, and DIF is negative. Impetigo herpetiformis, or pustular psoriasis of pregnancy, is a variant of generalized pustular psoriasis that occurs during pregnancy. Diffuse erythematous patches studded with pustules, rather than vesicles, are seen; DIF is negative. Intrahepatic cholestasis of pregnancy presents without primary skin findings and severe pruritus predominantly on the palms and soles, often with secondary excoriations. Polymorphous eruption of pregnancy presents as a polymorphous eruption of urticarial to erythematous papules and plaques commonly originating in striae. In contrast to PG, there is periumbilical sparing, vesiculation is rare, and DIF is negative.

The Diagnosis: Pemphigoid Gestationis

A lesional biopsy showed a subepidermal split with eosinophils and neutrophils. Perilesional biopsy for direct immunofluorescence (DIF) showed linear deposition of 3+ C3 along the basement membrane zone. The clinical, histopathologic, and immunofluorescent findings were consistent with pemphigoid gestationis (PG). Prednisone 1 mg/kg daily was initiated. Her condition continued to worsen, and cyclosporine 250 mg daily was added while prednisone was tapered, with remission of disease.

Pemphigoid gestationis is an autoimmune bullous dermatosis that occurs in the second or third trimester of pregnancy, with an incidence of 1 in 50,000 to 60,000 pregnancies.¹ In terms of pathogenesis, aberrant expression of major histocompatibility complex class II molecules on placental tissues causes the loss of immune tolerance of the placenta, which leads to the production of antibodies against the placental protein bullous pemphigoid 180.² Bullous pemphigoid 180 also is a hemidesmosomal protein found in the skin of the mother; therefore, the presence of the circulating antibodies leads to separation at the dermoepidermal junction and vesiculation.

Pemphigoid gestationis is characterized by the sudden eruption of intensely pruritic urticarial papules and plaques, classically with periumbilical involvement. Tense vesicles and bullae can develop. Women with PG have an increased risk for development of Graves disease. Histopathology shows subepidermal vesiculation with a predominance of eosinophils. Direct immunofluorescence classically shows linear deposition of C3 along the basement membrane zone. Fetal complications include prematurity and small size for gestational age. Additionally, blisters can be seen in 5% to 10% of neonates due to placental transmission of autoantibodies.³

Frequently PG flares shortly postpartum. Pemphigoid gestationis resolves within 6 months postdelivery but frequently reoccurs in subsequent pregnancies. Mild disease can be treated with mid- to high-potency topical corticosteroids. Severe disease is managed with oral corticosteroids, most commonly prednisone. Refractory disease is managed with azathioprine, cyclosporine, intravenous immunoglobulin, or plasmapheresis.

The differential diagnosis of PG includes other pregnancy-associated dermatoses such as atopic eruption of pregnancy, impetigo herpetiformis, intrahepatic cholestasis of pregnancy, and polymorphous eruption of pregnancy. Atopic eruption of pregnancy is the most common dermatosis of pregnancy and is characterized by an eczematous eruption in patients with an atopic history, typically in the first trimester. Blisters are not seen, and DIF is negative. Impetigo herpetiformis, or pustular psoriasis of pregnancy, is a variant of generalized pustular psoriasis that occurs during pregnancy. Diffuse erythematous patches studded with pustules, rather than vesicles, are seen; DIF is negative. Intrahepatic cholestasis of pregnancy presents without primary skin findings and severe pruritus predominantly on the palms and soles, often with secondary excoriations. Polymorphous eruption of pregnancy presents as a polymorphous eruption of urticarial to erythematous papules and plaques commonly originating in striae. In contrast to PG, there is periumbilical sparing, vesiculation is rare, and DIF is negative.