Critical Care

Following invasive ventilation for severe hypercapnic respiratory failure, patients with chronic obstructive pulmonary disease had similar levels of treatment failure if they received high-flow nasal cannula oxygen therapy or noninvasive ventilation, recent research in Critical Care has suggested.

However, for patients with COPD weaned off invasive ventilation, high-flow nasal cannula (HFNC) oxygen therapy was “more comfortable and better tolerated,” compared with noninvasive ventilation (NIV). In addition, “airway care interventions and the incidence of nasofacial skin breakdown associated with HFNC were significantly lower than in NIV,” according to Dingyu Tan of the Clinical Medical College of Yangzhou (China) University, Northern Jiangsu People’s Hospital, and colleagues. “HFNC appears to be an effective means of respiratory support for COPD patients extubated after severe hypercapnic respiratory failure,” they said.

The investigators screened patients with COPD and hypercapnic respiratory failure for enrollment, including those who met Global Initiative for Obstructive Lung Disease (GOLD) criteria, were 85 years old or younger and caring for themselves, had bronchopulmonary infection–induced respiratory failure, and had achieved pulmonary infection control criteria. Exclusion criteria were:

• Patients under age 18 years.
• Presence of oral or facial trauma.
• Poor sputum excretion ability.
• Hemodynamic instability that would contraindicate use of NIV.
• Poor cough during PIC window.
• Poor short-term prognosis.
• Failure of the heart, brain, liver or kidney.
• Patients who could not consent to treatment.

Patients were determined to have failed treatment if they returned to invasive mechanical ventilation or switched from one treatment to another (HFNC to NIV or NIV to HFNC). Investigators also performed an arterial blood gas analysis, recorded the number of duration of airway care interventions, and monitored vital signs at 1 hour, 24 hours, and 48 hours after extubation as secondary analyses.

Overall, 44 patients randomized to receive HFNC and 42 patients randomized for NIV were available for analysis. The investigators found 22.7% of patients in the HFNC group and 28.6% in the NIV group experienced treatment failure (risk difference, –5.8%; 95% confidence interval, −23.8 to 12.4%; P = .535), with patients in the HFNC group experiencing a significantly lower level of treatment intolerance, compared with patients in the NIV group (risk difference, ­–50.0%; 95% CI, −74.6 to −12.9%; P = .015). There were no significant differences between either group regarding intubation (−0.65%; 95% CI, −16.01 to 14.46%), while rate of switching treatments was lower in the HFNC group but not significant (−5.2%; 95% CI, −19.82 to 9.05%).

Patients in both the HFNC and NIV groups had faster mean respiratory rates 1 hour after extubation (P < .050). After 24 hours, the NIV group had higher-than-baseline respiratory rates, compared with the HFNC group, which had returned to normal (20 vs. 24.5 breaths per minute; P < .050). Both groups had returned to baseline by 48 hours after extubation. At 1 hour after extubation, patients in the HFNC group had lower PaO₂/FiO₂ (P < .050) and pH values (P < .050), and higher PaCO₂ values (P less than .050), compared with baseline. There were no statistically significant differences in PaO₂/FiO₂, pH, and PaCO₂ values in either group at 24 hours or 48 hours after extubation.

Daily airway care interventions were significantly higher on average in the NIV group, compared with the HFNC group (7 vs. 6; P = .0006), and the HFNC group also had significantly better comfort scores (7 vs. 5; P < .001) as measured by a modified visual analog scale, as well as incidence of nasal and facial skin breakdown (0 vs. 9.6%; P = .027), compared with the NIV group.
 

Results difficult to apply to North American patients

David L. Bowton, MD, FCCP, a professor specializing in critical care at Wake Forest University, Winston-Salem, N.C., said in an interview the results of this trial may not be applicable for patients with infection-related respiratory failure and COPD in North America “due to the differences in common weaning practices between North America and China.”

For example, the trial used the pulmonary infection control (PIC) window criteria for extubation, which requires a significant decrease in radiographic infiltrates, improvement in quality and quantity of sputum, normalizing of leukocyte count, a synchronized intermittent mandatory ventilation (SIMV) rate of 10-12 breaths per minute, and pressure support less than 10-12 cm/H₂O (Int J Chron Obstruct Pulmon Dis. 2017;12:1255-67).

“The process used to achieve these measures is not standardized. In North America, daily awakening and screening for spontaneous breathing trials would be usual, but this was not reported in the current trial,” he explained.

Differences in patient population also make the application of the results difficult, Dr. Bowton said. “Only 60% of the patients had spirometrically confirmed COPD and fewer than half were on at least dual inhaled therapy prior to hospitalization with only one-third taking beta agonists or anticholinergic agents,” he noted. “The cause of respiratory failure was infectious, requiring an infiltrate on chest radiograph; thus, patients with hypercarbic respiratory failure without a new infiltrate were excluded from the study. On average, patients were hypercarbic, yet alkalemic at the time of extubation; the PaCO₂ and pH at the time of intubation were not reported.

“This study suggests that in some patients with COPD and respiratory failure requiring invasive mechanical ventilation, HFO [high-flow oxygen] may be better tolerated and equally effective as NIPPV [noninvasive positive-pressure ventilation] at mitigating the need for reintubation following extubation. In this patient population where hypoxemia prior to extubation was not severe, the mechanisms by which HFO is beneficial remain speculative,” he said.

This study was funded by the Rui E special fund for emergency medicine research and the Yangzhou Science and Technology Development Plan. The authors report no relevant conflicts of interest. Dr. Bowton reports no relevant conflicts of interest.

SOURCE: Tan D et al. Crit Care. 2020 Aug 6. doi: 10.1186/s13054-020-03214-9.

Following invasive ventilation for severe hypercapnic respiratory failure, patients with chronic obstructive pulmonary disease had similar levels of treatment failure if they received high-flow nasal cannula oxygen therapy or noninvasive ventilation, recent research in Critical Care has suggested.

However, for patients with COPD weaned off invasive ventilation, high-flow nasal cannula (HFNC) oxygen therapy was “more comfortable and better tolerated,” compared with noninvasive ventilation (NIV). In addition, “airway care interventions and the incidence of nasofacial skin breakdown associated with HFNC were significantly lower than in NIV,” according to Dingyu Tan of the Clinical Medical College of Yangzhou (China) University, Northern Jiangsu People’s Hospital, and colleagues. “HFNC appears to be an effective means of respiratory support for COPD patients extubated after severe hypercapnic respiratory failure,” they said.

The investigators screened patients with COPD and hypercapnic respiratory failure for enrollment, including those who met Global Initiative for Obstructive Lung Disease (GOLD) criteria, were 85 years old or younger and caring for themselves, had bronchopulmonary infection–induced respiratory failure, and had achieved pulmonary infection control criteria. Exclusion criteria were:

• Patients under age 18 years.
• Presence of oral or facial trauma.
• Poor sputum excretion ability.
• Hemodynamic instability that would contraindicate use of NIV.
• Poor cough during PIC window.
• Poor short-term prognosis.
• Failure of the heart, brain, liver or kidney.
• Patients who could not consent to treatment.

Patients were determined to have failed treatment if they returned to invasive mechanical ventilation or switched from one treatment to another (HFNC to NIV or NIV to HFNC). Investigators also performed an arterial blood gas analysis, recorded the number of duration of airway care interventions, and monitored vital signs at 1 hour, 24 hours, and 48 hours after extubation as secondary analyses.

Overall, 44 patients randomized to receive HFNC and 42 patients randomized for NIV were available for analysis. The investigators found 22.7% of patients in the HFNC group and 28.6% in the NIV group experienced treatment failure (risk difference, –5.8%; 95% confidence interval, −23.8 to 12.4%; P = .535), with patients in the HFNC group experiencing a significantly lower level of treatment intolerance, compared with patients in the NIV group (risk difference, ­–50.0%; 95% CI, −74.6 to −12.9%; P = .015). There were no significant differences between either group regarding intubation (−0.65%; 95% CI, −16.01 to 14.46%), while rate of switching treatments was lower in the HFNC group but not significant (−5.2%; 95% CI, −19.82 to 9.05%).

Patients in both the HFNC and NIV groups had faster mean respiratory rates 1 hour after extubation (P < .050). After 24 hours, the NIV group had higher-than-baseline respiratory rates, compared with the HFNC group, which had returned to normal (20 vs. 24.5 breaths per minute; P < .050). Both groups had returned to baseline by 48 hours after extubation. At 1 hour after extubation, patients in the HFNC group had lower PaO₂/FiO₂ (P < .050) and pH values (P < .050), and higher PaCO₂ values (P less than .050), compared with baseline. There were no statistically significant differences in PaO₂/FiO₂, pH, and PaCO₂ values in either group at 24 hours or 48 hours after extubation.

Daily airway care interventions were significantly higher on average in the NIV group, compared with the HFNC group (7 vs. 6; P = .0006), and the HFNC group also had significantly better comfort scores (7 vs. 5; P < .001) as measured by a modified visual analog scale, as well as incidence of nasal and facial skin breakdown (0 vs. 9.6%; P = .027), compared with the NIV group.
 

Results difficult to apply to North American patients

David L. Bowton, MD, FCCP, a professor specializing in critical care at Wake Forest University, Winston-Salem, N.C., said in an interview the results of this trial may not be applicable for patients with infection-related respiratory failure and COPD in North America “due to the differences in common weaning practices between North America and China.”

For example, the trial used the pulmonary infection control (PIC) window criteria for extubation, which requires a significant decrease in radiographic infiltrates, improvement in quality and quantity of sputum, normalizing of leukocyte count, a synchronized intermittent mandatory ventilation (SIMV) rate of 10-12 breaths per minute, and pressure support less than 10-12 cm/H₂O (Int J Chron Obstruct Pulmon Dis. 2017;12:1255-67).

“The process used to achieve these measures is not standardized. In North America, daily awakening and screening for spontaneous breathing trials would be usual, but this was not reported in the current trial,” he explained.

Differences in patient population also make the application of the results difficult, Dr. Bowton said. “Only 60% of the patients had spirometrically confirmed COPD and fewer than half were on at least dual inhaled therapy prior to hospitalization with only one-third taking beta agonists or anticholinergic agents,” he noted. “The cause of respiratory failure was infectious, requiring an infiltrate on chest radiograph; thus, patients with hypercarbic respiratory failure without a new infiltrate were excluded from the study. On average, patients were hypercarbic, yet alkalemic at the time of extubation; the PaCO₂ and pH at the time of intubation were not reported.

“This study suggests that in some patients with COPD and respiratory failure requiring invasive mechanical ventilation, HFO [high-flow oxygen] may be better tolerated and equally effective as NIPPV [noninvasive positive-pressure ventilation] at mitigating the need for reintubation following extubation. In this patient population where hypoxemia prior to extubation was not severe, the mechanisms by which HFO is beneficial remain speculative,” he said.

This study was funded by the Rui E special fund for emergency medicine research and the Yangzhou Science and Technology Development Plan. The authors report no relevant conflicts of interest. Dr. Bowton reports no relevant conflicts of interest.

SOURCE: Tan D et al. Crit Care. 2020 Aug 6. doi: 10.1186/s13054-020-03214-9.

Following invasive ventilation for severe hypercapnic respiratory failure, patients with chronic obstructive pulmonary disease had similar levels of treatment failure if they received high-flow nasal cannula oxygen therapy or noninvasive ventilation, recent research in Critical Care has suggested.

However, for patients with COPD weaned off invasive ventilation, high-flow nasal cannula (HFNC) oxygen therapy was “more comfortable and better tolerated,” compared with noninvasive ventilation (NIV). In addition, “airway care interventions and the incidence of nasofacial skin breakdown associated with HFNC were significantly lower than in NIV,” according to Dingyu Tan of the Clinical Medical College of Yangzhou (China) University, Northern Jiangsu People’s Hospital, and colleagues. “HFNC appears to be an effective means of respiratory support for COPD patients extubated after severe hypercapnic respiratory failure,” they said.

The investigators screened patients with COPD and hypercapnic respiratory failure for enrollment, including those who met Global Initiative for Obstructive Lung Disease (GOLD) criteria, were 85 years old or younger and caring for themselves, had bronchopulmonary infection–induced respiratory failure, and had achieved pulmonary infection control criteria. Exclusion criteria were:

• Patients under age 18 years.
• Presence of oral or facial trauma.
• Poor sputum excretion ability.
• Hemodynamic instability that would contraindicate use of NIV.
• Poor cough during PIC window.
• Poor short-term prognosis.
• Failure of the heart, brain, liver or kidney.
• Patients who could not consent to treatment.

Patients were determined to have failed treatment if they returned to invasive mechanical ventilation or switched from one treatment to another (HFNC to NIV or NIV to HFNC). Investigators also performed an arterial blood gas analysis, recorded the number of duration of airway care interventions, and monitored vital signs at 1 hour, 24 hours, and 48 hours after extubation as secondary analyses.

Overall, 44 patients randomized to receive HFNC and 42 patients randomized for NIV were available for analysis. The investigators found 22.7% of patients in the HFNC group and 28.6% in the NIV group experienced treatment failure (risk difference, –5.8%; 95% confidence interval, −23.8 to 12.4%; P = .535), with patients in the HFNC group experiencing a significantly lower level of treatment intolerance, compared with patients in the NIV group (risk difference, ­–50.0%; 95% CI, −74.6 to −12.9%; P = .015). There were no significant differences between either group regarding intubation (−0.65%; 95% CI, −16.01 to 14.46%), while rate of switching treatments was lower in the HFNC group but not significant (−5.2%; 95% CI, −19.82 to 9.05%).

Patients in both the HFNC and NIV groups had faster mean respiratory rates 1 hour after extubation (P < .050). After 24 hours, the NIV group had higher-than-baseline respiratory rates, compared with the HFNC group, which had returned to normal (20 vs. 24.5 breaths per minute; P < .050). Both groups had returned to baseline by 48 hours after extubation. At 1 hour after extubation, patients in the HFNC group had lower PaO₂/FiO₂ (P < .050) and pH values (P < .050), and higher PaCO₂ values (P less than .050), compared with baseline. There were no statistically significant differences in PaO₂/FiO₂, pH, and PaCO₂ values in either group at 24 hours or 48 hours after extubation.

Daily airway care interventions were significantly higher on average in the NIV group, compared with the HFNC group (7 vs. 6; P = .0006), and the HFNC group also had significantly better comfort scores (7 vs. 5; P < .001) as measured by a modified visual analog scale, as well as incidence of nasal and facial skin breakdown (0 vs. 9.6%; P = .027), compared with the NIV group.
 

Results difficult to apply to North American patients

David L. Bowton, MD, FCCP, a professor specializing in critical care at Wake Forest University, Winston-Salem, N.C., said in an interview the results of this trial may not be applicable for patients with infection-related respiratory failure and COPD in North America “due to the differences in common weaning practices between North America and China.”

For example, the trial used the pulmonary infection control (PIC) window criteria for extubation, which requires a significant decrease in radiographic infiltrates, improvement in quality and quantity of sputum, normalizing of leukocyte count, a synchronized intermittent mandatory ventilation (SIMV) rate of 10-12 breaths per minute, and pressure support less than 10-12 cm/H₂O (Int J Chron Obstruct Pulmon Dis. 2017;12:1255-67).

“The process used to achieve these measures is not standardized. In North America, daily awakening and screening for spontaneous breathing trials would be usual, but this was not reported in the current trial,” he explained.

Differences in patient population also make the application of the results difficult, Dr. Bowton said. “Only 60% of the patients had spirometrically confirmed COPD and fewer than half were on at least dual inhaled therapy prior to hospitalization with only one-third taking beta agonists or anticholinergic agents,” he noted. “The cause of respiratory failure was infectious, requiring an infiltrate on chest radiograph; thus, patients with hypercarbic respiratory failure without a new infiltrate were excluded from the study. On average, patients were hypercarbic, yet alkalemic at the time of extubation; the PaCO₂ and pH at the time of intubation were not reported.

“This study suggests that in some patients with COPD and respiratory failure requiring invasive mechanical ventilation, HFO [high-flow oxygen] may be better tolerated and equally effective as NIPPV [noninvasive positive-pressure ventilation] at mitigating the need for reintubation following extubation. In this patient population where hypoxemia prior to extubation was not severe, the mechanisms by which HFO is beneficial remain speculative,” he said.

This study was funded by the Rui E special fund for emergency medicine research and the Yangzhou Science and Technology Development Plan. The authors report no relevant conflicts of interest. Dr. Bowton reports no relevant conflicts of interest.

SOURCE: Tan D et al. Crit Care. 2020 Aug 6. doi: 10.1186/s13054-020-03214-9.

A methodical, constructive, goal-oriented rapid repetition of emergency response simulations has emerged as a dominant strategy for pediatric readiness in the hospital setting, according to a detailed description of one such program at the virtual Pediatric Hospital Medicine.

Rather than a single run-through followed by a lengthy debriefing, which has been a traditional approach, short simulations done rapidly and repeatedly until skills are mastered improve skill development, according to Jeanmarie Schied, MD, of the department of pediatrics, University of Chicago Medicine.

A methodical, constructive, goal-oriented rapid repetition of emergency response simulations has emerged as a dominant strategy for pediatric readiness in the hospital setting, according to a detailed description of one such program at the virtual Pediatric Hospital Medicine.

Rather than a single run-through followed by a lengthy debriefing, which has been a traditional approach, short simulations done rapidly and repeatedly until skills are mastered improve skill development, according to Jeanmarie Schied, MD, of the department of pediatrics, University of Chicago Medicine.

A methodical, constructive, goal-oriented rapid repetition of emergency response simulations has emerged as a dominant strategy for pediatric readiness in the hospital setting, according to a detailed description of one such program at the virtual Pediatric Hospital Medicine.

Rather than a single run-through followed by a lengthy debriefing, which has been a traditional approach, short simulations done rapidly and repeatedly until skills are mastered improve skill development, according to Jeanmarie Schied, MD, of the department of pediatrics, University of Chicago Medicine.

Since 2019, more than 2,700 individuals have been hospitalized with electronic cigarette- (e-cigarette), or vaping-associated lung injury (EVALI). This entity first reached clinical attention after a series of otherwise healthy young adults presented with dyspnea, severe hypoxia, and diffuse pulmonary infiltrates in the Midwest (Layden J, et al. N Engl J Med. 2020;382[10]:903). Investigation of these cases revealed an association with the use of e-cigarettes, or vaping. As cases continued to mount, the link between vaping and acute lung injury became increasingly apparent.

How it presents

EVALI can present in variable ways, ranging from mild cough or dyspnea without hypoxia to severe acute respiratory distress syndrome (ARDS), requiring advanced life support. Although challenging in the ICU setting, obtaining a detailed history of vaping is crucial to make the diagnosis. Collateral history can be helpful, but if unrevealing, it should not be considered sufficient to exclude vaping as potential etiology, particularly in adolescent e-cigarette users, where parental awareness of substance use history may be limited. If a vaping history is obtained, it is important to assess the substance(s) vaped, how these substances were obtained, and methods of inhalation. While e-cigarettes are the most commonly recognized method of vaping, alternate methods such as “dabbing” and “dripping,” are increasingly popular among vape users, often utilizing modified e-liquid components that may not be reported by patients unless specifically queried.

About 82% of patients hospitalized with EVALI reported vaping tetrahydrocannabinol- (THC) containing fluid. This is important because, unlike nicotine based e-liquids that are primarily purchased over the counter, more than 70% of THC-containing e-liquids are reportedly obtained through informal sources, including illegal distributors. In contrast, only 14% of patients hospitalized with EVALI reported vaping of commercial nicotine products alone. Nicotine-based e-liquids can also be modified, and informal purchasing sources remain a concern, particularly among younger users.

The onset of respiratory symptoms in EVALI is often preceded by several days of a systemic prodrome, including low-grade fevers, myalgia, gastrointestinal complaints, and fatigue (MacMurdo M, et al. Chest. 2020;157[6]:e181). The diagnosis of EVALI is made clinically, and alternative etiologies of lung injury (eg, infections) should be excluded. As there is significant overlap between the presenting symptoms of EVALI and COVID-19 infection, patients should be tested for COVID-19 before a diagnosis of EVALI can be made.

Imaging patterns of EVALI include diffuse alveolar damage (the most common), comprising of diffuse ground-glass opacities, septal thickening, and heterogeneous consolidation (MacMurdo M, et al. Chest. 2020;157[6]:e181). Bilateral ground glass opacities suggestive of organizing pneumonia have also been described. Atypical patterns of nodularity suggestive of hypersensitivity pneumonitis are significantly less common. Given the variety of imaging patterns, EVALI should be considered as a differential diagnosis in all patients presenting with new bilateral pulmonary infiltrates and severe hypoxia.

Early evaluation of these patients revealed lipid-laden macrophages in the bronchoalveolar lavage (BAL) fluid of these patients, raising concern for exogenous lipid inhalation resulting in the development of lipoid pneumonia (Maddock SD, et al. N Engl J Med. 2019;381[15]:1488). Analysis of BAL fluid revealed the presence of vitamin E acetate, a diluent utilized to cut, or dilute, e-liquid (Blount BC, et al. MMWR. 2019;68[45]:1040). This supported the hypothesis that the outbreak of EVALI was being driven, at least in part, by contaminated or self-modified e-liquid. Evaluation of lung biopsies revealed different pathologic patterns of acute lung injury, including diffuse alveolar damage and organizing pneumonia. Importantly, while lipid-laden macrophages were detected, other characteristics of lipoid pneumonia were absent (Mukhopadhyay S, et al. Am J Clin Path. 2019;153[1]30).
 

How to manage EVALI

Approximately half of patients hospitalized with EVALI required ICU admission. However, there is likely a substantial portion of patients with mild disease who may not be represented in the current registry since they did not require hospitalization. The management is primarily supportive and, in patients who require mechanical ventilation, following lung-protective ventilator strategies is of paramount importance. Steroids have been used in some case series, particularly for patients presenting with more severe disease, but data on benefit, optimal dose, and duration are limited.

Vaping cessation is crucial and should be aggressively encouraged. Newer generations of e-cigarettes contain comparatively higher nicotine concentrations, and likely have high potential for nicotine addiction. Treatment for nicotine dependence, including pharmacologic therapy, needs to be considered in all patients following recovery from EVALI.

With supportive care and removal of ongoing exposure, recovery is anticipated in most patients. Long-term outcomes in patients who develop EVALI remain unclear. Although early fibrosis was present in some patients who had transbronchial biopsies, the long-term effects on pulmonary function that may be seen in patients with a history of EVALI are yet to be determined.
 

What about policy?

New regulations related to e-cigarette use have been proposed in response to the increasing prevalence of vaping and the EVALI outbreak. These regulations center primarily on limiting adolescent e-cigarette usage. Tobacco 21, federal legislation passed in 2019, makes it illegal to sell tobacco products to those under the age of 21. The FDA also issued an enforcement policy on unauthorized flavored e-cigarette products. However, this has been criticized for not being comprehensive enough. For example, tobacco and menthol flavors were not included in the ban. Furthermore, THC-containing e-liquid remains largely unregulated at the federal level, and state-level regulation varies significantly by marijuana legalization status.

Policy initiatives that restrict sales without also addressing drivers of e-cigarette use, such as nicotine dependence and aggressive marketing campaigns, are of particular concern and are likely to disproportionately impact younger users. Another unintended effect of e-cigarette sales restrictions may result in a new wave of illegal product distribution and e-liquid modification. Supporting this hypothesis was the finding that the risk of EVALI was higher in states without legalized recreational marijuana, suggesting that users who obtained e-liquid through these informal sources were at greater risk of exposure to contaminated product (Wing C, et al. JAMA Netw Open. 2020;3[4]:e202187). While the CDC is no longer actively tracking EVALI cases, they continue to be reported, and vape use remains common (Armatas C, et al. MMWR. 69[25]:801). As long as e-cigarettes remain in use, another EVALI outbreak remains possible.

It remains important for the intensivist to be familiar with the full spectrum of vaping methods, and to report suspected cases when they arise. While treatable, much remains unknown about the long-term effects on this patient population. Further research is needed to better understand the long-term outcomes in patients with EVALI, in addition to the treatment of nicotine dependence and substance use associated with vaping. Finally, comprehensive regulation to curb e-cigarette usage is needed, particularly among adolescents. However, legislation that is too narrow in scope runs the risk of channeling adolescent e-cigarette users to obtain product through informal sources, further increasing their risk for EVALI. As clinicians, we cannot afford to drop our guard!
 

Dr. Macmurdo and Dr. Choi are with Cleveland Clinic, Respiratory Institute, Cleveland, Ohio.

Since 2019, more than 2,700 individuals have been hospitalized with electronic cigarette- (e-cigarette), or vaping-associated lung injury (EVALI). This entity first reached clinical attention after a series of otherwise healthy young adults presented with dyspnea, severe hypoxia, and diffuse pulmonary infiltrates in the Midwest (Layden J, et al. N Engl J Med. 2020;382[10]:903). Investigation of these cases revealed an association with the use of e-cigarettes, or vaping. As cases continued to mount, the link between vaping and acute lung injury became increasingly apparent.

How it presents

EVALI can present in variable ways, ranging from mild cough or dyspnea without hypoxia to severe acute respiratory distress syndrome (ARDS), requiring advanced life support. Although challenging in the ICU setting, obtaining a detailed history of vaping is crucial to make the diagnosis. Collateral history can be helpful, but if unrevealing, it should not be considered sufficient to exclude vaping as potential etiology, particularly in adolescent e-cigarette users, where parental awareness of substance use history may be limited. If a vaping history is obtained, it is important to assess the substance(s) vaped, how these substances were obtained, and methods of inhalation. While e-cigarettes are the most commonly recognized method of vaping, alternate methods such as “dabbing” and “dripping,” are increasingly popular among vape users, often utilizing modified e-liquid components that may not be reported by patients unless specifically queried.

About 82% of patients hospitalized with EVALI reported vaping tetrahydrocannabinol- (THC) containing fluid. This is important because, unlike nicotine based e-liquids that are primarily purchased over the counter, more than 70% of THC-containing e-liquids are reportedly obtained through informal sources, including illegal distributors. In contrast, only 14% of patients hospitalized with EVALI reported vaping of commercial nicotine products alone. Nicotine-based e-liquids can also be modified, and informal purchasing sources remain a concern, particularly among younger users.

The onset of respiratory symptoms in EVALI is often preceded by several days of a systemic prodrome, including low-grade fevers, myalgia, gastrointestinal complaints, and fatigue (MacMurdo M, et al. Chest. 2020;157[6]:e181). The diagnosis of EVALI is made clinically, and alternative etiologies of lung injury (eg, infections) should be excluded. As there is significant overlap between the presenting symptoms of EVALI and COVID-19 infection, patients should be tested for COVID-19 before a diagnosis of EVALI can be made.

Imaging patterns of EVALI include diffuse alveolar damage (the most common), comprising of diffuse ground-glass opacities, septal thickening, and heterogeneous consolidation (MacMurdo M, et al. Chest. 2020;157[6]:e181). Bilateral ground glass opacities suggestive of organizing pneumonia have also been described. Atypical patterns of nodularity suggestive of hypersensitivity pneumonitis are significantly less common. Given the variety of imaging patterns, EVALI should be considered as a differential diagnosis in all patients presenting with new bilateral pulmonary infiltrates and severe hypoxia.

Early evaluation of these patients revealed lipid-laden macrophages in the bronchoalveolar lavage (BAL) fluid of these patients, raising concern for exogenous lipid inhalation resulting in the development of lipoid pneumonia (Maddock SD, et al. N Engl J Med. 2019;381[15]:1488). Analysis of BAL fluid revealed the presence of vitamin E acetate, a diluent utilized to cut, or dilute, e-liquid (Blount BC, et al. MMWR. 2019;68[45]:1040). This supported the hypothesis that the outbreak of EVALI was being driven, at least in part, by contaminated or self-modified e-liquid. Evaluation of lung biopsies revealed different pathologic patterns of acute lung injury, including diffuse alveolar damage and organizing pneumonia. Importantly, while lipid-laden macrophages were detected, other characteristics of lipoid pneumonia were absent (Mukhopadhyay S, et al. Am J Clin Path. 2019;153[1]30).
 

How to manage EVALI

Approximately half of patients hospitalized with EVALI required ICU admission. However, there is likely a substantial portion of patients with mild disease who may not be represented in the current registry since they did not require hospitalization. The management is primarily supportive and, in patients who require mechanical ventilation, following lung-protective ventilator strategies is of paramount importance. Steroids have been used in some case series, particularly for patients presenting with more severe disease, but data on benefit, optimal dose, and duration are limited.

Vaping cessation is crucial and should be aggressively encouraged. Newer generations of e-cigarettes contain comparatively higher nicotine concentrations, and likely have high potential for nicotine addiction. Treatment for nicotine dependence, including pharmacologic therapy, needs to be considered in all patients following recovery from EVALI.

With supportive care and removal of ongoing exposure, recovery is anticipated in most patients. Long-term outcomes in patients who develop EVALI remain unclear. Although early fibrosis was present in some patients who had transbronchial biopsies, the long-term effects on pulmonary function that may be seen in patients with a history of EVALI are yet to be determined.
 

What about policy?

New regulations related to e-cigarette use have been proposed in response to the increasing prevalence of vaping and the EVALI outbreak. These regulations center primarily on limiting adolescent e-cigarette usage. Tobacco 21, federal legislation passed in 2019, makes it illegal to sell tobacco products to those under the age of 21. The FDA also issued an enforcement policy on unauthorized flavored e-cigarette products. However, this has been criticized for not being comprehensive enough. For example, tobacco and menthol flavors were not included in the ban. Furthermore, THC-containing e-liquid remains largely unregulated at the federal level, and state-level regulation varies significantly by marijuana legalization status.

Policy initiatives that restrict sales without also addressing drivers of e-cigarette use, such as nicotine dependence and aggressive marketing campaigns, are of particular concern and are likely to disproportionately impact younger users. Another unintended effect of e-cigarette sales restrictions may result in a new wave of illegal product distribution and e-liquid modification. Supporting this hypothesis was the finding that the risk of EVALI was higher in states without legalized recreational marijuana, suggesting that users who obtained e-liquid through these informal sources were at greater risk of exposure to contaminated product (Wing C, et al. JAMA Netw Open. 2020;3[4]:e202187). While the CDC is no longer actively tracking EVALI cases, they continue to be reported, and vape use remains common (Armatas C, et al. MMWR. 69[25]:801). As long as e-cigarettes remain in use, another EVALI outbreak remains possible.

It remains important for the intensivist to be familiar with the full spectrum of vaping methods, and to report suspected cases when they arise. While treatable, much remains unknown about the long-term effects on this patient population. Further research is needed to better understand the long-term outcomes in patients with EVALI, in addition to the treatment of nicotine dependence and substance use associated with vaping. Finally, comprehensive regulation to curb e-cigarette usage is needed, particularly among adolescents. However, legislation that is too narrow in scope runs the risk of channeling adolescent e-cigarette users to obtain product through informal sources, further increasing their risk for EVALI. As clinicians, we cannot afford to drop our guard!
 

Dr. Macmurdo and Dr. Choi are with Cleveland Clinic, Respiratory Institute, Cleveland, Ohio.

Since 2019, more than 2,700 individuals have been hospitalized with electronic cigarette- (e-cigarette), or vaping-associated lung injury (EVALI). This entity first reached clinical attention after a series of otherwise healthy young adults presented with dyspnea, severe hypoxia, and diffuse pulmonary infiltrates in the Midwest (Layden J, et al. N Engl J Med. 2020;382[10]:903). Investigation of these cases revealed an association with the use of e-cigarettes, or vaping. As cases continued to mount, the link between vaping and acute lung injury became increasingly apparent.

How it presents

EVALI can present in variable ways, ranging from mild cough or dyspnea without hypoxia to severe acute respiratory distress syndrome (ARDS), requiring advanced life support. Although challenging in the ICU setting, obtaining a detailed history of vaping is crucial to make the diagnosis. Collateral history can be helpful, but if unrevealing, it should not be considered sufficient to exclude vaping as potential etiology, particularly in adolescent e-cigarette users, where parental awareness of substance use history may be limited. If a vaping history is obtained, it is important to assess the substance(s) vaped, how these substances were obtained, and methods of inhalation. While e-cigarettes are the most commonly recognized method of vaping, alternate methods such as “dabbing” and “dripping,” are increasingly popular among vape users, often utilizing modified e-liquid components that may not be reported by patients unless specifically queried.

About 82% of patients hospitalized with EVALI reported vaping tetrahydrocannabinol- (THC) containing fluid. This is important because, unlike nicotine based e-liquids that are primarily purchased over the counter, more than 70% of THC-containing e-liquids are reportedly obtained through informal sources, including illegal distributors. In contrast, only 14% of patients hospitalized with EVALI reported vaping of commercial nicotine products alone. Nicotine-based e-liquids can also be modified, and informal purchasing sources remain a concern, particularly among younger users.

The onset of respiratory symptoms in EVALI is often preceded by several days of a systemic prodrome, including low-grade fevers, myalgia, gastrointestinal complaints, and fatigue (MacMurdo M, et al. Chest. 2020;157[6]:e181). The diagnosis of EVALI is made clinically, and alternative etiologies of lung injury (eg, infections) should be excluded. As there is significant overlap between the presenting symptoms of EVALI and COVID-19 infection, patients should be tested for COVID-19 before a diagnosis of EVALI can be made.

Imaging patterns of EVALI include diffuse alveolar damage (the most common), comprising of diffuse ground-glass opacities, septal thickening, and heterogeneous consolidation (MacMurdo M, et al. Chest. 2020;157[6]:e181). Bilateral ground glass opacities suggestive of organizing pneumonia have also been described. Atypical patterns of nodularity suggestive of hypersensitivity pneumonitis are significantly less common. Given the variety of imaging patterns, EVALI should be considered as a differential diagnosis in all patients presenting with new bilateral pulmonary infiltrates and severe hypoxia.

Early evaluation of these patients revealed lipid-laden macrophages in the bronchoalveolar lavage (BAL) fluid of these patients, raising concern for exogenous lipid inhalation resulting in the development of lipoid pneumonia (Maddock SD, et al. N Engl J Med. 2019;381[15]:1488). Analysis of BAL fluid revealed the presence of vitamin E acetate, a diluent utilized to cut, or dilute, e-liquid (Blount BC, et al. MMWR. 2019;68[45]:1040). This supported the hypothesis that the outbreak of EVALI was being driven, at least in part, by contaminated or self-modified e-liquid. Evaluation of lung biopsies revealed different pathologic patterns of acute lung injury, including diffuse alveolar damage and organizing pneumonia. Importantly, while lipid-laden macrophages were detected, other characteristics of lipoid pneumonia were absent (Mukhopadhyay S, et al. Am J Clin Path. 2019;153[1]30).
 

How to manage EVALI

Approximately half of patients hospitalized with EVALI required ICU admission. However, there is likely a substantial portion of patients with mild disease who may not be represented in the current registry since they did not require hospitalization. The management is primarily supportive and, in patients who require mechanical ventilation, following lung-protective ventilator strategies is of paramount importance. Steroids have been used in some case series, particularly for patients presenting with more severe disease, but data on benefit, optimal dose, and duration are limited.

Vaping cessation is crucial and should be aggressively encouraged. Newer generations of e-cigarettes contain comparatively higher nicotine concentrations, and likely have high potential for nicotine addiction. Treatment for nicotine dependence, including pharmacologic therapy, needs to be considered in all patients following recovery from EVALI.

With supportive care and removal of ongoing exposure, recovery is anticipated in most patients. Long-term outcomes in patients who develop EVALI remain unclear. Although early fibrosis was present in some patients who had transbronchial biopsies, the long-term effects on pulmonary function that may be seen in patients with a history of EVALI are yet to be determined.
 

What about policy?

New regulations related to e-cigarette use have been proposed in response to the increasing prevalence of vaping and the EVALI outbreak. These regulations center primarily on limiting adolescent e-cigarette usage. Tobacco 21, federal legislation passed in 2019, makes it illegal to sell tobacco products to those under the age of 21. The FDA also issued an enforcement policy on unauthorized flavored e-cigarette products. However, this has been criticized for not being comprehensive enough. For example, tobacco and menthol flavors were not included in the ban. Furthermore, THC-containing e-liquid remains largely unregulated at the federal level, and state-level regulation varies significantly by marijuana legalization status.

Policy initiatives that restrict sales without also addressing drivers of e-cigarette use, such as nicotine dependence and aggressive marketing campaigns, are of particular concern and are likely to disproportionately impact younger users. Another unintended effect of e-cigarette sales restrictions may result in a new wave of illegal product distribution and e-liquid modification. Supporting this hypothesis was the finding that the risk of EVALI was higher in states without legalized recreational marijuana, suggesting that users who obtained e-liquid through these informal sources were at greater risk of exposure to contaminated product (Wing C, et al. JAMA Netw Open. 2020;3[4]:e202187). While the CDC is no longer actively tracking EVALI cases, they continue to be reported, and vape use remains common (Armatas C, et al. MMWR. 69[25]:801). As long as e-cigarettes remain in use, another EVALI outbreak remains possible.

It remains important for the intensivist to be familiar with the full spectrum of vaping methods, and to report suspected cases when they arise. While treatable, much remains unknown about the long-term effects on this patient population. Further research is needed to better understand the long-term outcomes in patients with EVALI, in addition to the treatment of nicotine dependence and substance use associated with vaping. Finally, comprehensive regulation to curb e-cigarette usage is needed, particularly among adolescents. However, legislation that is too narrow in scope runs the risk of channeling adolescent e-cigarette users to obtain product through informal sources, further increasing their risk for EVALI. As clinicians, we cannot afford to drop our guard!
 

Dr. Macmurdo and Dr. Choi are with Cleveland Clinic, Respiratory Institute, Cleveland, Ohio.

Background: Since the advent of early goal-directed therapy (EGDT), studies have challenged the notion that high-volume IV fluid resuscitation improves clinical outcomes in sepsis and septic shock. The optimal IV fluid resuscitation strategy for severe sepsis and septic shock remains unclear.

Limitations to RIFTS include its small sample size, single-system design, and inadequate power to detect noninferiority or superiority. While larger, multicenter trials are required for further investigation, hospitalists should note a trend toward conservative IV fluid administration in severe sepsis and septic shock.

Bottom line: Restrictive IV fluid resuscitation for severe sepsis and septic shock may result in mortality rates similar to those of usual care, but larger, multicenter studies are needed to confirm noninferiority.

Citation: Corl KA et al. The restrictive IV fluid trial in severe sepsis and septic shock (RIFTS): A randomized pilot study. Crit Care Med. 2019;47(7):951-9.

Dr. McIntyre is a hospitalist at Ochsner Health System, New Orleans.

Background: Since the advent of early goal-directed therapy (EGDT), studies have challenged the notion that high-volume IV fluid resuscitation improves clinical outcomes in sepsis and septic shock. The optimal IV fluid resuscitation strategy for severe sepsis and septic shock remains unclear.

Limitations to RIFTS include its small sample size, single-system design, and inadequate power to detect noninferiority or superiority. While larger, multicenter trials are required for further investigation, hospitalists should note a trend toward conservative IV fluid administration in severe sepsis and septic shock.

Bottom line: Restrictive IV fluid resuscitation for severe sepsis and septic shock may result in mortality rates similar to those of usual care, but larger, multicenter studies are needed to confirm noninferiority.

Citation: Corl KA et al. The restrictive IV fluid trial in severe sepsis and septic shock (RIFTS): A randomized pilot study. Crit Care Med. 2019;47(7):951-9.

Dr. McIntyre is a hospitalist at Ochsner Health System, New Orleans.

Background: Since the advent of early goal-directed therapy (EGDT), studies have challenged the notion that high-volume IV fluid resuscitation improves clinical outcomes in sepsis and septic shock. The optimal IV fluid resuscitation strategy for severe sepsis and septic shock remains unclear.

Limitations to RIFTS include its small sample size, single-system design, and inadequate power to detect noninferiority or superiority. While larger, multicenter trials are required for further investigation, hospitalists should note a trend toward conservative IV fluid administration in severe sepsis and septic shock.

Bottom line: Restrictive IV fluid resuscitation for severe sepsis and septic shock may result in mortality rates similar to those of usual care, but larger, multicenter studies are needed to confirm noninferiority.

Citation: Corl KA et al. The restrictive IV fluid trial in severe sepsis and septic shock (RIFTS): A randomized pilot study. Crit Care Med. 2019;47(7):951-9.

Dr. McIntyre is a hospitalist at Ochsner Health System, New Orleans.

“Anytime you have a maternal death, it sticks with you for life,” said Elliott Main, MD, a maternal fetal medicine specialist at Stanford (Calif.) University and one of the nation’s leaders in combating maternal mortality.

Courtesy Dr. Elliott Main

Dr. Main has had two maternal deaths in his career, years ago. One woman had a fatal stroke because of severe hypertension, and another died of cardiac complications. “We tried to do everything we possibly could, but you scrounge your memory for years and years [afterward]. To have a young healthy person go into labor and delivery and not come out is a tragedy at all levels. It charged me to not ever want to see that happen again,” he said.

Today, Dr. Main is the medical director of the California Maternal Quality Care Collaborative (CMQCC), a wide-ranging group of clinicians, state officials, hospitals, and others who have come together to address the issue. About 30 states have similar perinatal quality collaboratives (PQCs), and other states are forming them.

They work in collaboration with maternal mortality review committees (MMRCs), state-level groups that review maternal deaths, identify problems to address, and make recommendations to the quality collaboratives on how to prevent maternal deaths.

About 600-800 women die in the United States each year due to pregnancy-related complications, which ranks the United States behind other industrialized nations. Leading causes include hemorrhage and hemorrhagic strokes secondary to hypertension. It’s estimated that the majority of maternal deaths could be prevented with proper care.

To that end, states are enacting safety bundles from the Alliance for Innovation on Maternal Health (AIM), which was established by the American College of Obstetricians and Gynecologist several years ago. There are bundles that address obstetric hypertension, hemorrhage, mental health, venous thromboembolism, opioid use, racial disparities, and other problems. They were developed by experts in the field and published in multiple journals. California and other states have issued toolkits on how to implement them based on local circumstances.

The goal is to standardize best practices nationwide to prevent maternal morbidity and mortality, Dr. Main said.

AIM bundle implementation is “what’s happening in New Mexico and a lot of states, mostly through the efforts of state level quality care collaboratives. Some [states] are further ahead than others,” said Eve Espey, MD, professor and chair of the department of obstetrics and gynecology at the University of New Mexico, Albuquerque, and president of the New Mexico PQC.

“Most states now have a [MMRC] that collects maternal mortality and near-miss data. Those data are used by the action arm,” which is the PQC. “If the review committee says” opioid use disorder is a significant contributor “like in our state, the collaborative rolls out the opioid use disorder bundle,” she said.

Beginning next January, the Joint Commission, formerly known as the Joint Commission on Accreditation of Healthcare Organizations, will require that accredited hospitals enact key elements of the AIM bundles for both obstetric hemorrhage and severe hypertension. “Everyone’s [now] motivated to get on that bandwagon,” Dr. Espey said.

“The bundles are here to stay,” and the Joint Commission requirements are “a really important step for sustainability and basic implementation. We really want to get them adopted everywhere,” said Dr. Main, who is also the national implementation director for the AIM initiative.

“The key thing is to work on implementing the hemorrhage and hypertension bundles in your hospital. I would suggest contacting [your] state” PQC, he said.

The California model

California, which has been working to reduce maternal mortality and morbidity since the mid 2000s, has produced among the strongest evidence to date that the efforts make a difference.

By 2013, the state had halved its maternal mortality rate to a 3-year average of 7 deaths per 100,000 live births, which is comparable with the average Western Europe rate of 7.2 deaths. Nationwide, the rate was about 17.4 deaths per 100,000 live births in 2018, according to the Centers for Disease Control and Prevention

The reasons are multifactorial, but “we think” the quality improvement efforts have been “an important contributor,” Dr. Main said.
 

Improvements especially for Black women

Among the success stories has been California’s implementation of the AIM obstetric hemorrhage bundle about 5 years ago. Among other steps, the 17 evidence-based recommendations included early recognition, immediate access to oxytocin and other medications, immediate access to a hemorrhage cart with instructions for intrauterine balloons and compression stitches, the establishment of a hemorrhage response protocol and team, and regular unit-based drills with debriefing sessions afterward.

Mentoring teams consisting of a physician and nurse with maternal quality improvement experience were created to help hospitals come on board, with each team working with five to eight hospitals. Efforts included monthly telephone calls and face-to-face meetings, and providers were held accountable for progress. Hospitals shared data and tips on implementation, under the aegis of the CMQCC.

When the baseline period of 2011-2014 to the postintervention period of October 2015 to December 2016 were compared, the rate of severe maternal morbidity from hemorrhage fell from 22.1% to 18.5% across 99 hospitals and 73,476 women.

The benefit among Black women exceeded that among White women, with a 9% absolute rate reduction versus 2.1%. “If you adjusted for risk factors, [we found] you could eliminate [racial differences] completely,” which is something that hadn’t been shown before. “This is a really big deal,” Dr. Main said, because the risk of maternal morbidity and mortality is three to four times higher among Black women, compared with White women.

Dr. Main and his team found that the biggest clinical risk factor that accounted for racial differences was a higher rate of cesarean deliveries among Black women, followed by higher rates of anemia at hospital admission. “If you have a C-section when you are anemic, you are going to have a transfusion,” he explained.

More recently, there’s been a push in California to reduce the rate of primary cesarean deliveries by enacting the associated AIM bundle with use of the same approach as with the hemorrhage bundle. Dr. Main and his team recently reported a rate reduction from 29.3% to 25% without compromising birth outcomes.

However, “some changes are easier than others. Hemorrhage was an easy one to change because it didn’t deal with physician autonomy as much, and you saw more immediate results” with fewer hemorrhages. Reducing cesarean delivery rates is “a bigger lift” because “it’s really changing the culture of labor and delivery. It involves more group pressure and more reinforcing, but we were able to do that,” he said.
 

Problems in the Show Me State

“We’ve patterned a lot” of what’s being done in New Mexico “after California,” Dr. Espey said.

The AIM hemorrhage bundle, for instance, is being rolled out to New Mexico hospitals, with the help of virtual meetings and mentoring programs, plus outreach to the Navajo and others reservations because, as with Black women, rates of maternal morbidity and mortality are higher among Native American women.

It’s been tougher going, however, in states such as Missouri, which recently ranked 44th in the country for maternal mortality.

“We started a little bit late, and we are a little bit behind,” said ob.gyn. Karen L. Florio, DO, at the University of Missouri–Kansas City and also a leader of the state MMRC and member of its PQC.

The main problem is money. California’s efforts are funded by the Centers for Disease Control and Prevention, the state health department, and hospitals, among others.

But Missouri is “not as well funded as California for our mortality review board, and our [PQC] is mostly not funded. If we could get that funding, we would have more resources to implement these AIM bundles,” she said.

In addition to the issue, Missouri didn’t expand Medicaid under the Accountable Care Act – something that’s been linked to reduced maternal morbidity and mortality – and there are entire rural areas with no maternity care. Plus after generations of mistreatment, “our African American population has a valid distrust of the medical system that contributes to maternal mortality,” she said.

Obesity-related heart disease is also prevalent in Missouri, even among young people. “I cannot tell you how many women I have had who have had a heart attack at the age of 30 and who have had stents placed,” Dr. Florio said.

Dr. Florio and her colleagues are currently using teleconferences and other means to roll out the AIM hypertension bundle but can do so only selectively. “We don’t have the resources to reach every single rural hospital all over the state,” she said; they are working to address the funding issues.
 

For rural hospitals, implementation is “daunting”

Meanwhile, rural hospitals have been a particular concern in South Dakota, said Kimberlee McKay, MD, an ob.gyn. who is the clinical vice president of the ob.gyn. service line at Avera Health, a hospital system based in Sioux Falls, S.D.

She’s been overseeing Avera’s implementation of the hypertension, hemorrhage, and venous thromboembolism bundles. “What’s hard is that” the AIM protocols come “out of academic centers. Implementation of complex algorithms is daunting” for hospitals that only do a couple hundred deliveries a year, she said.

For small hospitals, the approach she’s found that works is to first assess what they can offer, and then have them “do what’s reasonable” for their resources. The second part is making sure high-risk women get to a regional center – with an adequate blood supply, in the case of hemorrhage, for instance – for complications. Dr. McKay and colleagues are working on a system by which regional centers can monitor smaller hospitals for potential maternity problems, and contact them proactively before they emerge.

They’ve also made access to hemorrhage and hypertension drugs easier on labor and delivery units with the help of close-by dedicated medicine boxes, and standardized protocols and order sets across Avera. “We try to make the right thing the easy thing to do,” Dr. McKay said.

Dr. Espey is an editorial adviser for Ob.Gyn. News. The physicians have no relevant financial disclosures.

[email protected]

“Anytime you have a maternal death, it sticks with you for life,” said Elliott Main, MD, a maternal fetal medicine specialist at Stanford (Calif.) University and one of the nation’s leaders in combating maternal mortality.

Courtesy Dr. Elliott Main

Dr. Main has had two maternal deaths in his career, years ago. One woman had a fatal stroke because of severe hypertension, and another died of cardiac complications. “We tried to do everything we possibly could, but you scrounge your memory for years and years [afterward]. To have a young healthy person go into labor and delivery and not come out is a tragedy at all levels. It charged me to not ever want to see that happen again,” he said.

Today, Dr. Main is the medical director of the California Maternal Quality Care Collaborative (CMQCC), a wide-ranging group of clinicians, state officials, hospitals, and others who have come together to address the issue. About 30 states have similar perinatal quality collaboratives (PQCs), and other states are forming them.

They work in collaboration with maternal mortality review committees (MMRCs), state-level groups that review maternal deaths, identify problems to address, and make recommendations to the quality collaboratives on how to prevent maternal deaths.

About 600-800 women die in the United States each year due to pregnancy-related complications, which ranks the United States behind other industrialized nations. Leading causes include hemorrhage and hemorrhagic strokes secondary to hypertension. It’s estimated that the majority of maternal deaths could be prevented with proper care.

To that end, states are enacting safety bundles from the Alliance for Innovation on Maternal Health (AIM), which was established by the American College of Obstetricians and Gynecologist several years ago. There are bundles that address obstetric hypertension, hemorrhage, mental health, venous thromboembolism, opioid use, racial disparities, and other problems. They were developed by experts in the field and published in multiple journals. California and other states have issued toolkits on how to implement them based on local circumstances.

The goal is to standardize best practices nationwide to prevent maternal morbidity and mortality, Dr. Main said.

AIM bundle implementation is “what’s happening in New Mexico and a lot of states, mostly through the efforts of state level quality care collaboratives. Some [states] are further ahead than others,” said Eve Espey, MD, professor and chair of the department of obstetrics and gynecology at the University of New Mexico, Albuquerque, and president of the New Mexico PQC.

“Most states now have a [MMRC] that collects maternal mortality and near-miss data. Those data are used by the action arm,” which is the PQC. “If the review committee says” opioid use disorder is a significant contributor “like in our state, the collaborative rolls out the opioid use disorder bundle,” she said.

Beginning next January, the Joint Commission, formerly known as the Joint Commission on Accreditation of Healthcare Organizations, will require that accredited hospitals enact key elements of the AIM bundles for both obstetric hemorrhage and severe hypertension. “Everyone’s [now] motivated to get on that bandwagon,” Dr. Espey said.

“The bundles are here to stay,” and the Joint Commission requirements are “a really important step for sustainability and basic implementation. We really want to get them adopted everywhere,” said Dr. Main, who is also the national implementation director for the AIM initiative.

“The key thing is to work on implementing the hemorrhage and hypertension bundles in your hospital. I would suggest contacting [your] state” PQC, he said.

The California model

California, which has been working to reduce maternal mortality and morbidity since the mid 2000s, has produced among the strongest evidence to date that the efforts make a difference.

By 2013, the state had halved its maternal mortality rate to a 3-year average of 7 deaths per 100,000 live births, which is comparable with the average Western Europe rate of 7.2 deaths. Nationwide, the rate was about 17.4 deaths per 100,000 live births in 2018, according to the Centers for Disease Control and Prevention

The reasons are multifactorial, but “we think” the quality improvement efforts have been “an important contributor,” Dr. Main said.
 

Improvements especially for Black women

Among the success stories has been California’s implementation of the AIM obstetric hemorrhage bundle about 5 years ago. Among other steps, the 17 evidence-based recommendations included early recognition, immediate access to oxytocin and other medications, immediate access to a hemorrhage cart with instructions for intrauterine balloons and compression stitches, the establishment of a hemorrhage response protocol and team, and regular unit-based drills with debriefing sessions afterward.

Mentoring teams consisting of a physician and nurse with maternal quality improvement experience were created to help hospitals come on board, with each team working with five to eight hospitals. Efforts included monthly telephone calls and face-to-face meetings, and providers were held accountable for progress. Hospitals shared data and tips on implementation, under the aegis of the CMQCC.

When the baseline period of 2011-2014 to the postintervention period of October 2015 to December 2016 were compared, the rate of severe maternal morbidity from hemorrhage fell from 22.1% to 18.5% across 99 hospitals and 73,476 women.

The benefit among Black women exceeded that among White women, with a 9% absolute rate reduction versus 2.1%. “If you adjusted for risk factors, [we found] you could eliminate [racial differences] completely,” which is something that hadn’t been shown before. “This is a really big deal,” Dr. Main said, because the risk of maternal morbidity and mortality is three to four times higher among Black women, compared with White women.

Dr. Main and his team found that the biggest clinical risk factor that accounted for racial differences was a higher rate of cesarean deliveries among Black women, followed by higher rates of anemia at hospital admission. “If you have a C-section when you are anemic, you are going to have a transfusion,” he explained.

More recently, there’s been a push in California to reduce the rate of primary cesarean deliveries by enacting the associated AIM bundle with use of the same approach as with the hemorrhage bundle. Dr. Main and his team recently reported a rate reduction from 29.3% to 25% without compromising birth outcomes.

However, “some changes are easier than others. Hemorrhage was an easy one to change because it didn’t deal with physician autonomy as much, and you saw more immediate results” with fewer hemorrhages. Reducing cesarean delivery rates is “a bigger lift” because “it’s really changing the culture of labor and delivery. It involves more group pressure and more reinforcing, but we were able to do that,” he said.
 

Problems in the Show Me State

“We’ve patterned a lot” of what’s being done in New Mexico “after California,” Dr. Espey said.

The AIM hemorrhage bundle, for instance, is being rolled out to New Mexico hospitals, with the help of virtual meetings and mentoring programs, plus outreach to the Navajo and others reservations because, as with Black women, rates of maternal morbidity and mortality are higher among Native American women.

It’s been tougher going, however, in states such as Missouri, which recently ranked 44th in the country for maternal mortality.

“We started a little bit late, and we are a little bit behind,” said ob.gyn. Karen L. Florio, DO, at the University of Missouri–Kansas City and also a leader of the state MMRC and member of its PQC.

The main problem is money. California’s efforts are funded by the Centers for Disease Control and Prevention, the state health department, and hospitals, among others.

But Missouri is “not as well funded as California for our mortality review board, and our [PQC] is mostly not funded. If we could get that funding, we would have more resources to implement these AIM bundles,” she said.

In addition to the issue, Missouri didn’t expand Medicaid under the Accountable Care Act – something that’s been linked to reduced maternal morbidity and mortality – and there are entire rural areas with no maternity care. Plus after generations of mistreatment, “our African American population has a valid distrust of the medical system that contributes to maternal mortality,” she said.

Obesity-related heart disease is also prevalent in Missouri, even among young people. “I cannot tell you how many women I have had who have had a heart attack at the age of 30 and who have had stents placed,” Dr. Florio said.

Dr. Florio and her colleagues are currently using teleconferences and other means to roll out the AIM hypertension bundle but can do so only selectively. “We don’t have the resources to reach every single rural hospital all over the state,” she said; they are working to address the funding issues.
 

For rural hospitals, implementation is “daunting”

Meanwhile, rural hospitals have been a particular concern in South Dakota, said Kimberlee McKay, MD, an ob.gyn. who is the clinical vice president of the ob.gyn. service line at Avera Health, a hospital system based in Sioux Falls, S.D.

She’s been overseeing Avera’s implementation of the hypertension, hemorrhage, and venous thromboembolism bundles. “What’s hard is that” the AIM protocols come “out of academic centers. Implementation of complex algorithms is daunting” for hospitals that only do a couple hundred deliveries a year, she said.

For small hospitals, the approach she’s found that works is to first assess what they can offer, and then have them “do what’s reasonable” for their resources. The second part is making sure high-risk women get to a regional center – with an adequate blood supply, in the case of hemorrhage, for instance – for complications. Dr. McKay and colleagues are working on a system by which regional centers can monitor smaller hospitals for potential maternity problems, and contact them proactively before they emerge.

They’ve also made access to hemorrhage and hypertension drugs easier on labor and delivery units with the help of close-by dedicated medicine boxes, and standardized protocols and order sets across Avera. “We try to make the right thing the easy thing to do,” Dr. McKay said.

Dr. Espey is an editorial adviser for Ob.Gyn. News. The physicians have no relevant financial disclosures.

[email protected]

“Anytime you have a maternal death, it sticks with you for life,” said Elliott Main, MD, a maternal fetal medicine specialist at Stanford (Calif.) University and one of the nation’s leaders in combating maternal mortality.

Courtesy Dr. Elliott Main

Dr. Main has had two maternal deaths in his career, years ago. One woman had a fatal stroke because of severe hypertension, and another died of cardiac complications. “We tried to do everything we possibly could, but you scrounge your memory for years and years [afterward]. To have a young healthy person go into labor and delivery and not come out is a tragedy at all levels. It charged me to not ever want to see that happen again,” he said.

Today, Dr. Main is the medical director of the California Maternal Quality Care Collaborative (CMQCC), a wide-ranging group of clinicians, state officials, hospitals, and others who have come together to address the issue. About 30 states have similar perinatal quality collaboratives (PQCs), and other states are forming them.

They work in collaboration with maternal mortality review committees (MMRCs), state-level groups that review maternal deaths, identify problems to address, and make recommendations to the quality collaboratives on how to prevent maternal deaths.

About 600-800 women die in the United States each year due to pregnancy-related complications, which ranks the United States behind other industrialized nations. Leading causes include hemorrhage and hemorrhagic strokes secondary to hypertension. It’s estimated that the majority of maternal deaths could be prevented with proper care.

To that end, states are enacting safety bundles from the Alliance for Innovation on Maternal Health (AIM), which was established by the American College of Obstetricians and Gynecologist several years ago. There are bundles that address obstetric hypertension, hemorrhage, mental health, venous thromboembolism, opioid use, racial disparities, and other problems. They were developed by experts in the field and published in multiple journals. California and other states have issued toolkits on how to implement them based on local circumstances.

The goal is to standardize best practices nationwide to prevent maternal morbidity and mortality, Dr. Main said.

AIM bundle implementation is “what’s happening in New Mexico and a lot of states, mostly through the efforts of state level quality care collaboratives. Some [states] are further ahead than others,” said Eve Espey, MD, professor and chair of the department of obstetrics and gynecology at the University of New Mexico, Albuquerque, and president of the New Mexico PQC.

“Most states now have a [MMRC] that collects maternal mortality and near-miss data. Those data are used by the action arm,” which is the PQC. “If the review committee says” opioid use disorder is a significant contributor “like in our state, the collaborative rolls out the opioid use disorder bundle,” she said.

Beginning next January, the Joint Commission, formerly known as the Joint Commission on Accreditation of Healthcare Organizations, will require that accredited hospitals enact key elements of the AIM bundles for both obstetric hemorrhage and severe hypertension. “Everyone’s [now] motivated to get on that bandwagon,” Dr. Espey said.

“The bundles are here to stay,” and the Joint Commission requirements are “a really important step for sustainability and basic implementation. We really want to get them adopted everywhere,” said Dr. Main, who is also the national implementation director for the AIM initiative.

“The key thing is to work on implementing the hemorrhage and hypertension bundles in your hospital. I would suggest contacting [your] state” PQC, he said.

The California model

California, which has been working to reduce maternal mortality and morbidity since the mid 2000s, has produced among the strongest evidence to date that the efforts make a difference.

By 2013, the state had halved its maternal mortality rate to a 3-year average of 7 deaths per 100,000 live births, which is comparable with the average Western Europe rate of 7.2 deaths. Nationwide, the rate was about 17.4 deaths per 100,000 live births in 2018, according to the Centers for Disease Control and Prevention

The reasons are multifactorial, but “we think” the quality improvement efforts have been “an important contributor,” Dr. Main said.
 

Improvements especially for Black women

Among the success stories has been California’s implementation of the AIM obstetric hemorrhage bundle about 5 years ago. Among other steps, the 17 evidence-based recommendations included early recognition, immediate access to oxytocin and other medications, immediate access to a hemorrhage cart with instructions for intrauterine balloons and compression stitches, the establishment of a hemorrhage response protocol and team, and regular unit-based drills with debriefing sessions afterward.

Mentoring teams consisting of a physician and nurse with maternal quality improvement experience were created to help hospitals come on board, with each team working with five to eight hospitals. Efforts included monthly telephone calls and face-to-face meetings, and providers were held accountable for progress. Hospitals shared data and tips on implementation, under the aegis of the CMQCC.

When the baseline period of 2011-2014 to the postintervention period of October 2015 to December 2016 were compared, the rate of severe maternal morbidity from hemorrhage fell from 22.1% to 18.5% across 99 hospitals and 73,476 women.

The benefit among Black women exceeded that among White women, with a 9% absolute rate reduction versus 2.1%. “If you adjusted for risk factors, [we found] you could eliminate [racial differences] completely,” which is something that hadn’t been shown before. “This is a really big deal,” Dr. Main said, because the risk of maternal morbidity and mortality is three to four times higher among Black women, compared with White women.

Dr. Main and his team found that the biggest clinical risk factor that accounted for racial differences was a higher rate of cesarean deliveries among Black women, followed by higher rates of anemia at hospital admission. “If you have a C-section when you are anemic, you are going to have a transfusion,” he explained.

More recently, there’s been a push in California to reduce the rate of primary cesarean deliveries by enacting the associated AIM bundle with use of the same approach as with the hemorrhage bundle. Dr. Main and his team recently reported a rate reduction from 29.3% to 25% without compromising birth outcomes.

However, “some changes are easier than others. Hemorrhage was an easy one to change because it didn’t deal with physician autonomy as much, and you saw more immediate results” with fewer hemorrhages. Reducing cesarean delivery rates is “a bigger lift” because “it’s really changing the culture of labor and delivery. It involves more group pressure and more reinforcing, but we were able to do that,” he said.
 

Problems in the Show Me State

“We’ve patterned a lot” of what’s being done in New Mexico “after California,” Dr. Espey said.

The AIM hemorrhage bundle, for instance, is being rolled out to New Mexico hospitals, with the help of virtual meetings and mentoring programs, plus outreach to the Navajo and others reservations because, as with Black women, rates of maternal morbidity and mortality are higher among Native American women.

It’s been tougher going, however, in states such as Missouri, which recently ranked 44th in the country for maternal mortality.

“We started a little bit late, and we are a little bit behind,” said ob.gyn. Karen L. Florio, DO, at the University of Missouri–Kansas City and also a leader of the state MMRC and member of its PQC.

The main problem is money. California’s efforts are funded by the Centers for Disease Control and Prevention, the state health department, and hospitals, among others.

But Missouri is “not as well funded as California for our mortality review board, and our [PQC] is mostly not funded. If we could get that funding, we would have more resources to implement these AIM bundles,” she said.

In addition to the issue, Missouri didn’t expand Medicaid under the Accountable Care Act – something that’s been linked to reduced maternal morbidity and mortality – and there are entire rural areas with no maternity care. Plus after generations of mistreatment, “our African American population has a valid distrust of the medical system that contributes to maternal mortality,” she said.

Obesity-related heart disease is also prevalent in Missouri, even among young people. “I cannot tell you how many women I have had who have had a heart attack at the age of 30 and who have had stents placed,” Dr. Florio said.

Dr. Florio and her colleagues are currently using teleconferences and other means to roll out the AIM hypertension bundle but can do so only selectively. “We don’t have the resources to reach every single rural hospital all over the state,” she said; they are working to address the funding issues.
 

For rural hospitals, implementation is “daunting”

Meanwhile, rural hospitals have been a particular concern in South Dakota, said Kimberlee McKay, MD, an ob.gyn. who is the clinical vice president of the ob.gyn. service line at Avera Health, a hospital system based in Sioux Falls, S.D.

She’s been overseeing Avera’s implementation of the hypertension, hemorrhage, and venous thromboembolism bundles. “What’s hard is that” the AIM protocols come “out of academic centers. Implementation of complex algorithms is daunting” for hospitals that only do a couple hundred deliveries a year, she said.

For small hospitals, the approach she’s found that works is to first assess what they can offer, and then have them “do what’s reasonable” for their resources. The second part is making sure high-risk women get to a regional center – with an adequate blood supply, in the case of hemorrhage, for instance – for complications. Dr. McKay and colleagues are working on a system by which regional centers can monitor smaller hospitals for potential maternity problems, and contact them proactively before they emerge.

They’ve also made access to hemorrhage and hypertension drugs easier on labor and delivery units with the help of close-by dedicated medicine boxes, and standardized protocols and order sets across Avera. “We try to make the right thing the easy thing to do,” Dr. McKay said.

Dr. Espey is an editorial adviser for Ob.Gyn. News. The physicians have no relevant financial disclosures.

[email protected]

Study Overview

Objective. To assess the clinical efficacy and safety of remdesivir in hospitalized adults with laboratory-confirmed COVID-19 and with evidence of lower respiratory tract involvement.

Design. Double-blinded, randomized, placebo-controlled, multicenter trial.

Setting and participants. Enrollment for the study took place between February 21, 2020, and April 19, 2020, at 60 trial sites and 13 subsites in the United States, Denmark, the United Kingdom, Greece, Germany, Korea, Mexico, Spain, Japan, and Singapore. Study participants included patients aged ≥ 18 years who were hospitalized and had laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as determined by a positive reverse transcription polymerase chain reaction assay on a respiratory specimen. Participants had evidence of lower respiratory tract infection at the time of enrollment; this was defined as radiographic infiltrates by imaging study, peripheral oxygen saturation (SpO₂) ≤ 94% on room air, or requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). Exclusion criteria for study participation included abnormal liver enzymes (alanine aminotransferase, aspartate aminotransferase) more than 5 times the upper limit of normal range; impaired renal function or need for hemodialysis or hemofiltration; pregnancy or breastfeeding; or anticipated hospital discharge or transfer to another hospital within 72 hours of enrollment.

Intervention. Participants were randomized in a 1:1 ratio to the remdesivir group or the placebo group and were administered either intravenous infusions of remdesivir (200-mg loading dose on day 1, followed by a 100-mg maintenance dose daily on days 2 through 10, or until hospital discharge or death) or placebo for up to 10 days. Blinding was maintained by masking infusions with an opaque bag and tubing. Randomization was stratified by study site and disease severity at enrollment. Supportive care was delivered to all participants according to the standard of care at each trial site hospital. Clinical status, determined using an 8-category ordinal scale and the National Early Warning Score, was assessed daily for each participant while hospitalized (day 1 through day 29).

Blood samples for safety laboratory tests were collected, and oropharyngeal or nasopharyngeal swab testing was performed for viral RNA detection and quantification on days 1, 3, 5, 8, and 11. All serious adverse events (AEs) and grade 3/4 AEs that represented an increase in severity from day 1 and any grade 2 or higher suspected drug-related hypersensitivity reactions associated with the study drug or placebo administration were recorded.

Main outcome measures. The primary endpoint measure of this study was time to recovery, defined as the first day during the 28 days after enrollment on which a participant satisfied category 1 (ie, not hospitalized, no limitations of activities), 2 (ie, not hospitalized, limitation of activities, home oxygen requirement, or both), or 3 (ie, hospitalized, not requiring supplemental oxygen and no longer requiring ongoing medical care; hospitalization was extended for infection-control reason) on the 8-category ordinal scale. Secondary outcomes included all-cause mortality at 14 and 28 days after enrollment and grade 3/4 AEs and serious AEs that occurred during trial participation. Analysis of the primary outcome was performed using a log-rank test of the time to recovery comparing remdesivir with placebo group, stratified by disease severity.

The study’s primary outcome was initially defined as a difference in clinical status as ascertained by the 8-category ordinal scale between groups of participants who were administered remdesivir versus placebo on day 15. Because of new knowledge gained external to the study about a more protracted COVID-19 clinical course than previously recognized, a change in primary outcome to time to recovery was proposed by trial statisticians, who were unaware of treatment assignments (72 participants had been enrolled) or outcome data (no interim data) on March 22, 2020, with subsequent amendment approval on April 2, 2020. On April 27, 2020, the Data and Safety Monitoring Board (DSMB) reviewed the interim study analysis (with data cutoff date of April 22, 2020) and recommended the report and mortality data to be provided to trial team members from the National Institute of Allergy and Infectious Diseases; these findings were subsequently made public.

Main results. A total of 1107 patients were assessed for eligibility, of whom 1063 underwent randomization, with 541 assigned to remdesivir and 522 to placebo. Results were unblinded early at the recommendation of DSMB due to findings from the interim analysis that showed reduced time to recovery in the group that received remdesivir. As of April 28, 2020, a total of 391 participants in the remdesivir group and 340 participants in the placebo group had completed the trial (day 29), recovered, or died. The mean age of participants was 58.9 ± 15.0 years, the majority were men (64.3%) and were White (53.2%), and the most common prespecified coexisting conditions were hypertension (49.6%), obesity (37.0%), and type 2 diabetes mellitus (29.7%). The vast majority of participants (88.7%) had severe COVID-19 disease at enrollment, defined as requiring invasive or noninvasive mechanical ventilation, requiring supplemental oxygen, SpO₂ ≤ 94% on room air, or tachypnea (respiratory rate ≥ 24 breaths per minute).

Based on available data from 1059 participants (538 from the remdesivir group and 521 from the placebo group), those in the remdesivir group had a shorter median recovery time of 11 days (95% confidence interval [CI], 9-12) as compared to 15 days (95% CI, 13-19) in the placebo group, with a rate ratio for recovery of 1.32 (95% CI, 1.12-1.55; P < 0.001). Moreover, the odds of improvement on day 15 in the 8-category ordinal scale score were higher in the remdesivir group, compared to the placebo group (proportional odds model; odds ratio, 1.50; 95% CI, 1.18-1.91; P = 0.001; 844 participants).

Mortality rate by 14 days was numerically lower in the remdesivir group (7.1%) compared to the placebo group (11.9%), but the difference was not statistically significant (Kaplan-Meier, hazard ratio for death, 0.70; 95% CI, 0.47-1.04). Serious AEs were reported in 114 of the 541 (21.1%) participants in the remdesivir group and 141 of the 522 (27.0%) participants in the placebo group. Moreover, grade 3/4 AEs occurred in 156 (28.8%) participants in the remdesivir group and in 172 (33.0%) in the placebo group.

Conclusion. The study found that remdesivir, compared to placebo, significantly shortened time to recovery in adult patients hospitalized with COVID-19 who had evidence of lower respiratory tract infection.

Commentary

Since the initial reporting of a cluster of cases of pneumonia in Wuhan, China, on December 31, 2019, SARS-CoV-2 has been identified as the cause of this new disease (COVID-19), and to-date SARS-CoV-2 infection has affected more than 15.2 million people globally, with more than 3.9 million cases in the United States alone.¹ Despite an unprecedented global research effort, as well as public-private research partnerships, both in terms of scale and scope, an effective pharmacologic therapy for COVID-19 has so far eluded the scientific and medical community. Early trials of hydroxychloroquine and lopinavir-ritonavir did not demonstrate a clinical benefit in patients with COVID-19.^2,3 Moreover, the first randomized controlled trial of remdesivir in COVID-19, a nucleoside analogue prodrug and a broad-spectrum antiviral agent previously shown to have inhibitory effects on pathogenic coronaviruses, was an underpowered study, and thus inconclusive.⁴ Thus, given the persistence of the COVID-19 pandemic and a current lack of effective vaccines or curative treatments, the study reported by Beigel and colleagues is timely and provides much needed knowledge in developing potential therapies for COVID-19.

The present report described the preliminary results of the first stage of the Adaptive Covid-19 Treatment Trial (ACCT-1), which aimed to evaluate the clinical efficacy and safety of intravenous remdesivir, as compared to placebo, in hospitalized adults with laboratory-confirmed COVID-19. The study itself was well-designed and conducted. The successful enrollment of more than 1000 participants randomized in a 1:1 ratio within a 2-month recruitment window, involving 60 international trial sites, shortly after the emergence of a new global pandemic was remarkable. This study provided the first evidence that remdesivir, an antiviral, can shorten time to recovery by approximately 31% compared to placebo in COVID-19 patients with lower respiratory tract involvement.

Interestingly, this beneficial effect of remdesivir on time to recovery was primarily observed in participants within the severe disease stratum (those requiring supplemental oxygen) at baseline (12 days in remdesivir group versus 18 days in placebo group), but not in those with mild-moderate disease at the time of study enrollment (5 days in either remdesivir or placebo group). Moreover, the beneficial effects of remdesivir on reducing time to recovery was not observed in participants who required mechanical ventilation or ECMO at enrollment. Thus, these preliminary results suggest that COVID-19 disease severity and timing, particularly in patients who require supplemental oxygen but prior to disease progression towards requiring mechanical ventilation, may present a window of opportunity to initiate remdesivir treatment in order to improve outcomes. Further analysis utilizing data from the entire cohort, including outcomes data from the full 28-day follow-up period, may better delineate the subgroup of hospitalized COVID-19 patients who may benefit most from remdesivir. Last, safety data from the present study, along with that reported by Wang and colleagues,⁴ provides evidence that intravenous remdesivir administration is likely safe in adults during the treatment period.

The preliminary results from the ACCT-1 provide early evidence that remdesivir shortens time to recovery in adult patients hospitalized for COVID-19 with pulmonary involvement. In light of these results, the US Food and Drug Administration issued an emergency use authorization for remdesivir on May 1, 2020, for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.⁵ In addition, remdesivir has also recently been approved as a therapy for COVID-19 in Japan, Taiwan, India, Singapore, and the United Arab Emirates, and has received conditional approval for use by the European Commission.⁶

Although these are encouraging developments in the race to identify effective therapeutics for COVID-19, a number of unanswered questions regarding the administration of remdesivir in the treatment of this disease remain. For instance, in an open-label, randomized, multicenter trial of patients with severe COVID-19 not requiring mechanical ventilation, treatment with a 5-day course versus a 10-day course of intravenous remdesivir did not result in a significant difference in efficacy.⁷ Thus, more studies are needed to better determine the shortest effective duration of remdesivir therapy in COVID-19 patients with different disease severity. Also, the mortality rate in COVID-19 patients who were treated with remdesivir remained high in the current study. Therefore, there is ample opportunity to evaluate treatment strategies, including multidrug interventions with remdesivir, to reduce mortality and improve clinical outcomes in patients hospitalized with COVID-19.

Applications for Clinical Practice

Remdesivir shortens time to recovery in adult patients hospitalized with COVID-19 who require supplemental oxygen therapy. While much needs to be learned in order to optimize treatment of COVID-19, preliminary findings from the current study provide an important first step towards these discoveries.

–Fred Ko, MD, MS

Study Overview

Objective. To assess the clinical efficacy and safety of remdesivir in hospitalized adults with laboratory-confirmed COVID-19 and with evidence of lower respiratory tract involvement.

Design. Double-blinded, randomized, placebo-controlled, multicenter trial.

Setting and participants. Enrollment for the study took place between February 21, 2020, and April 19, 2020, at 60 trial sites and 13 subsites in the United States, Denmark, the United Kingdom, Greece, Germany, Korea, Mexico, Spain, Japan, and Singapore. Study participants included patients aged ≥ 18 years who were hospitalized and had laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as determined by a positive reverse transcription polymerase chain reaction assay on a respiratory specimen. Participants had evidence of lower respiratory tract infection at the time of enrollment; this was defined as radiographic infiltrates by imaging study, peripheral oxygen saturation (SpO₂) ≤ 94% on room air, or requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). Exclusion criteria for study participation included abnormal liver enzymes (alanine aminotransferase, aspartate aminotransferase) more than 5 times the upper limit of normal range; impaired renal function or need for hemodialysis or hemofiltration; pregnancy or breastfeeding; or anticipated hospital discharge or transfer to another hospital within 72 hours of enrollment.

Intervention. Participants were randomized in a 1:1 ratio to the remdesivir group or the placebo group and were administered either intravenous infusions of remdesivir (200-mg loading dose on day 1, followed by a 100-mg maintenance dose daily on days 2 through 10, or until hospital discharge or death) or placebo for up to 10 days. Blinding was maintained by masking infusions with an opaque bag and tubing. Randomization was stratified by study site and disease severity at enrollment. Supportive care was delivered to all participants according to the standard of care at each trial site hospital. Clinical status, determined using an 8-category ordinal scale and the National Early Warning Score, was assessed daily for each participant while hospitalized (day 1 through day 29).

Blood samples for safety laboratory tests were collected, and oropharyngeal or nasopharyngeal swab testing was performed for viral RNA detection and quantification on days 1, 3, 5, 8, and 11. All serious adverse events (AEs) and grade 3/4 AEs that represented an increase in severity from day 1 and any grade 2 or higher suspected drug-related hypersensitivity reactions associated with the study drug or placebo administration were recorded.

Main outcome measures. The primary endpoint measure of this study was time to recovery, defined as the first day during the 28 days after enrollment on which a participant satisfied category 1 (ie, not hospitalized, no limitations of activities), 2 (ie, not hospitalized, limitation of activities, home oxygen requirement, or both), or 3 (ie, hospitalized, not requiring supplemental oxygen and no longer requiring ongoing medical care; hospitalization was extended for infection-control reason) on the 8-category ordinal scale. Secondary outcomes included all-cause mortality at 14 and 28 days after enrollment and grade 3/4 AEs and serious AEs that occurred during trial participation. Analysis of the primary outcome was performed using a log-rank test of the time to recovery comparing remdesivir with placebo group, stratified by disease severity.

The study’s primary outcome was initially defined as a difference in clinical status as ascertained by the 8-category ordinal scale between groups of participants who were administered remdesivir versus placebo on day 15. Because of new knowledge gained external to the study about a more protracted COVID-19 clinical course than previously recognized, a change in primary outcome to time to recovery was proposed by trial statisticians, who were unaware of treatment assignments (72 participants had been enrolled) or outcome data (no interim data) on March 22, 2020, with subsequent amendment approval on April 2, 2020. On April 27, 2020, the Data and Safety Monitoring Board (DSMB) reviewed the interim study analysis (with data cutoff date of April 22, 2020) and recommended the report and mortality data to be provided to trial team members from the National Institute of Allergy and Infectious Diseases; these findings were subsequently made public.

Main results. A total of 1107 patients were assessed for eligibility, of whom 1063 underwent randomization, with 541 assigned to remdesivir and 522 to placebo. Results were unblinded early at the recommendation of DSMB due to findings from the interim analysis that showed reduced time to recovery in the group that received remdesivir. As of April 28, 2020, a total of 391 participants in the remdesivir group and 340 participants in the placebo group had completed the trial (day 29), recovered, or died. The mean age of participants was 58.9 ± 15.0 years, the majority were men (64.3%) and were White (53.2%), and the most common prespecified coexisting conditions were hypertension (49.6%), obesity (37.0%), and type 2 diabetes mellitus (29.7%). The vast majority of participants (88.7%) had severe COVID-19 disease at enrollment, defined as requiring invasive or noninvasive mechanical ventilation, requiring supplemental oxygen, SpO₂ ≤ 94% on room air, or tachypnea (respiratory rate ≥ 24 breaths per minute).

Based on available data from 1059 participants (538 from the remdesivir group and 521 from the placebo group), those in the remdesivir group had a shorter median recovery time of 11 days (95% confidence interval [CI], 9-12) as compared to 15 days (95% CI, 13-19) in the placebo group, with a rate ratio for recovery of 1.32 (95% CI, 1.12-1.55; P < 0.001). Moreover, the odds of improvement on day 15 in the 8-category ordinal scale score were higher in the remdesivir group, compared to the placebo group (proportional odds model; odds ratio, 1.50; 95% CI, 1.18-1.91; P = 0.001; 844 participants).

Mortality rate by 14 days was numerically lower in the remdesivir group (7.1%) compared to the placebo group (11.9%), but the difference was not statistically significant (Kaplan-Meier, hazard ratio for death, 0.70; 95% CI, 0.47-1.04). Serious AEs were reported in 114 of the 541 (21.1%) participants in the remdesivir group and 141 of the 522 (27.0%) participants in the placebo group. Moreover, grade 3/4 AEs occurred in 156 (28.8%) participants in the remdesivir group and in 172 (33.0%) in the placebo group.

Conclusion. The study found that remdesivir, compared to placebo, significantly shortened time to recovery in adult patients hospitalized with COVID-19 who had evidence of lower respiratory tract infection.

Commentary

Since the initial reporting of a cluster of cases of pneumonia in Wuhan, China, on December 31, 2019, SARS-CoV-2 has been identified as the cause of this new disease (COVID-19), and to-date SARS-CoV-2 infection has affected more than 15.2 million people globally, with more than 3.9 million cases in the United States alone.¹ Despite an unprecedented global research effort, as well as public-private research partnerships, both in terms of scale and scope, an effective pharmacologic therapy for COVID-19 has so far eluded the scientific and medical community. Early trials of hydroxychloroquine and lopinavir-ritonavir did not demonstrate a clinical benefit in patients with COVID-19.^2,3 Moreover, the first randomized controlled trial of remdesivir in COVID-19, a nucleoside analogue prodrug and a broad-spectrum antiviral agent previously shown to have inhibitory effects on pathogenic coronaviruses, was an underpowered study, and thus inconclusive.⁴ Thus, given the persistence of the COVID-19 pandemic and a current lack of effective vaccines or curative treatments, the study reported by Beigel and colleagues is timely and provides much needed knowledge in developing potential therapies for COVID-19.

The present report described the preliminary results of the first stage of the Adaptive Covid-19 Treatment Trial (ACCT-1), which aimed to evaluate the clinical efficacy and safety of intravenous remdesivir, as compared to placebo, in hospitalized adults with laboratory-confirmed COVID-19. The study itself was well-designed and conducted. The successful enrollment of more than 1000 participants randomized in a 1:1 ratio within a 2-month recruitment window, involving 60 international trial sites, shortly after the emergence of a new global pandemic was remarkable. This study provided the first evidence that remdesivir, an antiviral, can shorten time to recovery by approximately 31% compared to placebo in COVID-19 patients with lower respiratory tract involvement.

Interestingly, this beneficial effect of remdesivir on time to recovery was primarily observed in participants within the severe disease stratum (those requiring supplemental oxygen) at baseline (12 days in remdesivir group versus 18 days in placebo group), but not in those with mild-moderate disease at the time of study enrollment (5 days in either remdesivir or placebo group). Moreover, the beneficial effects of remdesivir on reducing time to recovery was not observed in participants who required mechanical ventilation or ECMO at enrollment. Thus, these preliminary results suggest that COVID-19 disease severity and timing, particularly in patients who require supplemental oxygen but prior to disease progression towards requiring mechanical ventilation, may present a window of opportunity to initiate remdesivir treatment in order to improve outcomes. Further analysis utilizing data from the entire cohort, including outcomes data from the full 28-day follow-up period, may better delineate the subgroup of hospitalized COVID-19 patients who may benefit most from remdesivir. Last, safety data from the present study, along with that reported by Wang and colleagues,⁴ provides evidence that intravenous remdesivir administration is likely safe in adults during the treatment period.

The preliminary results from the ACCT-1 provide early evidence that remdesivir shortens time to recovery in adult patients hospitalized for COVID-19 with pulmonary involvement. In light of these results, the US Food and Drug Administration issued an emergency use authorization for remdesivir on May 1, 2020, for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.⁵ In addition, remdesivir has also recently been approved as a therapy for COVID-19 in Japan, Taiwan, India, Singapore, and the United Arab Emirates, and has received conditional approval for use by the European Commission.⁶

Although these are encouraging developments in the race to identify effective therapeutics for COVID-19, a number of unanswered questions regarding the administration of remdesivir in the treatment of this disease remain. For instance, in an open-label, randomized, multicenter trial of patients with severe COVID-19 not requiring mechanical ventilation, treatment with a 5-day course versus a 10-day course of intravenous remdesivir did not result in a significant difference in efficacy.⁷ Thus, more studies are needed to better determine the shortest effective duration of remdesivir therapy in COVID-19 patients with different disease severity. Also, the mortality rate in COVID-19 patients who were treated with remdesivir remained high in the current study. Therefore, there is ample opportunity to evaluate treatment strategies, including multidrug interventions with remdesivir, to reduce mortality and improve clinical outcomes in patients hospitalized with COVID-19.

Applications for Clinical Practice

Remdesivir shortens time to recovery in adult patients hospitalized with COVID-19 who require supplemental oxygen therapy. While much needs to be learned in order to optimize treatment of COVID-19, preliminary findings from the current study provide an important first step towards these discoveries.

–Fred Ko, MD, MS

Study Overview

Objective. To assess the clinical efficacy and safety of remdesivir in hospitalized adults with laboratory-confirmed COVID-19 and with evidence of lower respiratory tract involvement.

Design. Double-blinded, randomized, placebo-controlled, multicenter trial.

Setting and participants. Enrollment for the study took place between February 21, 2020, and April 19, 2020, at 60 trial sites and 13 subsites in the United States, Denmark, the United Kingdom, Greece, Germany, Korea, Mexico, Spain, Japan, and Singapore. Study participants included patients aged ≥ 18 years who were hospitalized and had laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as determined by a positive reverse transcription polymerase chain reaction assay on a respiratory specimen. Participants had evidence of lower respiratory tract infection at the time of enrollment; this was defined as radiographic infiltrates by imaging study, peripheral oxygen saturation (SpO₂) ≤ 94% on room air, or requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). Exclusion criteria for study participation included abnormal liver enzymes (alanine aminotransferase, aspartate aminotransferase) more than 5 times the upper limit of normal range; impaired renal function or need for hemodialysis or hemofiltration; pregnancy or breastfeeding; or anticipated hospital discharge or transfer to another hospital within 72 hours of enrollment.

Intervention. Participants were randomized in a 1:1 ratio to the remdesivir group or the placebo group and were administered either intravenous infusions of remdesivir (200-mg loading dose on day 1, followed by a 100-mg maintenance dose daily on days 2 through 10, or until hospital discharge or death) or placebo for up to 10 days. Blinding was maintained by masking infusions with an opaque bag and tubing. Randomization was stratified by study site and disease severity at enrollment. Supportive care was delivered to all participants according to the standard of care at each trial site hospital. Clinical status, determined using an 8-category ordinal scale and the National Early Warning Score, was assessed daily for each participant while hospitalized (day 1 through day 29).

Blood samples for safety laboratory tests were collected, and oropharyngeal or nasopharyngeal swab testing was performed for viral RNA detection and quantification on days 1, 3, 5, 8, and 11. All serious adverse events (AEs) and grade 3/4 AEs that represented an increase in severity from day 1 and any grade 2 or higher suspected drug-related hypersensitivity reactions associated with the study drug or placebo administration were recorded.

Main outcome measures. The primary endpoint measure of this study was time to recovery, defined as the first day during the 28 days after enrollment on which a participant satisfied category 1 (ie, not hospitalized, no limitations of activities), 2 (ie, not hospitalized, limitation of activities, home oxygen requirement, or both), or 3 (ie, hospitalized, not requiring supplemental oxygen and no longer requiring ongoing medical care; hospitalization was extended for infection-control reason) on the 8-category ordinal scale. Secondary outcomes included all-cause mortality at 14 and 28 days after enrollment and grade 3/4 AEs and serious AEs that occurred during trial participation. Analysis of the primary outcome was performed using a log-rank test of the time to recovery comparing remdesivir with placebo group, stratified by disease severity.

The study’s primary outcome was initially defined as a difference in clinical status as ascertained by the 8-category ordinal scale between groups of participants who were administered remdesivir versus placebo on day 15. Because of new knowledge gained external to the study about a more protracted COVID-19 clinical course than previously recognized, a change in primary outcome to time to recovery was proposed by trial statisticians, who were unaware of treatment assignments (72 participants had been enrolled) or outcome data (no interim data) on March 22, 2020, with subsequent amendment approval on April 2, 2020. On April 27, 2020, the Data and Safety Monitoring Board (DSMB) reviewed the interim study analysis (with data cutoff date of April 22, 2020) and recommended the report and mortality data to be provided to trial team members from the National Institute of Allergy and Infectious Diseases; these findings were subsequently made public.

Main results. A total of 1107 patients were assessed for eligibility, of whom 1063 underwent randomization, with 541 assigned to remdesivir and 522 to placebo. Results were unblinded early at the recommendation of DSMB due to findings from the interim analysis that showed reduced time to recovery in the group that received remdesivir. As of April 28, 2020, a total of 391 participants in the remdesivir group and 340 participants in the placebo group had completed the trial (day 29), recovered, or died. The mean age of participants was 58.9 ± 15.0 years, the majority were men (64.3%) and were White (53.2%), and the most common prespecified coexisting conditions were hypertension (49.6%), obesity (37.0%), and type 2 diabetes mellitus (29.7%). The vast majority of participants (88.7%) had severe COVID-19 disease at enrollment, defined as requiring invasive or noninvasive mechanical ventilation, requiring supplemental oxygen, SpO₂ ≤ 94% on room air, or tachypnea (respiratory rate ≥ 24 breaths per minute).

Based on available data from 1059 participants (538 from the remdesivir group and 521 from the placebo group), those in the remdesivir group had a shorter median recovery time of 11 days (95% confidence interval [CI], 9-12) as compared to 15 days (95% CI, 13-19) in the placebo group, with a rate ratio for recovery of 1.32 (95% CI, 1.12-1.55; P < 0.001). Moreover, the odds of improvement on day 15 in the 8-category ordinal scale score were higher in the remdesivir group, compared to the placebo group (proportional odds model; odds ratio, 1.50; 95% CI, 1.18-1.91; P = 0.001; 844 participants).

Mortality rate by 14 days was numerically lower in the remdesivir group (7.1%) compared to the placebo group (11.9%), but the difference was not statistically significant (Kaplan-Meier, hazard ratio for death, 0.70; 95% CI, 0.47-1.04). Serious AEs were reported in 114 of the 541 (21.1%) participants in the remdesivir group and 141 of the 522 (27.0%) participants in the placebo group. Moreover, grade 3/4 AEs occurred in 156 (28.8%) participants in the remdesivir group and in 172 (33.0%) in the placebo group.

Conclusion. The study found that remdesivir, compared to placebo, significantly shortened time to recovery in adult patients hospitalized with COVID-19 who had evidence of lower respiratory tract infection.

Commentary

Since the initial reporting of a cluster of cases of pneumonia in Wuhan, China, on December 31, 2019, SARS-CoV-2 has been identified as the cause of this new disease (COVID-19), and to-date SARS-CoV-2 infection has affected more than 15.2 million people globally, with more than 3.9 million cases in the United States alone.¹ Despite an unprecedented global research effort, as well as public-private research partnerships, both in terms of scale and scope, an effective pharmacologic therapy for COVID-19 has so far eluded the scientific and medical community. Early trials of hydroxychloroquine and lopinavir-ritonavir did not demonstrate a clinical benefit in patients with COVID-19.^2,3 Moreover, the first randomized controlled trial of remdesivir in COVID-19, a nucleoside analogue prodrug and a broad-spectrum antiviral agent previously shown to have inhibitory effects on pathogenic coronaviruses, was an underpowered study, and thus inconclusive.⁴ Thus, given the persistence of the COVID-19 pandemic and a current lack of effective vaccines or curative treatments, the study reported by Beigel and colleagues is timely and provides much needed knowledge in developing potential therapies for COVID-19.

The present report described the preliminary results of the first stage of the Adaptive Covid-19 Treatment Trial (ACCT-1), which aimed to evaluate the clinical efficacy and safety of intravenous remdesivir, as compared to placebo, in hospitalized adults with laboratory-confirmed COVID-19. The study itself was well-designed and conducted. The successful enrollment of more than 1000 participants randomized in a 1:1 ratio within a 2-month recruitment window, involving 60 international trial sites, shortly after the emergence of a new global pandemic was remarkable. This study provided the first evidence that remdesivir, an antiviral, can shorten time to recovery by approximately 31% compared to placebo in COVID-19 patients with lower respiratory tract involvement.

Interestingly, this beneficial effect of remdesivir on time to recovery was primarily observed in participants within the severe disease stratum (those requiring supplemental oxygen) at baseline (12 days in remdesivir group versus 18 days in placebo group), but not in those with mild-moderate disease at the time of study enrollment (5 days in either remdesivir or placebo group). Moreover, the beneficial effects of remdesivir on reducing time to recovery was not observed in participants who required mechanical ventilation or ECMO at enrollment. Thus, these preliminary results suggest that COVID-19 disease severity and timing, particularly in patients who require supplemental oxygen but prior to disease progression towards requiring mechanical ventilation, may present a window of opportunity to initiate remdesivir treatment in order to improve outcomes. Further analysis utilizing data from the entire cohort, including outcomes data from the full 28-day follow-up period, may better delineate the subgroup of hospitalized COVID-19 patients who may benefit most from remdesivir. Last, safety data from the present study, along with that reported by Wang and colleagues,⁴ provides evidence that intravenous remdesivir administration is likely safe in adults during the treatment period.

The preliminary results from the ACCT-1 provide early evidence that remdesivir shortens time to recovery in adult patients hospitalized for COVID-19 with pulmonary involvement. In light of these results, the US Food and Drug Administration issued an emergency use authorization for remdesivir on May 1, 2020, for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.⁵ In addition, remdesivir has also recently been approved as a therapy for COVID-19 in Japan, Taiwan, India, Singapore, and the United Arab Emirates, and has received conditional approval for use by the European Commission.⁶

Although these are encouraging developments in the race to identify effective therapeutics for COVID-19, a number of unanswered questions regarding the administration of remdesivir in the treatment of this disease remain. For instance, in an open-label, randomized, multicenter trial of patients with severe COVID-19 not requiring mechanical ventilation, treatment with a 5-day course versus a 10-day course of intravenous remdesivir did not result in a significant difference in efficacy.⁷ Thus, more studies are needed to better determine the shortest effective duration of remdesivir therapy in COVID-19 patients with different disease severity. Also, the mortality rate in COVID-19 patients who were treated with remdesivir remained high in the current study. Therefore, there is ample opportunity to evaluate treatment strategies, including multidrug interventions with remdesivir, to reduce mortality and improve clinical outcomes in patients hospitalized with COVID-19.

Applications for Clinical Practice

Remdesivir shortens time to recovery in adult patients hospitalized with COVID-19 who require supplemental oxygen therapy. While much needs to be learned in order to optimize treatment of COVID-19, preliminary findings from the current study provide an important first step towards these discoveries.

–Fred Ko, MD, MS

Sepsis is the number one killer in U.S. hospitals. About one in three patient deaths in a hospital are attributable to sepsis, according to the Centers for Disease Control and Prevention, and it is the leading cause of readmission for U.S. hospitals as well.

Patricia Kritek MD, EdM, of the division of pulmonary, critical care, and sleep medicine at the University of Washington, Seattle, hopes to bring attendees up to speed on sepsis with her presentation, “Put SIRS on the SOFA and Let’s get Septic! Update in Sepsis” at HM20 Virtual.

Each year, approximately 1.7 million American adults develop sepsis, and nearly 270,000 Americans will die from sepsis annually. Although sepsis disproportionately affects young children, older adults, patients with chronic diseases, and those with a weak immune system, the disease can affect anyone.

With that reputation, sepsis is on the forefront of hospitalists’ minds. Hospitalists are traditionally well versed in current sepsis guidelines, but time to treatment is paramount, and it can be difficult to stay up to date on the latest studies in the field. In addition, some newer, controversial treatments have emerged recently, and there is currently a debate regarding the efficacy of these treatments in the care of patients with sepsis.

The title of Dr. Kritek’s presentation hints at the theme: Hospitalists may have learned the systemic inflammatory response syndrome (SIRS) criteria for diagnosing sepsis, but the Sequential Organ Failure Assessment (SOFA) Score developed by the Third International Consensus Definitions for Sepsis and Septic Shock – previously known as the sepsis-related organ failure assessment score – has been the new method since 2016 to assess the clinical outcomes of patients with sepsis.

The quick SOFA score (qSOFA), developed by the Society of Critical Care and European Society of Intensive Care Medicine in 2016 guidelines, further helps hospitalists and other hospital physicians identify those patients at highest risk of mortality from sepsis outside an intensive care unit setting.

Dr. Kritek, who is a board-certified critical care medicine physician, has previously presented this talk at the Society for Hospital Medicine Annual Conference in the past. This year the presentation will include a number of studies that examine what role vitamin C, thiamine, and glucocorticoids have in treating patients with sepsis, she said. For example, it is thought that parenteral administration of vitamin C could raise plasma levels and reduce multiorgan failure. Thiamine could be useful in sepsis treatment because of its role in glucose metabolism and lactate production, while glucocorticoids could help improve the mortality rate of patients with sepsis.

While Dr. Kritek said she is not going to be advocating for the benefit of vitamin C and thiamine during the session, “this is an area of ongoing debate, and we will walk through the most recent data to try to make sense of it,” she said.

Dr. Kritek noted that the role of balanced crystalloids in resuscitation will be discussed versus when to use saline, as well as the potential of new vasopressors for the treatment of septic shock.

“Our goal will be to integrate the most recent literature into day-to-day practice,” Dr. Kritek said.Dr. Kritek reports no conflicts of interest.

“Put SIRS on the SOFA and Let’s get Septic! Update in Sepsis”

Sepsis is the number one killer in U.S. hospitals. About one in three patient deaths in a hospital are attributable to sepsis, according to the Centers for Disease Control and Prevention, and it is the leading cause of readmission for U.S. hospitals as well.

Patricia Kritek MD, EdM, of the division of pulmonary, critical care, and sleep medicine at the University of Washington, Seattle, hopes to bring attendees up to speed on sepsis with her presentation, “Put SIRS on the SOFA and Let’s get Septic! Update in Sepsis” at HM20 Virtual.

Each year, approximately 1.7 million American adults develop sepsis, and nearly 270,000 Americans will die from sepsis annually. Although sepsis disproportionately affects young children, older adults, patients with chronic diseases, and those with a weak immune system, the disease can affect anyone.

With that reputation, sepsis is on the forefront of hospitalists’ minds. Hospitalists are traditionally well versed in current sepsis guidelines, but time to treatment is paramount, and it can be difficult to stay up to date on the latest studies in the field. In addition, some newer, controversial treatments have emerged recently, and there is currently a debate regarding the efficacy of these treatments in the care of patients with sepsis.

The title of Dr. Kritek’s presentation hints at the theme: Hospitalists may have learned the systemic inflammatory response syndrome (SIRS) criteria for diagnosing sepsis, but the Sequential Organ Failure Assessment (SOFA) Score developed by the Third International Consensus Definitions for Sepsis and Septic Shock – previously known as the sepsis-related organ failure assessment score – has been the new method since 2016 to assess the clinical outcomes of patients with sepsis.

The quick SOFA score (qSOFA), developed by the Society of Critical Care and European Society of Intensive Care Medicine in 2016 guidelines, further helps hospitalists and other hospital physicians identify those patients at highest risk of mortality from sepsis outside an intensive care unit setting.

Dr. Kritek, who is a board-certified critical care medicine physician, has previously presented this talk at the Society for Hospital Medicine Annual Conference in the past. This year the presentation will include a number of studies that examine what role vitamin C, thiamine, and glucocorticoids have in treating patients with sepsis, she said. For example, it is thought that parenteral administration of vitamin C could raise plasma levels and reduce multiorgan failure. Thiamine could be useful in sepsis treatment because of its role in glucose metabolism and lactate production, while glucocorticoids could help improve the mortality rate of patients with sepsis.

While Dr. Kritek said she is not going to be advocating for the benefit of vitamin C and thiamine during the session, “this is an area of ongoing debate, and we will walk through the most recent data to try to make sense of it,” she said.

Dr. Kritek noted that the role of balanced crystalloids in resuscitation will be discussed versus when to use saline, as well as the potential of new vasopressors for the treatment of septic shock.

“Our goal will be to integrate the most recent literature into day-to-day practice,” Dr. Kritek said.Dr. Kritek reports no conflicts of interest.

“Put SIRS on the SOFA and Let’s get Septic! Update in Sepsis”

Sepsis is the number one killer in U.S. hospitals. About one in three patient deaths in a hospital are attributable to sepsis, according to the Centers for Disease Control and Prevention, and it is the leading cause of readmission for U.S. hospitals as well.

Patricia Kritek MD, EdM, of the division of pulmonary, critical care, and sleep medicine at the University of Washington, Seattle, hopes to bring attendees up to speed on sepsis with her presentation, “Put SIRS on the SOFA and Let’s get Septic! Update in Sepsis” at HM20 Virtual.

Each year, approximately 1.7 million American adults develop sepsis, and nearly 270,000 Americans will die from sepsis annually. Although sepsis disproportionately affects young children, older adults, patients with chronic diseases, and those with a weak immune system, the disease can affect anyone.

With that reputation, sepsis is on the forefront of hospitalists’ minds. Hospitalists are traditionally well versed in current sepsis guidelines, but time to treatment is paramount, and it can be difficult to stay up to date on the latest studies in the field. In addition, some newer, controversial treatments have emerged recently, and there is currently a debate regarding the efficacy of these treatments in the care of patients with sepsis.

The title of Dr. Kritek’s presentation hints at the theme: Hospitalists may have learned the systemic inflammatory response syndrome (SIRS) criteria for diagnosing sepsis, but the Sequential Organ Failure Assessment (SOFA) Score developed by the Third International Consensus Definitions for Sepsis and Septic Shock – previously known as the sepsis-related organ failure assessment score – has been the new method since 2016 to assess the clinical outcomes of patients with sepsis.

The quick SOFA score (qSOFA), developed by the Society of Critical Care and European Society of Intensive Care Medicine in 2016 guidelines, further helps hospitalists and other hospital physicians identify those patients at highest risk of mortality from sepsis outside an intensive care unit setting.

Dr. Kritek, who is a board-certified critical care medicine physician, has previously presented this talk at the Society for Hospital Medicine Annual Conference in the past. This year the presentation will include a number of studies that examine what role vitamin C, thiamine, and glucocorticoids have in treating patients with sepsis, she said. For example, it is thought that parenteral administration of vitamin C could raise plasma levels and reduce multiorgan failure. Thiamine could be useful in sepsis treatment because of its role in glucose metabolism and lactate production, while glucocorticoids could help improve the mortality rate of patients with sepsis.

While Dr. Kritek said she is not going to be advocating for the benefit of vitamin C and thiamine during the session, “this is an area of ongoing debate, and we will walk through the most recent data to try to make sense of it,” she said.

Dr. Kritek noted that the role of balanced crystalloids in resuscitation will be discussed versus when to use saline, as well as the potential of new vasopressors for the treatment of septic shock.

“Our goal will be to integrate the most recent literature into day-to-day practice,” Dr. Kritek said.Dr. Kritek reports no conflicts of interest.

“Put SIRS on the SOFA and Let’s get Septic! Update in Sepsis”

Clear aerosol boxes designed to keep COVID-19 patients’ airborne droplets from infecting health care workers during intubation may actually increase providers’ exposure to the virus, a small study suggests.

Joanna P. Simpson, MbChB, an intensivist in the department of anaesthesia and perioperative medicine at Eastern Health in Melbourne, and colleagues tested five models of barriers used for protection while intubating simulated “patients” with COVID-19 and compared the interventions with a control of having no protection. They published their findings online in Anaesthesia.

Coauthor Peter Chan, MBBS, also an intensivist at Eastern Health, said in an interview that the virus essentially concentrates inside the box and because the box has holes on the sides to allow providers’ arms in, the gaps “act as nozzles, so when a patient coughs, it creates a sudden wave of air that pushes all these particles out the path of least resistance” and into the face of the intubator.

Their institution stopped using any such aerosol-containment devices during intubation until safety can be proven.
 

Many forms for boxes

The boxes take different forms and are made by various designers and manufacturers around the world, including in the United States, but they generally cover the head and upper body of patients and allow providers to reach through holes to intubate.

The U.S. Food and Drug Administration on May 1 issued an emergency use authorization (EUA) for “protective barrier enclosures ... to prevent [health care provider] exposure to pathogenic biological airborne particulates by providing an extra layer of barrier protection in addition to personal protective equipment [PPE].”

Others refer to them as “intubation boxes.” A search of GoFundMe campaigns showed hundreds of campaigns for intubation boxes.

Dr. Simpson and colleagues used an in-situ simulation model to evaluate laryngoscopist exposure to airborne particles sized 0.3-5.0 mcm using five aerosol containment devices (aerosol box, sealed box with suction, sealed box without suction, vertical drapes, and horizontal drapes) compared with no aerosol containment device.

Nebulized saline was used in an aerosol-generating model for 300 seconds, at which point the devices were removed to gauge particle spread for another 60 seconds.

Compared with no device use, the sealed intubation box with suction resulted in a decreased exposure for particle sizes of 0.3, 0.5, 1.0, and 2.5 mcm – but not 5.0 mcm – over all time periods (P = .003 for all time periods, which ranged from 30 to 360 seconds).

Conversely, the aerosol box, compared with no device use, showed an increase in 1.0, 2.5, and 5.0 mcm airborne-particle exposure at 300 seconds (P = .002, 0.008, and .002, respectively). Compared with no device use, neither horizontal nor vertical drapes showed any difference in any particle size exposure at any time.

The researchers used seven volunteers who took turns acting as the patient or the intubator. As each of the seven volunteers did all six trials (the five interventions plus no intervention), the study generated 42 sets of results.
 

More evidence passive boxes are ineffective

Plastic surgeon Dave Turer, MD, MS, who is also an electrical and biomedical engineer, and some emergency physician colleagues had doubts about these boxes early on and wrote about the need for thorough testing.

He told this news organization, “I find it kind of infuriating that if you search for ‘intubation box’ there are all these companies making claims that are totally unsubstantiated.”

A desperate need to stop the virus is leading to unacceptable practices, he said.

His team at the University of Pittsburgh Medical Center in Pennsylvania tested commercially available boxes using white vapor to simulate patients› exhaled breath and found the vapor billowed into the surrounding environment.

He said Simpson and colleagues had similar findings: The boxes didn’t contain the patients’ breaths and may even increase the stream heading toward intubators.

Dr. Turer said his team has designed a different kind of box, without armholes for the intubators, and with active airflow and filtering and have submitted their design and research to the FDA for an EUA.

The FDA’s current EUA is for boxes “that are no different from a face shield or a splash shield,” Dr. Turer said, adding that “they specifically state that they are not designed or intended to contain aerosol.”

He said while this study is a good start, his team’s findings will help demonstrate why the common passive boxes should not be used.

One of the most prevalent designs, he pointed out, was one by Taiwanese anesthesiologist Hsien Yung Lai that was widely circulated in March.

David W. Kaczka, MD, PhD, associate professor of anesthesia, biomedical engineering, and radiology at University of Iowa in Iowa City, is one of the researchers who modified that design and made prototypes. He said in an interview he thinks the study conclusion by Simpson et al is “not as dismal as the authors are making it out to be.”

He pointed to the relative success of the sealed box with suction. His team’s adapted model added a suction port to generate a negative pressure field around the patient.

The biggest critique he had of the study, Dr. Kaczka said, was a lack of a true control group.

“They tested all their conditions with nebulized saline,” he pointed out. “I think a more appropriately designed study would have also looked at a group where no saline was being nebulized and see what the particle counts were afterwards. It’s not clear how the device would distinguish between a particle coming from a saline nebulizer vs. coming from a simulated patient vs. coming from the laryngoscopist.”

He also noted that what comes out of a patient is not going to be saline and will have different density and viscosity.

That said, the study by Dr. Simpson and colleagues highlights the need to take a hard look at these boxes with more research, he said, adding, “I think there’s some hope there.”

He noted that a letter to the editor by Boston researchers, published online April 3 in the New England Journal of Medicine, describes how they used fluorescent dye forced from a balloon to simulate a patient’s cough to see whether an aerosol box protected intubators.

That letter concludes, “We suggest that our ad hoc barrier enclosure provided a modicum of additional protection and could be considered to be an adjunct to standard PPE.”

The Anaesthesia findings come as a second global wave becomes more likely as does awareness of the potential of airborne droplets to spread the virus.

Scientists from 32 countries warned the World Health Organization that the spread of COVID-19 through airborne droplets may have been severely underestimated.

On Wednesday, the World Health Organization formally acknowledged evidence regarding potential spread of the virus through these droplets and on Thursday issued an updated brief.

Intellectual property surrounding the device invented by Dr. Turer’s team is owned by UPMC. Dr. Chan and Dr. Kaczka have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Clear aerosol boxes designed to keep COVID-19 patients’ airborne droplets from infecting health care workers during intubation may actually increase providers’ exposure to the virus, a small study suggests.

Joanna P. Simpson, MbChB, an intensivist in the department of anaesthesia and perioperative medicine at Eastern Health in Melbourne, and colleagues tested five models of barriers used for protection while intubating simulated “patients” with COVID-19 and compared the interventions with a control of having no protection. They published their findings online in Anaesthesia.

Coauthor Peter Chan, MBBS, also an intensivist at Eastern Health, said in an interview that the virus essentially concentrates inside the box and because the box has holes on the sides to allow providers’ arms in, the gaps “act as nozzles, so when a patient coughs, it creates a sudden wave of air that pushes all these particles out the path of least resistance” and into the face of the intubator.

Their institution stopped using any such aerosol-containment devices during intubation until safety can be proven.
 

Many forms for boxes

The boxes take different forms and are made by various designers and manufacturers around the world, including in the United States, but they generally cover the head and upper body of patients and allow providers to reach through holes to intubate.

The U.S. Food and Drug Administration on May 1 issued an emergency use authorization (EUA) for “protective barrier enclosures ... to prevent [health care provider] exposure to pathogenic biological airborne particulates by providing an extra layer of barrier protection in addition to personal protective equipment [PPE].”

Others refer to them as “intubation boxes.” A search of GoFundMe campaigns showed hundreds of campaigns for intubation boxes.

Dr. Simpson and colleagues used an in-situ simulation model to evaluate laryngoscopist exposure to airborne particles sized 0.3-5.0 mcm using five aerosol containment devices (aerosol box, sealed box with suction, sealed box without suction, vertical drapes, and horizontal drapes) compared with no aerosol containment device.

Nebulized saline was used in an aerosol-generating model for 300 seconds, at which point the devices were removed to gauge particle spread for another 60 seconds.

Compared with no device use, the sealed intubation box with suction resulted in a decreased exposure for particle sizes of 0.3, 0.5, 1.0, and 2.5 mcm – but not 5.0 mcm – over all time periods (P = .003 for all time periods, which ranged from 30 to 360 seconds).

Conversely, the aerosol box, compared with no device use, showed an increase in 1.0, 2.5, and 5.0 mcm airborne-particle exposure at 300 seconds (P = .002, 0.008, and .002, respectively). Compared with no device use, neither horizontal nor vertical drapes showed any difference in any particle size exposure at any time.

The researchers used seven volunteers who took turns acting as the patient or the intubator. As each of the seven volunteers did all six trials (the five interventions plus no intervention), the study generated 42 sets of results.
 

More evidence passive boxes are ineffective

Plastic surgeon Dave Turer, MD, MS, who is also an electrical and biomedical engineer, and some emergency physician colleagues had doubts about these boxes early on and wrote about the need for thorough testing.

He told this news organization, “I find it kind of infuriating that if you search for ‘intubation box’ there are all these companies making claims that are totally unsubstantiated.”

A desperate need to stop the virus is leading to unacceptable practices, he said.

His team at the University of Pittsburgh Medical Center in Pennsylvania tested commercially available boxes using white vapor to simulate patients› exhaled breath and found the vapor billowed into the surrounding environment.

He said Simpson and colleagues had similar findings: The boxes didn’t contain the patients’ breaths and may even increase the stream heading toward intubators.

Dr. Turer said his team has designed a different kind of box, without armholes for the intubators, and with active airflow and filtering and have submitted their design and research to the FDA for an EUA.

The FDA’s current EUA is for boxes “that are no different from a face shield or a splash shield,” Dr. Turer said, adding that “they specifically state that they are not designed or intended to contain aerosol.”

He said while this study is a good start, his team’s findings will help demonstrate why the common passive boxes should not be used.

One of the most prevalent designs, he pointed out, was one by Taiwanese anesthesiologist Hsien Yung Lai that was widely circulated in March.

David W. Kaczka, MD, PhD, associate professor of anesthesia, biomedical engineering, and radiology at University of Iowa in Iowa City, is one of the researchers who modified that design and made prototypes. He said in an interview he thinks the study conclusion by Simpson et al is “not as dismal as the authors are making it out to be.”

He pointed to the relative success of the sealed box with suction. His team’s adapted model added a suction port to generate a negative pressure field around the patient.

The biggest critique he had of the study, Dr. Kaczka said, was a lack of a true control group.

“They tested all their conditions with nebulized saline,” he pointed out. “I think a more appropriately designed study would have also looked at a group where no saline was being nebulized and see what the particle counts were afterwards. It’s not clear how the device would distinguish between a particle coming from a saline nebulizer vs. coming from a simulated patient vs. coming from the laryngoscopist.”

He also noted that what comes out of a patient is not going to be saline and will have different density and viscosity.

That said, the study by Dr. Simpson and colleagues highlights the need to take a hard look at these boxes with more research, he said, adding, “I think there’s some hope there.”

He noted that a letter to the editor by Boston researchers, published online April 3 in the New England Journal of Medicine, describes how they used fluorescent dye forced from a balloon to simulate a patient’s cough to see whether an aerosol box protected intubators.

That letter concludes, “We suggest that our ad hoc barrier enclosure provided a modicum of additional protection and could be considered to be an adjunct to standard PPE.”

The Anaesthesia findings come as a second global wave becomes more likely as does awareness of the potential of airborne droplets to spread the virus.

Scientists from 32 countries warned the World Health Organization that the spread of COVID-19 through airborne droplets may have been severely underestimated.

On Wednesday, the World Health Organization formally acknowledged evidence regarding potential spread of the virus through these droplets and on Thursday issued an updated brief.

Intellectual property surrounding the device invented by Dr. Turer’s team is owned by UPMC. Dr. Chan and Dr. Kaczka have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Clear aerosol boxes designed to keep COVID-19 patients’ airborne droplets from infecting health care workers during intubation may actually increase providers’ exposure to the virus, a small study suggests.

Joanna P. Simpson, MbChB, an intensivist in the department of anaesthesia and perioperative medicine at Eastern Health in Melbourne, and colleagues tested five models of barriers used for protection while intubating simulated “patients” with COVID-19 and compared the interventions with a control of having no protection. They published their findings online in Anaesthesia.

Coauthor Peter Chan, MBBS, also an intensivist at Eastern Health, said in an interview that the virus essentially concentrates inside the box and because the box has holes on the sides to allow providers’ arms in, the gaps “act as nozzles, so when a patient coughs, it creates a sudden wave of air that pushes all these particles out the path of least resistance” and into the face of the intubator.

Their institution stopped using any such aerosol-containment devices during intubation until safety can be proven.
 

Many forms for boxes

The boxes take different forms and are made by various designers and manufacturers around the world, including in the United States, but they generally cover the head and upper body of patients and allow providers to reach through holes to intubate.

The U.S. Food and Drug Administration on May 1 issued an emergency use authorization (EUA) for “protective barrier enclosures ... to prevent [health care provider] exposure to pathogenic biological airborne particulates by providing an extra layer of barrier protection in addition to personal protective equipment [PPE].”

Others refer to them as “intubation boxes.” A search of GoFundMe campaigns showed hundreds of campaigns for intubation boxes.

Dr. Simpson and colleagues used an in-situ simulation model to evaluate laryngoscopist exposure to airborne particles sized 0.3-5.0 mcm using five aerosol containment devices (aerosol box, sealed box with suction, sealed box without suction, vertical drapes, and horizontal drapes) compared with no aerosol containment device.

Nebulized saline was used in an aerosol-generating model for 300 seconds, at which point the devices were removed to gauge particle spread for another 60 seconds.

Compared with no device use, the sealed intubation box with suction resulted in a decreased exposure for particle sizes of 0.3, 0.5, 1.0, and 2.5 mcm – but not 5.0 mcm – over all time periods (P = .003 for all time periods, which ranged from 30 to 360 seconds).

Conversely, the aerosol box, compared with no device use, showed an increase in 1.0, 2.5, and 5.0 mcm airborne-particle exposure at 300 seconds (P = .002, 0.008, and .002, respectively). Compared with no device use, neither horizontal nor vertical drapes showed any difference in any particle size exposure at any time.

The researchers used seven volunteers who took turns acting as the patient or the intubator. As each of the seven volunteers did all six trials (the five interventions plus no intervention), the study generated 42 sets of results.
 

More evidence passive boxes are ineffective

Plastic surgeon Dave Turer, MD, MS, who is also an electrical and biomedical engineer, and some emergency physician colleagues had doubts about these boxes early on and wrote about the need for thorough testing.

He told this news organization, “I find it kind of infuriating that if you search for ‘intubation box’ there are all these companies making claims that are totally unsubstantiated.”

A desperate need to stop the virus is leading to unacceptable practices, he said.

His team at the University of Pittsburgh Medical Center in Pennsylvania tested commercially available boxes using white vapor to simulate patients› exhaled breath and found the vapor billowed into the surrounding environment.

He said Simpson and colleagues had similar findings: The boxes didn’t contain the patients’ breaths and may even increase the stream heading toward intubators.

Dr. Turer said his team has designed a different kind of box, without armholes for the intubators, and with active airflow and filtering and have submitted their design and research to the FDA for an EUA.

The FDA’s current EUA is for boxes “that are no different from a face shield or a splash shield,” Dr. Turer said, adding that “they specifically state that they are not designed or intended to contain aerosol.”

He said while this study is a good start, his team’s findings will help demonstrate why the common passive boxes should not be used.

One of the most prevalent designs, he pointed out, was one by Taiwanese anesthesiologist Hsien Yung Lai that was widely circulated in March.

David W. Kaczka, MD, PhD, associate professor of anesthesia, biomedical engineering, and radiology at University of Iowa in Iowa City, is one of the researchers who modified that design and made prototypes. He said in an interview he thinks the study conclusion by Simpson et al is “not as dismal as the authors are making it out to be.”

He pointed to the relative success of the sealed box with suction. His team’s adapted model added a suction port to generate a negative pressure field around the patient.

The biggest critique he had of the study, Dr. Kaczka said, was a lack of a true control group.

“They tested all their conditions with nebulized saline,” he pointed out. “I think a more appropriately designed study would have also looked at a group where no saline was being nebulized and see what the particle counts were afterwards. It’s not clear how the device would distinguish between a particle coming from a saline nebulizer vs. coming from a simulated patient vs. coming from the laryngoscopist.”

He also noted that what comes out of a patient is not going to be saline and will have different density and viscosity.

That said, the study by Dr. Simpson and colleagues highlights the need to take a hard look at these boxes with more research, he said, adding, “I think there’s some hope there.”

He noted that a letter to the editor by Boston researchers, published online April 3 in the New England Journal of Medicine, describes how they used fluorescent dye forced from a balloon to simulate a patient’s cough to see whether an aerosol box protected intubators.

That letter concludes, “We suggest that our ad hoc barrier enclosure provided a modicum of additional protection and could be considered to be an adjunct to standard PPE.”

The Anaesthesia findings come as a second global wave becomes more likely as does awareness of the potential of airborne droplets to spread the virus.

Scientists from 32 countries warned the World Health Organization that the spread of COVID-19 through airborne droplets may have been severely underestimated.

On Wednesday, the World Health Organization formally acknowledged evidence regarding potential spread of the virus through these droplets and on Thursday issued an updated brief.

Intellectual property surrounding the device invented by Dr. Turer’s team is owned by UPMC. Dr. Chan and Dr. Kaczka have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Background: Previous studies suggest that clinicians and surrogates rarely discuss patient values in ICU family conferences about goals of care despite recommendations from international critical care societies.

Moreover, there was no deliberation about how to apply patient values and preferences to clinical decisions in 55.7% of the conferences. Surrogates were more likely to bring up these elements of shared decision making than were physicians.

Bottom line: Care providers and surrogates of critically ill ICU patients often fail to discuss patient preferences, values, and how they apply to care decisions in goals of care conferences.

Citation: Scheunemann LP et al. Clinician-family communication about patients’ values and preferences in intensive care units. JAMA Intern Med. 2019;179(5):676-84.

Dr. Mastalerz is a hospitalist and medical director of 9A Accountable Care Unit at the Colorado Health Foundation.

Background: Previous studies suggest that clinicians and surrogates rarely discuss patient values in ICU family conferences about goals of care despite recommendations from international critical care societies.

Moreover, there was no deliberation about how to apply patient values and preferences to clinical decisions in 55.7% of the conferences. Surrogates were more likely to bring up these elements of shared decision making than were physicians.

Bottom line: Care providers and surrogates of critically ill ICU patients often fail to discuss patient preferences, values, and how they apply to care decisions in goals of care conferences.

Citation: Scheunemann LP et al. Clinician-family communication about patients’ values and preferences in intensive care units. JAMA Intern Med. 2019;179(5):676-84.

Dr. Mastalerz is a hospitalist and medical director of 9A Accountable Care Unit at the Colorado Health Foundation.

Background: Previous studies suggest that clinicians and surrogates rarely discuss patient values in ICU family conferences about goals of care despite recommendations from international critical care societies.

Moreover, there was no deliberation about how to apply patient values and preferences to clinical decisions in 55.7% of the conferences. Surrogates were more likely to bring up these elements of shared decision making than were physicians.

Bottom line: Care providers and surrogates of critically ill ICU patients often fail to discuss patient preferences, values, and how they apply to care decisions in goals of care conferences.

Citation: Scheunemann LP et al. Clinician-family communication about patients’ values and preferences in intensive care units. JAMA Intern Med. 2019;179(5):676-84.

Dr. Mastalerz is a hospitalist and medical director of 9A Accountable Care Unit at the Colorado Health Foundation.

Patients hospitalized for sepsis are more likely to require readmission within a month after discharge if they live in disadvantaged neighborhoods, according to a study published in Critical Care Medicine.

The association between living in a disadvantaged neighborhood and 30-day readmission remained significant even after adjustment for “individual demographic variables, active tobacco use, length of index hospitalization, severity of acute and chronic morbidity, and place of initial discharge,” wrote Panagis Galiatsatos, MD, of Johns Hopkins University in Baltimore, and colleagues.

“Our findings suggest the need for interventions that emphasize neighborhood-level socioeconomic variables in addition to individual-level efforts in an effort to promote and achieve health equity for patients who survive a hospitalization due to sepsis,” the authors wrote. “With a third of our cohort rehospitalized with infections, and other studies emphasizing that the most common readmission diagnosis was infection, attention toward both anticipating and attenuating the risk of infection in sepsis survivors, especially among those who live in higher risk neighborhoods, must be a priority for the prevention of readmissions.”

Although she did not find the study results surprising, Eva DuGoff, PhD, a senior managing consultant with the Berkeley Research Group and a visiting assistant professor at University of Maryland School of Public Health, College Park, said in an interview that she was impressed with how clinically rigorous the analysis was, both in confirming an accurate sepsis diagnosis and in using the more refined measure of the Area Deprivation Index (ADI) to assess neighborhood disadvantage.

“I think it makes sense that people who have less means and are in neighborhoods with fewer resources would run into more issues and would need to return to the hospital, above and beyond the clinical risk factors, such as smoking and chronic conditions,” said Dr. DuGoff, who studies health disparities but was not involved in this study.

Shayla N.M. Durfey MD, ScM, a pediatric resident at Hasbro Children’s Hospital in Providence, R.I., said in an interview she was similarly unsurprised by the findings.

“People who live in disadvantaged neighborhoods may have less access to walking spaces, healthy food, and safe housing and more exposure to poor air quality, toxic stress, and violence – any of which can negatively impact health or recovery from illness through stress responses, nutritional deficiencies, or comorbidities, such as reactive airway disease, obesity, hypertension, and diabetes,” said Dr. Durfey, who studies health disparities but was not involved in this study. “Our research has found these neighborhood-level factors often matter above and beyond individual social determinants of health.”

Dr. Galiatsatos and associates conducted a retrospective study in Baltimore that compared readmission rates in 2017 at Johns Hopkins Bayview Medical Center among patients discharged after a hospitalization for sepsis, coded via ICD-10. They relied on the ADI to categorize the neighborhoods of patients’ residential addresses. The ADI rates various socioeconomic components, including income, education, employment, and housing characteristics, on a scale of 1-100 in geographic blocks, with higher score indicating a greater level of disadvantage.

Among 647 hospitalized patients with an ICD-10 code of sepsis who also met criteria for sepsis or septic shock per the Sepsis-3 definition, 17.9% were excluded from the analysis because they died or were transferred to hospice care. The other 531 patients had an average age of 61, and just under one-third (30.9%) were active smokers. Their average length of stay was 6.9 days, with a mean Charlson Comorbidity Index of 4.2 and a mean Sequential Organ Failure Assessment score of 4.9.

The average ADI for all the patients was 54.2, but the average score was 63 for the 22% of patients who were readmitted within 30 days of initial discharge, compared with an average 51.8 for patients not readmitted (P < .001).

Among those 117 readmitted, “39 patients had a reinfection, 68 had an exacerbation of their chronic conditions, and 10 were admitted for ‘concerning symptoms’ without a primary admitting diagnosis,” the investigators reported. Because “a third of our cohort was readmitted with an infection, it is possible that more disadvantaged neighborhoods created more challenges for a person’s immune system, which may be compromised after recovering from sepsis.”

Dr. DuGoff further noted that health literacy may be lower among people living in less advantaged neighborhoods.

“A number of studies suggest when patients leave the hospital, they’re not sure what they need to do. The language is complicated, and it’s hard to know what kind of medication to take when, and when you’re supposed to return to the doctor or the hospital,” Dr. DuGoff said. “Managing all of that can be pretty scary for people, particularly after a traumatic experience with sepsis at the hospital.”

Most patients had been discharged home (67.3%), but the 31.6% discharged to a skilled nursing facility had a greater likelihood of readmission, compared with those discharged home (P < .01); 1% were discharged to acute rehabilitation. The average length of stay during the index hospitalization was also greater for those readmitted (8.7 days) than for those not readmitted (6.4 days). The groups did not differ in terms of their acute organ dysfunction or severity of their comorbidities.

However, even after adjustment for these factors, “neighborhood disadvantage remained significantly associated with 30-day rehospitalization in patients who were discharged with sepsis,” the authors said. Specifically, each additional standard deviation greater in patients’ ADI was associated with increased risk of 30-day readmission (P < .001).

“Given that the ADI is a composite score, we cannot identify which component is the predominant driver of rehospitalizations for patients who survive sepsis,” the authors wrote. “However, all components that make up the index are intertwined, and policy efforts targeting one (i.e., unemployment) will likely impact others (i.e., housing).”

Dr. Durfey said that medical schools have not traditionally provided training related to management of social risk factors, although this is changing in more recent curricula. But the findings still have clinical relevance for practitioners.

“Certainly, the first step is awareness of where and how patients live and being mindful of how treatment plans may be impacted by social factors at both the individual and community levels,” Dr. Durfey said. “An important part of this is working in partnership with social workers and case managers. Importantly, clinicians can also partner with disadvantaged communities to advocate for improved conditions through policy change and act as expert witnesses to how neighborhood level factors impact health.”

Dr. DuGoff also wondered what implications these findings might have currently, with regards to COVID-19.

“People living in disadvantaged neighborhoods are already at higher risk for getting the disease, and this study raises really good questions about how we should be monitoring discharge now in anticipation of these types of issues,” she said.

The authors noted that their study is cross-sectional and cannot indicate causation, and the findings of a single urban institution may not be generalizable elsewhere. They also did not consider what interventions individual patients had during their index hospitalization that could have increased frailty.

The study did not note external funding. One coauthor of the study, Suchi Saria, PhD, reported receiving honoraria and travel reimbursement from two dozen biotechnology companies for keynotes and advisory board service; she also holds equity in Patient Ping and Bayesian Health. The other authors reported no industry disclosures. In addition to consulting for Berkeley Research Group, Dr. DuGoff has received a past honorarium from Zimmer Biomet. Dr. Durfey has no disclosures.

SOURCE: Galiatsatos P et al. Crit Care Med. 2020 Jun;48(6):808-14.

Patients hospitalized for sepsis are more likely to require readmission within a month after discharge if they live in disadvantaged neighborhoods, according to a study published in Critical Care Medicine.

The association between living in a disadvantaged neighborhood and 30-day readmission remained significant even after adjustment for “individual demographic variables, active tobacco use, length of index hospitalization, severity of acute and chronic morbidity, and place of initial discharge,” wrote Panagis Galiatsatos, MD, of Johns Hopkins University in Baltimore, and colleagues.

“Our findings suggest the need for interventions that emphasize neighborhood-level socioeconomic variables in addition to individual-level efforts in an effort to promote and achieve health equity for patients who survive a hospitalization due to sepsis,” the authors wrote. “With a third of our cohort rehospitalized with infections, and other studies emphasizing that the most common readmission diagnosis was infection, attention toward both anticipating and attenuating the risk of infection in sepsis survivors, especially among those who live in higher risk neighborhoods, must be a priority for the prevention of readmissions.”

Although she did not find the study results surprising, Eva DuGoff, PhD, a senior managing consultant with the Berkeley Research Group and a visiting assistant professor at University of Maryland School of Public Health, College Park, said in an interview that she was impressed with how clinically rigorous the analysis was, both in confirming an accurate sepsis diagnosis and in using the more refined measure of the Area Deprivation Index (ADI) to assess neighborhood disadvantage.

“I think it makes sense that people who have less means and are in neighborhoods with fewer resources would run into more issues and would need to return to the hospital, above and beyond the clinical risk factors, such as smoking and chronic conditions,” said Dr. DuGoff, who studies health disparities but was not involved in this study.

Shayla N.M. Durfey MD, ScM, a pediatric resident at Hasbro Children’s Hospital in Providence, R.I., said in an interview she was similarly unsurprised by the findings.

“People who live in disadvantaged neighborhoods may have less access to walking spaces, healthy food, and safe housing and more exposure to poor air quality, toxic stress, and violence – any of which can negatively impact health or recovery from illness through stress responses, nutritional deficiencies, or comorbidities, such as reactive airway disease, obesity, hypertension, and diabetes,” said Dr. Durfey, who studies health disparities but was not involved in this study. “Our research has found these neighborhood-level factors often matter above and beyond individual social determinants of health.”

Dr. Galiatsatos and associates conducted a retrospective study in Baltimore that compared readmission rates in 2017 at Johns Hopkins Bayview Medical Center among patients discharged after a hospitalization for sepsis, coded via ICD-10. They relied on the ADI to categorize the neighborhoods of patients’ residential addresses. The ADI rates various socioeconomic components, including income, education, employment, and housing characteristics, on a scale of 1-100 in geographic blocks, with higher score indicating a greater level of disadvantage.

Among 647 hospitalized patients with an ICD-10 code of sepsis who also met criteria for sepsis or septic shock per the Sepsis-3 definition, 17.9% were excluded from the analysis because they died or were transferred to hospice care. The other 531 patients had an average age of 61, and just under one-third (30.9%) were active smokers. Their average length of stay was 6.9 days, with a mean Charlson Comorbidity Index of 4.2 and a mean Sequential Organ Failure Assessment score of 4.9.

The average ADI for all the patients was 54.2, but the average score was 63 for the 22% of patients who were readmitted within 30 days of initial discharge, compared with an average 51.8 for patients not readmitted (P < .001).

Among those 117 readmitted, “39 patients had a reinfection, 68 had an exacerbation of their chronic conditions, and 10 were admitted for ‘concerning symptoms’ without a primary admitting diagnosis,” the investigators reported. Because “a third of our cohort was readmitted with an infection, it is possible that more disadvantaged neighborhoods created more challenges for a person’s immune system, which may be compromised after recovering from sepsis.”

Dr. DuGoff further noted that health literacy may be lower among people living in less advantaged neighborhoods.

“A number of studies suggest when patients leave the hospital, they’re not sure what they need to do. The language is complicated, and it’s hard to know what kind of medication to take when, and when you’re supposed to return to the doctor or the hospital,” Dr. DuGoff said. “Managing all of that can be pretty scary for people, particularly after a traumatic experience with sepsis at the hospital.”

Most patients had been discharged home (67.3%), but the 31.6% discharged to a skilled nursing facility had a greater likelihood of readmission, compared with those discharged home (P < .01); 1% were discharged to acute rehabilitation. The average length of stay during the index hospitalization was also greater for those readmitted (8.7 days) than for those not readmitted (6.4 days). The groups did not differ in terms of their acute organ dysfunction or severity of their comorbidities.

However, even after adjustment for these factors, “neighborhood disadvantage remained significantly associated with 30-day rehospitalization in patients who were discharged with sepsis,” the authors said. Specifically, each additional standard deviation greater in patients’ ADI was associated with increased risk of 30-day readmission (P < .001).

“Given that the ADI is a composite score, we cannot identify which component is the predominant driver of rehospitalizations for patients who survive sepsis,” the authors wrote. “However, all components that make up the index are intertwined, and policy efforts targeting one (i.e., unemployment) will likely impact others (i.e., housing).”

Dr. Durfey said that medical schools have not traditionally provided training related to management of social risk factors, although this is changing in more recent curricula. But the findings still have clinical relevance for practitioners.

“Certainly, the first step is awareness of where and how patients live and being mindful of how treatment plans may be impacted by social factors at both the individual and community levels,” Dr. Durfey said. “An important part of this is working in partnership with social workers and case managers. Importantly, clinicians can also partner with disadvantaged communities to advocate for improved conditions through policy change and act as expert witnesses to how neighborhood level factors impact health.”

Dr. DuGoff also wondered what implications these findings might have currently, with regards to COVID-19.

“People living in disadvantaged neighborhoods are already at higher risk for getting the disease, and this study raises really good questions about how we should be monitoring discharge now in anticipation of these types of issues,” she said.

The authors noted that their study is cross-sectional and cannot indicate causation, and the findings of a single urban institution may not be generalizable elsewhere. They also did not consider what interventions individual patients had during their index hospitalization that could have increased frailty.

The study did not note external funding. One coauthor of the study, Suchi Saria, PhD, reported receiving honoraria and travel reimbursement from two dozen biotechnology companies for keynotes and advisory board service; she also holds equity in Patient Ping and Bayesian Health. The other authors reported no industry disclosures. In addition to consulting for Berkeley Research Group, Dr. DuGoff has received a past honorarium from Zimmer Biomet. Dr. Durfey has no disclosures.

SOURCE: Galiatsatos P et al. Crit Care Med. 2020 Jun;48(6):808-14.

Patients hospitalized for sepsis are more likely to require readmission within a month after discharge if they live in disadvantaged neighborhoods, according to a study published in Critical Care Medicine.

The association between living in a disadvantaged neighborhood and 30-day readmission remained significant even after adjustment for “individual demographic variables, active tobacco use, length of index hospitalization, severity of acute and chronic morbidity, and place of initial discharge,” wrote Panagis Galiatsatos, MD, of Johns Hopkins University in Baltimore, and colleagues.

“Our findings suggest the need for interventions that emphasize neighborhood-level socioeconomic variables in addition to individual-level efforts in an effort to promote and achieve health equity for patients who survive a hospitalization due to sepsis,” the authors wrote. “With a third of our cohort rehospitalized with infections, and other studies emphasizing that the most common readmission diagnosis was infection, attention toward both anticipating and attenuating the risk of infection in sepsis survivors, especially among those who live in higher risk neighborhoods, must be a priority for the prevention of readmissions.”

Although she did not find the study results surprising, Eva DuGoff, PhD, a senior managing consultant with the Berkeley Research Group and a visiting assistant professor at University of Maryland School of Public Health, College Park, said in an interview that she was impressed with how clinically rigorous the analysis was, both in confirming an accurate sepsis diagnosis and in using the more refined measure of the Area Deprivation Index (ADI) to assess neighborhood disadvantage.

“I think it makes sense that people who have less means and are in neighborhoods with fewer resources would run into more issues and would need to return to the hospital, above and beyond the clinical risk factors, such as smoking and chronic conditions,” said Dr. DuGoff, who studies health disparities but was not involved in this study.

Shayla N.M. Durfey MD, ScM, a pediatric resident at Hasbro Children’s Hospital in Providence, R.I., said in an interview she was similarly unsurprised by the findings.

“People who live in disadvantaged neighborhoods may have less access to walking spaces, healthy food, and safe housing and more exposure to poor air quality, toxic stress, and violence – any of which can negatively impact health or recovery from illness through stress responses, nutritional deficiencies, or comorbidities, such as reactive airway disease, obesity, hypertension, and diabetes,” said Dr. Durfey, who studies health disparities but was not involved in this study. “Our research has found these neighborhood-level factors often matter above and beyond individual social determinants of health.”

Dr. Galiatsatos and associates conducted a retrospective study in Baltimore that compared readmission rates in 2017 at Johns Hopkins Bayview Medical Center among patients discharged after a hospitalization for sepsis, coded via ICD-10. They relied on the ADI to categorize the neighborhoods of patients’ residential addresses. The ADI rates various socioeconomic components, including income, education, employment, and housing characteristics, on a scale of 1-100 in geographic blocks, with higher score indicating a greater level of disadvantage.

Among 647 hospitalized patients with an ICD-10 code of sepsis who also met criteria for sepsis or septic shock per the Sepsis-3 definition, 17.9% were excluded from the analysis because they died or were transferred to hospice care. The other 531 patients had an average age of 61, and just under one-third (30.9%) were active smokers. Their average length of stay was 6.9 days, with a mean Charlson Comorbidity Index of 4.2 and a mean Sequential Organ Failure Assessment score of 4.9.

The average ADI for all the patients was 54.2, but the average score was 63 for the 22% of patients who were readmitted within 30 days of initial discharge, compared with an average 51.8 for patients not readmitted (P < .001).

Among those 117 readmitted, “39 patients had a reinfection, 68 had an exacerbation of their chronic conditions, and 10 were admitted for ‘concerning symptoms’ without a primary admitting diagnosis,” the investigators reported. Because “a third of our cohort was readmitted with an infection, it is possible that more disadvantaged neighborhoods created more challenges for a person’s immune system, which may be compromised after recovering from sepsis.”

Dr. DuGoff further noted that health literacy may be lower among people living in less advantaged neighborhoods.

“A number of studies suggest when patients leave the hospital, they’re not sure what they need to do. The language is complicated, and it’s hard to know what kind of medication to take when, and when you’re supposed to return to the doctor or the hospital,” Dr. DuGoff said. “Managing all of that can be pretty scary for people, particularly after a traumatic experience with sepsis at the hospital.”

Most patients had been discharged home (67.3%), but the 31.6% discharged to a skilled nursing facility had a greater likelihood of readmission, compared with those discharged home (P < .01); 1% were discharged to acute rehabilitation. The average length of stay during the index hospitalization was also greater for those readmitted (8.7 days) than for those not readmitted (6.4 days). The groups did not differ in terms of their acute organ dysfunction or severity of their comorbidities.

However, even after adjustment for these factors, “neighborhood disadvantage remained significantly associated with 30-day rehospitalization in patients who were discharged with sepsis,” the authors said. Specifically, each additional standard deviation greater in patients’ ADI was associated with increased risk of 30-day readmission (P < .001).

“Given that the ADI is a composite score, we cannot identify which component is the predominant driver of rehospitalizations for patients who survive sepsis,” the authors wrote. “However, all components that make up the index are intertwined, and policy efforts targeting one (i.e., unemployment) will likely impact others (i.e., housing).”

Dr. Durfey said that medical schools have not traditionally provided training related to management of social risk factors, although this is changing in more recent curricula. But the findings still have clinical relevance for practitioners.

“Certainly, the first step is awareness of where and how patients live and being mindful of how treatment plans may be impacted by social factors at both the individual and community levels,” Dr. Durfey said. “An important part of this is working in partnership with social workers and case managers. Importantly, clinicians can also partner with disadvantaged communities to advocate for improved conditions through policy change and act as expert witnesses to how neighborhood level factors impact health.”

Dr. DuGoff also wondered what implications these findings might have currently, with regards to COVID-19.

“People living in disadvantaged neighborhoods are already at higher risk for getting the disease, and this study raises really good questions about how we should be monitoring discharge now in anticipation of these types of issues,” she said.

The authors noted that their study is cross-sectional and cannot indicate causation, and the findings of a single urban institution may not be generalizable elsewhere. They also did not consider what interventions individual patients had during their index hospitalization that could have increased frailty.

The study did not note external funding. One coauthor of the study, Suchi Saria, PhD, reported receiving honoraria and travel reimbursement from two dozen biotechnology companies for keynotes and advisory board service; she also holds equity in Patient Ping and Bayesian Health. The other authors reported no industry disclosures. In addition to consulting for Berkeley Research Group, Dr. DuGoff has received a past honorarium from Zimmer Biomet. Dr. Durfey has no disclosures.

SOURCE: Galiatsatos P et al. Crit Care Med. 2020 Jun;48(6):808-14.