A new study has linked recent-onset diabetes and subsequent weight loss to an increased risk of pancreatic cancer, indicating a distinct group of individuals to screen early for this deadly disease.

“The likelihood of a pancreatic cancer diagnosis was even further elevated among individuals with older age, healthy weight before weight loss, and unintentional weight loss,” wrote Chen Yuan, ScD, of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston. The study was published in JAMA Oncology.

To determine whether an association exists between diabetes plus weight change and pancreatic cancer, the researchers analyzed decades of medical history data from the Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS). The study population from the NHS included 112,818 women with a mean age of 59 years; the population from the HPFS included 46,207 men with a mean age of 65 years. Since enrollment – the baseline was 1978 for the NHS and 1988 for the HPFS – participants have provided follow-up information via biennial questionnaires.

Recent diabetes onset, weight loss boost cancer risk

From those combined groups, 1,116 incident cases of pancreatic cancer (0.7%) were identified. Compared with patients with no diabetes, patients with recent-onset diabetes had triple the risk of pancreatic cancer (age-adjusted hazard ratio, 2.97; 95% confidence interval, 2.31-3.82) and patients with longstanding diabetes had more than double the risk (HR, 2.16; 95% CI, 1.78-2.60). Patients with longer disease duration also had more than twice the risk of pancreatic cancer, with HRs of 2.25 for those with diabetes for 4-10 years (95% CI, 1.74-2.92) and 2.07 for more than 10 years (95% CI, 1.61-2.66).

Compared with patients who hadn’t lost any weight, patients who reported a 1- to 4-pound weight loss (HR, 1.25; 95% CI, 1.03-1.52), a 5- to 8-pound weight loss (HR, 1.33; 95% CI, 1.06-1.66), and a more than 8-pound weight loss (HR, 1.92; 95% CI, 1.58-2.32) had higher risks of pancreatic cancer. Patients with recent-onset diabetes and a 1- to 8-pound weight loss (91 incident cases per 100,000 person-years; 95% CI, 55-151) or a weight loss of more than 8 pounds (164 incident cases per 100,000 person years; 95% CI, 114-238) had a much higher incidence of pancreatic cancer, compared with patients with neither (16 incident cases per 100,000 person-years; 95% CI, 14-17).

After stratified analyses of patients with both recent-onset diabetes and weight loss, rates of pancreatic cancer were also notably high in those 70 years or older (234 cases per 100,000 person years), those with a body mass index of less than 25 kg/m² before weight loss (400 cases per 100,000 person years), and those with a low likelihood of intentional weight loss (334 cases per 100,000 person years).

“I like the study because it reminds us of the importance of not thinking everyone that presents with type 2 diabetes necessarily has garden-variety diabetes,” Paul Jellinger, MD, of the Center for Diabetes and Endocrine Care in Hollywood, Fla., said in an interview. “I have always been concerned when a new-onset diabetic individual presents with no family history of diabetes or prediabetes, especially if they’re neither overweight nor obese. I have sometimes screened those individuals for pancreatic abnormalities.”
 

A call for screening

“This study highlights the consideration for further screening to those with weight loss at the time of diabetes diagnosis, which is very sensible given how unusual weight loss is as a presenting symptom at the time of diagnosis of typical type 2 diabetes,” Dr. Jellinger added. “The combination of weight loss and no family history of diabetes at the time of diagnosis should be an even stronger signal for pancreatic cancer screening and potential detection at a much earlier stage.”

The authors acknowledged their study’s limitations, including some patients with pancreatic cancer not returning their questionnaires and the timing of the questionnaires meaning that patients could’ve developed diabetes after returning it. In addition, they recognized that the participants were “predominantly White health professionals” and recommended a study of “additional patient populations” in the future.

The authors noted numerous potential conflicts of interest, including receiving grants and personal fees from various initiatives, organizations, and pharmaceutical companies.

SOURCE: Yuan C et al. JAMA Oncol. 2020 Aug 13. doi: 10.1001/jamaoncol.2020.2948.

A new study has linked recent-onset diabetes and subsequent weight loss to an increased risk of pancreatic cancer, indicating a distinct group of individuals to screen early for this deadly disease.

“The likelihood of a pancreatic cancer diagnosis was even further elevated among individuals with older age, healthy weight before weight loss, and unintentional weight loss,” wrote Chen Yuan, ScD, of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston. The study was published in JAMA Oncology.

To determine whether an association exists between diabetes plus weight change and pancreatic cancer, the researchers analyzed decades of medical history data from the Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS). The study population from the NHS included 112,818 women with a mean age of 59 years; the population from the HPFS included 46,207 men with a mean age of 65 years. Since enrollment – the baseline was 1978 for the NHS and 1988 for the HPFS – participants have provided follow-up information via biennial questionnaires.

Recent diabetes onset, weight loss boost cancer risk

From those combined groups, 1,116 incident cases of pancreatic cancer (0.7%) were identified. Compared with patients with no diabetes, patients with recent-onset diabetes had triple the risk of pancreatic cancer (age-adjusted hazard ratio, 2.97; 95% confidence interval, 2.31-3.82) and patients with longstanding diabetes had more than double the risk (HR, 2.16; 95% CI, 1.78-2.60). Patients with longer disease duration also had more than twice the risk of pancreatic cancer, with HRs of 2.25 for those with diabetes for 4-10 years (95% CI, 1.74-2.92) and 2.07 for more than 10 years (95% CI, 1.61-2.66).

Compared with patients who hadn’t lost any weight, patients who reported a 1- to 4-pound weight loss (HR, 1.25; 95% CI, 1.03-1.52), a 5- to 8-pound weight loss (HR, 1.33; 95% CI, 1.06-1.66), and a more than 8-pound weight loss (HR, 1.92; 95% CI, 1.58-2.32) had higher risks of pancreatic cancer. Patients with recent-onset diabetes and a 1- to 8-pound weight loss (91 incident cases per 100,000 person-years; 95% CI, 55-151) or a weight loss of more than 8 pounds (164 incident cases per 100,000 person years; 95% CI, 114-238) had a much higher incidence of pancreatic cancer, compared with patients with neither (16 incident cases per 100,000 person-years; 95% CI, 14-17).

After stratified analyses of patients with both recent-onset diabetes and weight loss, rates of pancreatic cancer were also notably high in those 70 years or older (234 cases per 100,000 person years), those with a body mass index of less than 25 kg/m² before weight loss (400 cases per 100,000 person years), and those with a low likelihood of intentional weight loss (334 cases per 100,000 person years).

“I like the study because it reminds us of the importance of not thinking everyone that presents with type 2 diabetes necessarily has garden-variety diabetes,” Paul Jellinger, MD, of the Center for Diabetes and Endocrine Care in Hollywood, Fla., said in an interview. “I have always been concerned when a new-onset diabetic individual presents with no family history of diabetes or prediabetes, especially if they’re neither overweight nor obese. I have sometimes screened those individuals for pancreatic abnormalities.”
 

A call for screening

“This study highlights the consideration for further screening to those with weight loss at the time of diabetes diagnosis, which is very sensible given how unusual weight loss is as a presenting symptom at the time of diagnosis of typical type 2 diabetes,” Dr. Jellinger added. “The combination of weight loss and no family history of diabetes at the time of diagnosis should be an even stronger signal for pancreatic cancer screening and potential detection at a much earlier stage.”

The authors acknowledged their study’s limitations, including some patients with pancreatic cancer not returning their questionnaires and the timing of the questionnaires meaning that patients could’ve developed diabetes after returning it. In addition, they recognized that the participants were “predominantly White health professionals” and recommended a study of “additional patient populations” in the future.

The authors noted numerous potential conflicts of interest, including receiving grants and personal fees from various initiatives, organizations, and pharmaceutical companies.

SOURCE: Yuan C et al. JAMA Oncol. 2020 Aug 13. doi: 10.1001/jamaoncol.2020.2948.

A new study has linked recent-onset diabetes and subsequent weight loss to an increased risk of pancreatic cancer, indicating a distinct group of individuals to screen early for this deadly disease.

“The likelihood of a pancreatic cancer diagnosis was even further elevated among individuals with older age, healthy weight before weight loss, and unintentional weight loss,” wrote Chen Yuan, ScD, of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston. The study was published in JAMA Oncology.

To determine whether an association exists between diabetes plus weight change and pancreatic cancer, the researchers analyzed decades of medical history data from the Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS). The study population from the NHS included 112,818 women with a mean age of 59 years; the population from the HPFS included 46,207 men with a mean age of 65 years. Since enrollment – the baseline was 1978 for the NHS and 1988 for the HPFS – participants have provided follow-up information via biennial questionnaires.

Recent diabetes onset, weight loss boost cancer risk

From those combined groups, 1,116 incident cases of pancreatic cancer (0.7%) were identified. Compared with patients with no diabetes, patients with recent-onset diabetes had triple the risk of pancreatic cancer (age-adjusted hazard ratio, 2.97; 95% confidence interval, 2.31-3.82) and patients with longstanding diabetes had more than double the risk (HR, 2.16; 95% CI, 1.78-2.60). Patients with longer disease duration also had more than twice the risk of pancreatic cancer, with HRs of 2.25 for those with diabetes for 4-10 years (95% CI, 1.74-2.92) and 2.07 for more than 10 years (95% CI, 1.61-2.66).

Compared with patients who hadn’t lost any weight, patients who reported a 1- to 4-pound weight loss (HR, 1.25; 95% CI, 1.03-1.52), a 5- to 8-pound weight loss (HR, 1.33; 95% CI, 1.06-1.66), and a more than 8-pound weight loss (HR, 1.92; 95% CI, 1.58-2.32) had higher risks of pancreatic cancer. Patients with recent-onset diabetes and a 1- to 8-pound weight loss (91 incident cases per 100,000 person-years; 95% CI, 55-151) or a weight loss of more than 8 pounds (164 incident cases per 100,000 person years; 95% CI, 114-238) had a much higher incidence of pancreatic cancer, compared with patients with neither (16 incident cases per 100,000 person-years; 95% CI, 14-17).

After stratified analyses of patients with both recent-onset diabetes and weight loss, rates of pancreatic cancer were also notably high in those 70 years or older (234 cases per 100,000 person years), those with a body mass index of less than 25 kg/m² before weight loss (400 cases per 100,000 person years), and those with a low likelihood of intentional weight loss (334 cases per 100,000 person years).

“I like the study because it reminds us of the importance of not thinking everyone that presents with type 2 diabetes necessarily has garden-variety diabetes,” Paul Jellinger, MD, of the Center for Diabetes and Endocrine Care in Hollywood, Fla., said in an interview. “I have always been concerned when a new-onset diabetic individual presents with no family history of diabetes or prediabetes, especially if they’re neither overweight nor obese. I have sometimes screened those individuals for pancreatic abnormalities.”
 

A call for screening

“This study highlights the consideration for further screening to those with weight loss at the time of diabetes diagnosis, which is very sensible given how unusual weight loss is as a presenting symptom at the time of diagnosis of typical type 2 diabetes,” Dr. Jellinger added. “The combination of weight loss and no family history of diabetes at the time of diagnosis should be an even stronger signal for pancreatic cancer screening and potential detection at a much earlier stage.”

The authors acknowledged their study’s limitations, including some patients with pancreatic cancer not returning their questionnaires and the timing of the questionnaires meaning that patients could’ve developed diabetes after returning it. In addition, they recognized that the participants were “predominantly White health professionals” and recommended a study of “additional patient populations” in the future.

The authors noted numerous potential conflicts of interest, including receiving grants and personal fees from various initiatives, organizations, and pharmaceutical companies.

SOURCE: Yuan C et al. JAMA Oncol. 2020 Aug 13. doi: 10.1001/jamaoncol.2020.2948.

Obesity in adults with axial spondyloarthritis is associated with significantly worse scores on measures of disease activity when compared with normal-weight patients, according to findings from a meta-analysis of 10 studies.

Obesity or overweight could influence axial spondyloarthritis (axSpA) disease activity in several ways, including production of inflammatory mediators by adipose tissue, joint pain caused by excess weight, loss of muscle mass, and increased atherosclerosis, wrote Augusta Ortolan, MD, of the University of Padova (Italy), and colleagues.

However, “it is less clear whether overweight or obesity per se may be a cause of higher disease activity scores,” they added.

In a systematic review published in Arthritis Care & Research, the investigators identified 10 studies to use in the meta-analysis that involved associations between body mass index (BMI) and disease activity in adults with axSpA. The review included three cohort studies and seven cross-sectional studies of patients aged 18 years and older. Disease activity was assessed using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Ankylosing Spondylitis Disease Activity Score (ASDAS).

Overall, the mean difference in BASDAI between patients with normal BMI and overweight or obese patients was –0.38 (P < .0001), and the mean difference in ASDAS between the same groups was –0.19 (P < .0001). When separated into overweight and obese categories, only the difference between normal weight and obesity remained significantly associated with differences in scores on both measures (–0.78 and –0.42, respectively; P < .0001 for both measures). The difference in scores between normal-weight and overweight/obese patients increased with BMI categories, which suggests a possible “dose-effect” relationship between fat mass and disease activity, the researchers wrote.

The study findings were limited by several factors, including the lack of randomized, controlled trials, and potential bias and inconsistency involving BMI measurements, the researchers noted.

However, “we were able to mitigate such limitations via a strict methodology and consistency in the outcomes, thus allowing us to use mean differences – instead of standardized mean differences – as outcomes, which are much easier to interpret and can be directly related to the measurement unit of the outcome,” they wrote.

The results extend data from previous studies, which “could help interpret disease activity measures and understand the difference we could expect between an axSpA patient with normal BMI and increased BMI,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

SOURCE: Ortolan A et al. Arthritis Care Res. 2020 Aug 16. doi: 10.1002/acr.24416.

Obesity in adults with axial spondyloarthritis is associated with significantly worse scores on measures of disease activity when compared with normal-weight patients, according to findings from a meta-analysis of 10 studies.

Obesity or overweight could influence axial spondyloarthritis (axSpA) disease activity in several ways, including production of inflammatory mediators by adipose tissue, joint pain caused by excess weight, loss of muscle mass, and increased atherosclerosis, wrote Augusta Ortolan, MD, of the University of Padova (Italy), and colleagues.

However, “it is less clear whether overweight or obesity per se may be a cause of higher disease activity scores,” they added.

In a systematic review published in Arthritis Care & Research, the investigators identified 10 studies to use in the meta-analysis that involved associations between body mass index (BMI) and disease activity in adults with axSpA. The review included three cohort studies and seven cross-sectional studies of patients aged 18 years and older. Disease activity was assessed using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Ankylosing Spondylitis Disease Activity Score (ASDAS).

Overall, the mean difference in BASDAI between patients with normal BMI and overweight or obese patients was –0.38 (P < .0001), and the mean difference in ASDAS between the same groups was –0.19 (P < .0001). When separated into overweight and obese categories, only the difference between normal weight and obesity remained significantly associated with differences in scores on both measures (–0.78 and –0.42, respectively; P < .0001 for both measures). The difference in scores between normal-weight and overweight/obese patients increased with BMI categories, which suggests a possible “dose-effect” relationship between fat mass and disease activity, the researchers wrote.

The study findings were limited by several factors, including the lack of randomized, controlled trials, and potential bias and inconsistency involving BMI measurements, the researchers noted.

However, “we were able to mitigate such limitations via a strict methodology and consistency in the outcomes, thus allowing us to use mean differences – instead of standardized mean differences – as outcomes, which are much easier to interpret and can be directly related to the measurement unit of the outcome,” they wrote.

The results extend data from previous studies, which “could help interpret disease activity measures and understand the difference we could expect between an axSpA patient with normal BMI and increased BMI,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

SOURCE: Ortolan A et al. Arthritis Care Res. 2020 Aug 16. doi: 10.1002/acr.24416.

Obesity in adults with axial spondyloarthritis is associated with significantly worse scores on measures of disease activity when compared with normal-weight patients, according to findings from a meta-analysis of 10 studies.

Obesity or overweight could influence axial spondyloarthritis (axSpA) disease activity in several ways, including production of inflammatory mediators by adipose tissue, joint pain caused by excess weight, loss of muscle mass, and increased atherosclerosis, wrote Augusta Ortolan, MD, of the University of Padova (Italy), and colleagues.

However, “it is less clear whether overweight or obesity per se may be a cause of higher disease activity scores,” they added.

In a systematic review published in Arthritis Care & Research, the investigators identified 10 studies to use in the meta-analysis that involved associations between body mass index (BMI) and disease activity in adults with axSpA. The review included three cohort studies and seven cross-sectional studies of patients aged 18 years and older. Disease activity was assessed using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Ankylosing Spondylitis Disease Activity Score (ASDAS).

Overall, the mean difference in BASDAI between patients with normal BMI and overweight or obese patients was –0.38 (P < .0001), and the mean difference in ASDAS between the same groups was –0.19 (P < .0001). When separated into overweight and obese categories, only the difference between normal weight and obesity remained significantly associated with differences in scores on both measures (–0.78 and –0.42, respectively; P < .0001 for both measures). The difference in scores between normal-weight and overweight/obese patients increased with BMI categories, which suggests a possible “dose-effect” relationship between fat mass and disease activity, the researchers wrote.

The study findings were limited by several factors, including the lack of randomized, controlled trials, and potential bias and inconsistency involving BMI measurements, the researchers noted.

However, “we were able to mitigate such limitations via a strict methodology and consistency in the outcomes, thus allowing us to use mean differences – instead of standardized mean differences – as outcomes, which are much easier to interpret and can be directly related to the measurement unit of the outcome,” they wrote.

The results extend data from previous studies, which “could help interpret disease activity measures and understand the difference we could expect between an axSpA patient with normal BMI and increased BMI,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

SOURCE: Ortolan A et al. Arthritis Care Res. 2020 Aug 16. doi: 10.1002/acr.24416.

Rates of thyrotoxicosis are significantly higher among patients who are critically ill with COVID-19 than among patients who are critically ill but who do not not have COVID-19, suggesting an atypical form of thyroiditis related to the novel coronavirus infection, according to new research.

“We suggest routine assessment of thyroid function in patients with COVID-19 requiring high-intensity care because they frequently present with thyrotoxicosis due to a form of subacute thyroiditis related to SARS-CoV-2,” the authors wrote in correspondence published online in The Lancet Diabetes and Endocrinology.

However, notably, the study – which compared critically ill ICU patients who had COVID-19 with those who did not have COVID-19 or who had milder cases of COVID-19 – indicates that thyroid disorders do not appear to increase the risk of developing COVID-19, first author Ilaria Muller, MD, PhD, of the department of endocrinology, IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Milan, said in an interview.

“It is important to highlight that we did not find an increased prevalence of preexisting thyroid disorders in COVID-19 patients (contrary to early media reports),” she said. “So far, clinical observations do not support this fear, and we need to reassure people with thyroid disorders, since such disorders are very common among the general population.”

Yet the findings add to emerging evidence of a COVID-19/thyroid relationship, Angela M. Leung, MD, said in an interview.

“Given the health care impacts of the current COVID-19 pandemic worldwide, this study provides some insight on the potential systemic inflammation, as well as thyroid-specific inflammation, of the SARS-Cov-2 virus that is described in some emerging reports,” she said.

“This study joins at least six others that have reported a clinical presentation resembling subacute thyroiditis in critically ill patients with COVID-19,” noted Dr. Leung, of the division of endocrinology, diabetes, and metabolism in the department of medicine at the University of California, Los Angeles.
 

Thyroid function analysis in those with severe COVID-19

Dr. Muller explained that preliminary data from her institution showed thyroid abnormalities in patients who were severely ill with COVID-19. She and her team extended the evaluation to include thyroid data and other data on 93 patients with COVID-19 who were admitted to high-intensity care units (HICUs) in Italy during the 2020 pandemic.

Those data were compared with data on 101 critically ill patients admitted to the same HICUs in 2019 who did not have COVID-19. A third group of 52 patients with COVID-19 who were admitted to low-intensity care units (LICUs) in Italy in 2020 were also included in the analysis.

The mean age of the patients in the HICU 2020 group was 65.3 years; in the HICU 2019 group, it was 73 years; and in the LICU group, it was 70 years (P = .001). In addition, the HICU 2020 group included more men than the other two groups (69% vs. 56% and 48%; P = .03).

Of note, only 9% of patients in the HICU 2020 group had preexisting thyroid disorders, compared with 21% in the LICU group and 23% in the HICU 2019 group (P = .017).

These findings suggest that “such conditions are not a risk factor for SARS-CoV-2 infection or severity of COVID-19,” the authors wrote.

The patients with the preexisting thyroid conditions were excluded from the thyroid function analysis.

A significantly higher proportion of patients in the HICU 2020 group (13; 15%) were thyrotoxic upon admission, compared with just 1 (1%) of 78 patients in the HICU 2019 group (P = .002) and one (2%) of 41 patients in the LICU group (P = .025).

Among the 14 patients in the two COVID-19 groups who had thyrotoxicosis, the majority were male (9; 64%)

Among those in the HICU 2020 group, serum thyroid-stimulating hormone concentrations were lower than in either of the other two groups (P = .018), and serum free thyroxine (free T4) concentrations were higher than in the LICU group (P = .016) but not the HICU 2019 group.
 

Differences compared with other infection-related thyroiditis

Although thyrotoxicosis relating to subacute viral thyroiditis can result from a wide variety of viral infections, there are some key differences with COVID-19, Dr. Muller said.

“Thyroid dysfunction related to SARS-CoV-2 seems to be milder than that of classic subacute thyroiditis due to other viruses,” she explained. Furthermore, thyroid dysfunction associated with other viral infections is more common in women, whereas there were more male patients with the COVID-19–related atypical thyroiditis.

In addition, the thyroid effects developed early with COVID-19, whereas they usually emerge after the infections by other viruses.

Patients did not demonstrate the neck pain that is common with classic viral thyroiditis, and the thyroid abnormalities appear to correlate with the severity of COVID-19, whereas they are seen even in patients with mild symptoms when other viral infections are the cause.

In addition to the risk for subacute viral thyroiditis, critically ill patients in general are at risk of developing nonthyroidal illness syndrome, with alterations in thyroid function. However, thyroid hormone measures in the patients severely ill with COVID-19 were not consistent with that syndrome.

A subanalysis of eight HICU 2020 patients with thyroid dysfunction who were followed for 55 days after discharge showed that two experienced hyperthyroidism but likely not from COVID-19; in the remaining six, thyroid function normalized.

Muller speculated that, when ill with COVID-19, the patients likely had a combination of SARS-CoV-2–related atypical thyroiditis and nonthyroidal illness syndrome, known as T4 toxicosis.
 

Will there be any long-term effects?

Importantly, it remains unknown whether the novel coronavirus has longer-term effects on the thyroid, Dr. Muller said.

“We cannot predict what will be the long-lasting thyroid effects after COVID-19,” she said.

With classic subacute viral thyroiditis, “After a few years ... 5%-20% of patients develop permanent hypothyroidism, [and] the same might happen in COVID-19 patients,” she hypothesized. “We will follow our patients long term to answer this question – this study is already ongoing.”

In the meantime, diagnosis of thyroid dysfunction in patients with COVID-19 is important, inasmuch as it could worsen the already critical conditions of patients, Muller stressed.

“The gold-standard treatment for thyroiditis is steroids, so the presence of thyroid dysfunction might represent an additional indication to such treatment in COVID-19 patients, to be verified in properly designed clinical trials,” she advised.
 

ACE2 cell receptors highly expressed in thyroid

Dr. Muller and colleagues also noted recent research showing that ACE2 – demonstrated to be a key host-cell entry receptor for both SARS-CoV and SARS-CoV-2 – is expressed in even higher levels in the thyroid than the lungs, where it causes COVID-19’s notorious pulmonary effects.

Dr. Muller said the implications of ACE2 expression in the thyroid remain to be elucidated.

“If ACE2 is confirmed to be expressed at higher levels, compared with the lungs in the thyroid gland and other tissues, i.e., small intestine, testis, kidney, heart, etc, dedicated studies will be needed to correlate ACE2 expression with the organs’ susceptibility to SARS-CoV-2 reflected by clinical presentation,” she said.

Dr. Leung added that, as a take-home message from these and the other thyroid/COVID-19 studies, “data are starting to show us that COVID-19 infection may cause thyrotoxicosis that is possibly related to thyroid and systemic inflammation. However, the serum thyroid function test abnormalities seen in COVID-19 patients with subacute thyroiditis are also likely exacerbated to a substantial extent by nonthyroidal illness physiology.”

The authors have disclosed no relevant financial relationships. Dr. Leung is on the advisory board of Medscape Diabetes and Endocrinology.

A version of this article originally appeared on Medscape.com.

Rates of thyrotoxicosis are significantly higher among patients who are critically ill with COVID-19 than among patients who are critically ill but who do not not have COVID-19, suggesting an atypical form of thyroiditis related to the novel coronavirus infection, according to new research.

“We suggest routine assessment of thyroid function in patients with COVID-19 requiring high-intensity care because they frequently present with thyrotoxicosis due to a form of subacute thyroiditis related to SARS-CoV-2,” the authors wrote in correspondence published online in The Lancet Diabetes and Endocrinology.

However, notably, the study – which compared critically ill ICU patients who had COVID-19 with those who did not have COVID-19 or who had milder cases of COVID-19 – indicates that thyroid disorders do not appear to increase the risk of developing COVID-19, first author Ilaria Muller, MD, PhD, of the department of endocrinology, IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Milan, said in an interview.

“It is important to highlight that we did not find an increased prevalence of preexisting thyroid disorders in COVID-19 patients (contrary to early media reports),” she said. “So far, clinical observations do not support this fear, and we need to reassure people with thyroid disorders, since such disorders are very common among the general population.”

Yet the findings add to emerging evidence of a COVID-19/thyroid relationship, Angela M. Leung, MD, said in an interview.

“Given the health care impacts of the current COVID-19 pandemic worldwide, this study provides some insight on the potential systemic inflammation, as well as thyroid-specific inflammation, of the SARS-Cov-2 virus that is described in some emerging reports,” she said.

“This study joins at least six others that have reported a clinical presentation resembling subacute thyroiditis in critically ill patients with COVID-19,” noted Dr. Leung, of the division of endocrinology, diabetes, and metabolism in the department of medicine at the University of California, Los Angeles.
 

Thyroid function analysis in those with severe COVID-19

Dr. Muller explained that preliminary data from her institution showed thyroid abnormalities in patients who were severely ill with COVID-19. She and her team extended the evaluation to include thyroid data and other data on 93 patients with COVID-19 who were admitted to high-intensity care units (HICUs) in Italy during the 2020 pandemic.

Those data were compared with data on 101 critically ill patients admitted to the same HICUs in 2019 who did not have COVID-19. A third group of 52 patients with COVID-19 who were admitted to low-intensity care units (LICUs) in Italy in 2020 were also included in the analysis.

The mean age of the patients in the HICU 2020 group was 65.3 years; in the HICU 2019 group, it was 73 years; and in the LICU group, it was 70 years (P = .001). In addition, the HICU 2020 group included more men than the other two groups (69% vs. 56% and 48%; P = .03).

Of note, only 9% of patients in the HICU 2020 group had preexisting thyroid disorders, compared with 21% in the LICU group and 23% in the HICU 2019 group (P = .017).

These findings suggest that “such conditions are not a risk factor for SARS-CoV-2 infection or severity of COVID-19,” the authors wrote.

The patients with the preexisting thyroid conditions were excluded from the thyroid function analysis.

A significantly higher proportion of patients in the HICU 2020 group (13; 15%) were thyrotoxic upon admission, compared with just 1 (1%) of 78 patients in the HICU 2019 group (P = .002) and one (2%) of 41 patients in the LICU group (P = .025).

Among the 14 patients in the two COVID-19 groups who had thyrotoxicosis, the majority were male (9; 64%)

Among those in the HICU 2020 group, serum thyroid-stimulating hormone concentrations were lower than in either of the other two groups (P = .018), and serum free thyroxine (free T4) concentrations were higher than in the LICU group (P = .016) but not the HICU 2019 group.
 

Differences compared with other infection-related thyroiditis

Although thyrotoxicosis relating to subacute viral thyroiditis can result from a wide variety of viral infections, there are some key differences with COVID-19, Dr. Muller said.

“Thyroid dysfunction related to SARS-CoV-2 seems to be milder than that of classic subacute thyroiditis due to other viruses,” she explained. Furthermore, thyroid dysfunction associated with other viral infections is more common in women, whereas there were more male patients with the COVID-19–related atypical thyroiditis.

In addition, the thyroid effects developed early with COVID-19, whereas they usually emerge after the infections by other viruses.

Patients did not demonstrate the neck pain that is common with classic viral thyroiditis, and the thyroid abnormalities appear to correlate with the severity of COVID-19, whereas they are seen even in patients with mild symptoms when other viral infections are the cause.

In addition to the risk for subacute viral thyroiditis, critically ill patients in general are at risk of developing nonthyroidal illness syndrome, with alterations in thyroid function. However, thyroid hormone measures in the patients severely ill with COVID-19 were not consistent with that syndrome.

A subanalysis of eight HICU 2020 patients with thyroid dysfunction who were followed for 55 days after discharge showed that two experienced hyperthyroidism but likely not from COVID-19; in the remaining six, thyroid function normalized.

Muller speculated that, when ill with COVID-19, the patients likely had a combination of SARS-CoV-2–related atypical thyroiditis and nonthyroidal illness syndrome, known as T4 toxicosis.
 

Will there be any long-term effects?

Importantly, it remains unknown whether the novel coronavirus has longer-term effects on the thyroid, Dr. Muller said.

“We cannot predict what will be the long-lasting thyroid effects after COVID-19,” she said.

With classic subacute viral thyroiditis, “After a few years ... 5%-20% of patients develop permanent hypothyroidism, [and] the same might happen in COVID-19 patients,” she hypothesized. “We will follow our patients long term to answer this question – this study is already ongoing.”

In the meantime, diagnosis of thyroid dysfunction in patients with COVID-19 is important, inasmuch as it could worsen the already critical conditions of patients, Muller stressed.

“The gold-standard treatment for thyroiditis is steroids, so the presence of thyroid dysfunction might represent an additional indication to such treatment in COVID-19 patients, to be verified in properly designed clinical trials,” she advised.
 

ACE2 cell receptors highly expressed in thyroid

Dr. Muller and colleagues also noted recent research showing that ACE2 – demonstrated to be a key host-cell entry receptor for both SARS-CoV and SARS-CoV-2 – is expressed in even higher levels in the thyroid than the lungs, where it causes COVID-19’s notorious pulmonary effects.

Dr. Muller said the implications of ACE2 expression in the thyroid remain to be elucidated.

“If ACE2 is confirmed to be expressed at higher levels, compared with the lungs in the thyroid gland and other tissues, i.e., small intestine, testis, kidney, heart, etc, dedicated studies will be needed to correlate ACE2 expression with the organs’ susceptibility to SARS-CoV-2 reflected by clinical presentation,” she said.

Dr. Leung added that, as a take-home message from these and the other thyroid/COVID-19 studies, “data are starting to show us that COVID-19 infection may cause thyrotoxicosis that is possibly related to thyroid and systemic inflammation. However, the serum thyroid function test abnormalities seen in COVID-19 patients with subacute thyroiditis are also likely exacerbated to a substantial extent by nonthyroidal illness physiology.”

The authors have disclosed no relevant financial relationships. Dr. Leung is on the advisory board of Medscape Diabetes and Endocrinology.

A version of this article originally appeared on Medscape.com.

Rates of thyrotoxicosis are significantly higher among patients who are critically ill with COVID-19 than among patients who are critically ill but who do not not have COVID-19, suggesting an atypical form of thyroiditis related to the novel coronavirus infection, according to new research.

“We suggest routine assessment of thyroid function in patients with COVID-19 requiring high-intensity care because they frequently present with thyrotoxicosis due to a form of subacute thyroiditis related to SARS-CoV-2,” the authors wrote in correspondence published online in The Lancet Diabetes and Endocrinology.

However, notably, the study – which compared critically ill ICU patients who had COVID-19 with those who did not have COVID-19 or who had milder cases of COVID-19 – indicates that thyroid disorders do not appear to increase the risk of developing COVID-19, first author Ilaria Muller, MD, PhD, of the department of endocrinology, IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Milan, said in an interview.

“It is important to highlight that we did not find an increased prevalence of preexisting thyroid disorders in COVID-19 patients (contrary to early media reports),” she said. “So far, clinical observations do not support this fear, and we need to reassure people with thyroid disorders, since such disorders are very common among the general population.”

Yet the findings add to emerging evidence of a COVID-19/thyroid relationship, Angela M. Leung, MD, said in an interview.

“Given the health care impacts of the current COVID-19 pandemic worldwide, this study provides some insight on the potential systemic inflammation, as well as thyroid-specific inflammation, of the SARS-Cov-2 virus that is described in some emerging reports,” she said.

“This study joins at least six others that have reported a clinical presentation resembling subacute thyroiditis in critically ill patients with COVID-19,” noted Dr. Leung, of the division of endocrinology, diabetes, and metabolism in the department of medicine at the University of California, Los Angeles.
 

Thyroid function analysis in those with severe COVID-19

Dr. Muller explained that preliminary data from her institution showed thyroid abnormalities in patients who were severely ill with COVID-19. She and her team extended the evaluation to include thyroid data and other data on 93 patients with COVID-19 who were admitted to high-intensity care units (HICUs) in Italy during the 2020 pandemic.

Those data were compared with data on 101 critically ill patients admitted to the same HICUs in 2019 who did not have COVID-19. A third group of 52 patients with COVID-19 who were admitted to low-intensity care units (LICUs) in Italy in 2020 were also included in the analysis.

The mean age of the patients in the HICU 2020 group was 65.3 years; in the HICU 2019 group, it was 73 years; and in the LICU group, it was 70 years (P = .001). In addition, the HICU 2020 group included more men than the other two groups (69% vs. 56% and 48%; P = .03).

Of note, only 9% of patients in the HICU 2020 group had preexisting thyroid disorders, compared with 21% in the LICU group and 23% in the HICU 2019 group (P = .017).

These findings suggest that “such conditions are not a risk factor for SARS-CoV-2 infection or severity of COVID-19,” the authors wrote.

The patients with the preexisting thyroid conditions were excluded from the thyroid function analysis.

A significantly higher proportion of patients in the HICU 2020 group (13; 15%) were thyrotoxic upon admission, compared with just 1 (1%) of 78 patients in the HICU 2019 group (P = .002) and one (2%) of 41 patients in the LICU group (P = .025).

Among the 14 patients in the two COVID-19 groups who had thyrotoxicosis, the majority were male (9; 64%)

Among those in the HICU 2020 group, serum thyroid-stimulating hormone concentrations were lower than in either of the other two groups (P = .018), and serum free thyroxine (free T4) concentrations were higher than in the LICU group (P = .016) but not the HICU 2019 group.
 

Differences compared with other infection-related thyroiditis

Although thyrotoxicosis relating to subacute viral thyroiditis can result from a wide variety of viral infections, there are some key differences with COVID-19, Dr. Muller said.

“Thyroid dysfunction related to SARS-CoV-2 seems to be milder than that of classic subacute thyroiditis due to other viruses,” she explained. Furthermore, thyroid dysfunction associated with other viral infections is more common in women, whereas there were more male patients with the COVID-19–related atypical thyroiditis.

In addition, the thyroid effects developed early with COVID-19, whereas they usually emerge after the infections by other viruses.

Patients did not demonstrate the neck pain that is common with classic viral thyroiditis, and the thyroid abnormalities appear to correlate with the severity of COVID-19, whereas they are seen even in patients with mild symptoms when other viral infections are the cause.

In addition to the risk for subacute viral thyroiditis, critically ill patients in general are at risk of developing nonthyroidal illness syndrome, with alterations in thyroid function. However, thyroid hormone measures in the patients severely ill with COVID-19 were not consistent with that syndrome.

A subanalysis of eight HICU 2020 patients with thyroid dysfunction who were followed for 55 days after discharge showed that two experienced hyperthyroidism but likely not from COVID-19; in the remaining six, thyroid function normalized.

Muller speculated that, when ill with COVID-19, the patients likely had a combination of SARS-CoV-2–related atypical thyroiditis and nonthyroidal illness syndrome, known as T4 toxicosis.
 

Will there be any long-term effects?

Importantly, it remains unknown whether the novel coronavirus has longer-term effects on the thyroid, Dr. Muller said.

“We cannot predict what will be the long-lasting thyroid effects after COVID-19,” she said.

With classic subacute viral thyroiditis, “After a few years ... 5%-20% of patients develop permanent hypothyroidism, [and] the same might happen in COVID-19 patients,” she hypothesized. “We will follow our patients long term to answer this question – this study is already ongoing.”

In the meantime, diagnosis of thyroid dysfunction in patients with COVID-19 is important, inasmuch as it could worsen the already critical conditions of patients, Muller stressed.

“The gold-standard treatment for thyroiditis is steroids, so the presence of thyroid dysfunction might represent an additional indication to such treatment in COVID-19 patients, to be verified in properly designed clinical trials,” she advised.
 

ACE2 cell receptors highly expressed in thyroid

Dr. Muller and colleagues also noted recent research showing that ACE2 – demonstrated to be a key host-cell entry receptor for both SARS-CoV and SARS-CoV-2 – is expressed in even higher levels in the thyroid than the lungs, where it causes COVID-19’s notorious pulmonary effects.

Dr. Muller said the implications of ACE2 expression in the thyroid remain to be elucidated.

“If ACE2 is confirmed to be expressed at higher levels, compared with the lungs in the thyroid gland and other tissues, i.e., small intestine, testis, kidney, heart, etc, dedicated studies will be needed to correlate ACE2 expression with the organs’ susceptibility to SARS-CoV-2 reflected by clinical presentation,” she said.

Dr. Leung added that, as a take-home message from these and the other thyroid/COVID-19 studies, “data are starting to show us that COVID-19 infection may cause thyrotoxicosis that is possibly related to thyroid and systemic inflammation. However, the serum thyroid function test abnormalities seen in COVID-19 patients with subacute thyroiditis are also likely exacerbated to a substantial extent by nonthyroidal illness physiology.”

The authors have disclosed no relevant financial relationships. Dr. Leung is on the advisory board of Medscape Diabetes and Endocrinology.

A version of this article originally appeared on Medscape.com.

The COVID-19 pandemic has created unique and unprecedented challenges for the clinical research world, with potentially long-lasting consequences.

A new analysis of the extent of disruption shows that the average rate of stopped trials nearly doubled during the first 5 months of 2020, compared with the 2 previous years.

“Typically, clinical research precedes clinical practice by several years, so this disruption we’re seeing now will be felt for many years to come,” said Mario Guadino, MD, of Weill Cornell Medicine, New York.

The analysis was published online July 31 in the Journal of the American College of Cardiology.

The researchers used Python software to query meta-data from all trials reported on ClinicalTrials.gov. Of 321,218 non-COVID-19 trials queried, 28,672 (8.9%) were reported as stopped, defined as a switch in trial status from “recruiting” to “active and not recruiting,” “completed,” “suspended,” “terminated,” or “withdrawn.”

The average rate of discontinuation was 638 trials/month from January 2017 to December 2019, rising to 1,147 trials/month between January 2020 and May 2020 (P < .001 for trend).

Once stopped (as opposed to paused), restarting a trial is a tricky prospect, said Dr. Guadino. “You can’t stop and restart a trial because it creates a lot of issues, so we should expect many of these stopped trials to never be completed.”

He said these figures likely represent an underestimate of the true impact of the pandemic because there is typically a delay in the updating of the status of a trial on ClinicalTrials.gov.

“We are likely looking only at the tip of the iceberg,” he added. “My impression is that the number of trials that will be affected and even canceled will be very high.”

As for cardiology trials, one of the report’s authors, Deepak Bhatt, MD, Brigham and Women’s Hospital, Boston, without naming specific trials, had this to say: “Several cardiovascular trials were paused, and some were permanently discontinued. It may be a while before we fully appreciate just how much information was lost and how much might be salvaged.”

He’s not worried, however, that upcoming cardiology meetings, which have moved online for the foreseeable future, might get a bit boring. “Fortunately, there is enough good work going on in the cardiovascular and cardiometabolic space that I believe there will still be ample randomized and observational data of high quality to present at the major meetings,” Dr. Bhatt said in an email.

The researchers found a weak correlation between the national population-adjusted numbers of COVID-19 cases and the proportion of non-COVID-19 trials stopped by country.

Even for trials that stopped recruiting for a period of time but are continuing, there are myriad issues involving compliance, data integrity, statistical interpretability, etc.

“Even if there is just a temporary disruption, that will most likely lead to reduced enrollment, missing follow-up visits, and protocol deviations, all things that would be red flags during normal times and impact the quality of the clinical trial,” said Dr. Guadino.

“And if your outcome of interest is mortality, well, how exactly do you measure that during a pandemic?” he added.
 

Stopped for lack of funding

Besides the logistical issues, another reason trials may be in jeopardy is funding. A warning early in the pandemic from the research community in Canada that funding was quickly drying up, leaving both jobs and data at risk, led to an aid package from the government to keep the lights on.

The National Institutes of Health (NIH), the Canadian Institutes of Health Research, and similar groups “have devoted large sums of money to research in COVID, which is of course very appropriate, but that clearly reduces the amount of funding that is available for other researchers,” said Dr. Guadino.

Some funding agencies around the world have canceled or put on hold all non-COVID-19 clinical trials still at the design state, Dr. Guadino said in an interview.

The NIH, he stressed, has not canceled funding and has been “extremely open and cooperative” in trying to help trialists navigate the many COVID-generated issues. They’ve even issued guidance on how to manage trials during COVID-19.

Of note, in the survey, the majority of the trials stopped (95.4%) had nongovernmental funding.

“The data are not very granular, so we’re only able to make some very simple, descriptive comments, but it does seem like the more fragile trials – those that are smaller and industry-funded – are the ones more likely to be disrupted,” said Dr. Guadino.

In some cases, he said, priorities have shifted to COVID-19. “If a small company is sponsoring a trial and they decide they want to sponsor something related to COVID, or they realize that because of the slow enrollment, the trial becomes too expensive to complete, they may opt to just abandon it,” said Dr. Guadino.

At what cost? It will take years to sort that out, he said.

This study received no funding. Dr. Guadino and Dr. Bhatt are both active trialists, participating in both industry- and government-sponsored clinical research.
 

A version of this article originally appeared on Medscape.com.

The COVID-19 pandemic has created unique and unprecedented challenges for the clinical research world, with potentially long-lasting consequences.

A new analysis of the extent of disruption shows that the average rate of stopped trials nearly doubled during the first 5 months of 2020, compared with the 2 previous years.

“Typically, clinical research precedes clinical practice by several years, so this disruption we’re seeing now will be felt for many years to come,” said Mario Guadino, MD, of Weill Cornell Medicine, New York.

The analysis was published online July 31 in the Journal of the American College of Cardiology.

The researchers used Python software to query meta-data from all trials reported on ClinicalTrials.gov. Of 321,218 non-COVID-19 trials queried, 28,672 (8.9%) were reported as stopped, defined as a switch in trial status from “recruiting” to “active and not recruiting,” “completed,” “suspended,” “terminated,” or “withdrawn.”

The average rate of discontinuation was 638 trials/month from January 2017 to December 2019, rising to 1,147 trials/month between January 2020 and May 2020 (P < .001 for trend).

Once stopped (as opposed to paused), restarting a trial is a tricky prospect, said Dr. Guadino. “You can’t stop and restart a trial because it creates a lot of issues, so we should expect many of these stopped trials to never be completed.”

He said these figures likely represent an underestimate of the true impact of the pandemic because there is typically a delay in the updating of the status of a trial on ClinicalTrials.gov.

“We are likely looking only at the tip of the iceberg,” he added. “My impression is that the number of trials that will be affected and even canceled will be very high.”

As for cardiology trials, one of the report’s authors, Deepak Bhatt, MD, Brigham and Women’s Hospital, Boston, without naming specific trials, had this to say: “Several cardiovascular trials were paused, and some were permanently discontinued. It may be a while before we fully appreciate just how much information was lost and how much might be salvaged.”

He’s not worried, however, that upcoming cardiology meetings, which have moved online for the foreseeable future, might get a bit boring. “Fortunately, there is enough good work going on in the cardiovascular and cardiometabolic space that I believe there will still be ample randomized and observational data of high quality to present at the major meetings,” Dr. Bhatt said in an email.

The researchers found a weak correlation between the national population-adjusted numbers of COVID-19 cases and the proportion of non-COVID-19 trials stopped by country.

Even for trials that stopped recruiting for a period of time but are continuing, there are myriad issues involving compliance, data integrity, statistical interpretability, etc.

“Even if there is just a temporary disruption, that will most likely lead to reduced enrollment, missing follow-up visits, and protocol deviations, all things that would be red flags during normal times and impact the quality of the clinical trial,” said Dr. Guadino.

“And if your outcome of interest is mortality, well, how exactly do you measure that during a pandemic?” he added.
 

Stopped for lack of funding

Besides the logistical issues, another reason trials may be in jeopardy is funding. A warning early in the pandemic from the research community in Canada that funding was quickly drying up, leaving both jobs and data at risk, led to an aid package from the government to keep the lights on.

The National Institutes of Health (NIH), the Canadian Institutes of Health Research, and similar groups “have devoted large sums of money to research in COVID, which is of course very appropriate, but that clearly reduces the amount of funding that is available for other researchers,” said Dr. Guadino.

Some funding agencies around the world have canceled or put on hold all non-COVID-19 clinical trials still at the design state, Dr. Guadino said in an interview.

The NIH, he stressed, has not canceled funding and has been “extremely open and cooperative” in trying to help trialists navigate the many COVID-generated issues. They’ve even issued guidance on how to manage trials during COVID-19.

Of note, in the survey, the majority of the trials stopped (95.4%) had nongovernmental funding.

“The data are not very granular, so we’re only able to make some very simple, descriptive comments, but it does seem like the more fragile trials – those that are smaller and industry-funded – are the ones more likely to be disrupted,” said Dr. Guadino.

In some cases, he said, priorities have shifted to COVID-19. “If a small company is sponsoring a trial and they decide they want to sponsor something related to COVID, or they realize that because of the slow enrollment, the trial becomes too expensive to complete, they may opt to just abandon it,” said Dr. Guadino.

At what cost? It will take years to sort that out, he said.

This study received no funding. Dr. Guadino and Dr. Bhatt are both active trialists, participating in both industry- and government-sponsored clinical research.
 

A version of this article originally appeared on Medscape.com.

The COVID-19 pandemic has created unique and unprecedented challenges for the clinical research world, with potentially long-lasting consequences.

A new analysis of the extent of disruption shows that the average rate of stopped trials nearly doubled during the first 5 months of 2020, compared with the 2 previous years.

“Typically, clinical research precedes clinical practice by several years, so this disruption we’re seeing now will be felt for many years to come,” said Mario Guadino, MD, of Weill Cornell Medicine, New York.

The analysis was published online July 31 in the Journal of the American College of Cardiology.

The researchers used Python software to query meta-data from all trials reported on ClinicalTrials.gov. Of 321,218 non-COVID-19 trials queried, 28,672 (8.9%) were reported as stopped, defined as a switch in trial status from “recruiting” to “active and not recruiting,” “completed,” “suspended,” “terminated,” or “withdrawn.”

The average rate of discontinuation was 638 trials/month from January 2017 to December 2019, rising to 1,147 trials/month between January 2020 and May 2020 (P < .001 for trend).

Once stopped (as opposed to paused), restarting a trial is a tricky prospect, said Dr. Guadino. “You can’t stop and restart a trial because it creates a lot of issues, so we should expect many of these stopped trials to never be completed.”

He said these figures likely represent an underestimate of the true impact of the pandemic because there is typically a delay in the updating of the status of a trial on ClinicalTrials.gov.

“We are likely looking only at the tip of the iceberg,” he added. “My impression is that the number of trials that will be affected and even canceled will be very high.”

As for cardiology trials, one of the report’s authors, Deepak Bhatt, MD, Brigham and Women’s Hospital, Boston, without naming specific trials, had this to say: “Several cardiovascular trials were paused, and some were permanently discontinued. It may be a while before we fully appreciate just how much information was lost and how much might be salvaged.”

He’s not worried, however, that upcoming cardiology meetings, which have moved online for the foreseeable future, might get a bit boring. “Fortunately, there is enough good work going on in the cardiovascular and cardiometabolic space that I believe there will still be ample randomized and observational data of high quality to present at the major meetings,” Dr. Bhatt said in an email.

The researchers found a weak correlation between the national population-adjusted numbers of COVID-19 cases and the proportion of non-COVID-19 trials stopped by country.

Even for trials that stopped recruiting for a period of time but are continuing, there are myriad issues involving compliance, data integrity, statistical interpretability, etc.

“Even if there is just a temporary disruption, that will most likely lead to reduced enrollment, missing follow-up visits, and protocol deviations, all things that would be red flags during normal times and impact the quality of the clinical trial,” said Dr. Guadino.

“And if your outcome of interest is mortality, well, how exactly do you measure that during a pandemic?” he added.
 

Stopped for lack of funding

Besides the logistical issues, another reason trials may be in jeopardy is funding. A warning early in the pandemic from the research community in Canada that funding was quickly drying up, leaving both jobs and data at risk, led to an aid package from the government to keep the lights on.

The National Institutes of Health (NIH), the Canadian Institutes of Health Research, and similar groups “have devoted large sums of money to research in COVID, which is of course very appropriate, but that clearly reduces the amount of funding that is available for other researchers,” said Dr. Guadino.

Some funding agencies around the world have canceled or put on hold all non-COVID-19 clinical trials still at the design state, Dr. Guadino said in an interview.

The NIH, he stressed, has not canceled funding and has been “extremely open and cooperative” in trying to help trialists navigate the many COVID-generated issues. They’ve even issued guidance on how to manage trials during COVID-19.

Of note, in the survey, the majority of the trials stopped (95.4%) had nongovernmental funding.

“The data are not very granular, so we’re only able to make some very simple, descriptive comments, but it does seem like the more fragile trials – those that are smaller and industry-funded – are the ones more likely to be disrupted,” said Dr. Guadino.

In some cases, he said, priorities have shifted to COVID-19. “If a small company is sponsoring a trial and they decide they want to sponsor something related to COVID, or they realize that because of the slow enrollment, the trial becomes too expensive to complete, they may opt to just abandon it,” said Dr. Guadino.

At what cost? It will take years to sort that out, he said.

This study received no funding. Dr. Guadino and Dr. Bhatt are both active trialists, participating in both industry- and government-sponsored clinical research.
 

A version of this article originally appeared on Medscape.com.

The abrupt transition to online learning for American children in kindergarten through 12th grade has left educators and parents unprepared, but virtual learning can be a successful part of education going forward, according to a viewpoint published in JAMA Pediatrics. However, schools also can reopen safely if precautions are taken, and students would benefit in many ways, according to a second viewpoint.

monkeybusinessimages/Thinkstock

“As policy makers, health care professionals, and parents prepare for the fall semester and as public and private schools grapple with how to make that possible, a better understanding of K-12 virtual learning options and outcomes may facilitate those difficult decisions,” wrote Erik Black, PhD, of the University of Florida, Gainesville; Richard Ferdig, PhD, of Kent State University, Ohio; and Lindsay A. Thompson, MD, of the University of Florida, Gainesville.

“Importantly, K-12 virtual schooling is not suited for all students or all families.”

In a viewpoint published in JAMA Pediatrics, the authors noted that virtual schooling has existed in the United States in various forms for some time. “Just like the myriad options that are available for face-to-face schooling in the U.S., virtual schooling exists in a complex landscape of for-profit, charter, and public options.”
 

Not all virtual schools are equal

Consequently, not all virtual schools are created equal, they emphasized. Virtual education can be successful for many students when presented by trained online instructors using a curriculum designed to be effective in an online venue.

“Parents need to seek reviews and ask for educational outcomes from each virtual school system to assess the quality of the provided education,” Dr. Black, Dr. Ferdig, and Dr. Thompson emphasized.

Key questions for parents to consider when faced with online learning include the type of technology needed to participate; whether their child can maintain a study schedule and complete assignments with limited supervision; whether their child could ask for help and communicate with teachers through technology including phone, text, email, or video; and whether their child has the basic reading, math, and computer literacy skills to engage in online learning, the authors said. Other questions include the school’s expectations for parents and caregivers, how student information may be shared, and how the virtual school lines up with state standards for K-12 educators (in the case of options outside the public school system).

“The COVID-19 pandemic offers a unique challenge for educators, policymakers, and health care professionals to partner with parents to make the best local and individual decisions for children,” Dr. Black, Dr. Ferdig, and Dr. Thompson concluded.
 

Schools may be able to open safely

Children continue to make up a low percentage of COVID-19 cases and appear less likely to experience illness, wrote C. Jason Wang, MD, PhD, and Henry Bair, BS, of Stanford (Calif.) University in a second viewpoint also published in JAMA Pediatrics. The impact of long-term school closures extends beyond education and can “exacerbate socioeconomic disparities, amplify existing educational inequalities, and aggravate food insecurity, domestic violence, and mental health disorders,” they wrote.

Dr. Wang and Mr. Bair proposed that school districts “engage key stakeholders to establish a COVID-19 task force, composed of the superintendent, members of the school board, teachers, parents, and health care professionals to develop policies and procedures,” that would allow schools to open safely.

The authors outlined strategies including adapting teaching spaces to accommodate physical distance, with the addition of temporary modular buildings if needed. They advised assigned seating on school buses, and acknowledged the need for the availability of protective equipment, including hand sanitizer and masks, as well as the possible use of transparent barriers on the sides of student desks.

“As the AAP [American Academy of Pediatrics] guidance suggests, teachers who must work closely with students with special needs or with students who are unable to wear masks should wear N95 masks if possible or wear face shields in addition to surgical masks,” Dr. Wang and Mr. Bair noted. Other elements of the AAP guidance include the creation of fixed cohorts of students and teachers to limit virus exposure.

“Even with all the precautions in place, COVID-19 outbreaks within schools are still likely,” they said. “Therefore, schools will need to remain flexible and consider temporary closures if there is an outbreak involving multiple students and/or staff and be ready to transition to online education.”

The AAP guidance does not address operational approaches to identifying signs and symptoms of COVID-19, the authors noted. “To address this, we recommend that schools implement multilevel screening for students and staff.”

“In summary, to maximize health and educational outcomes, school districts should adopt some or all of the measures of the AAP guidance and prioritize them after considering local COVID-19 incidence, key stakeholder input, and budgetary constraints,” Dr. Wang and Mr. Bair concluded.
 

Schools opening is a regional decision

“The mission of the AAP is to attain optimal physical, mental, and social health and well-being for all infants, children, adolescents, and young adults,” Howard Smart, MD, said in an interview. The question of school reopening “is of national importance, and the AAP has a national role in making recommendations regarding national policy affecting the health of the children.”

“The decision to open schools will be made regionally, but it is important for a nonpolitical national voice to make expert recommendations,” he emphasized.

“Many of the recommendations are ideal goals,” noted Dr. Smart, chairman of the department of pediatrics at the Sharp Rees-Stealy Medical Group in San Diego. “It will be difficult, for example, to implement symptom screening every day before school, no matter where it is performed. Some of the measures may be quite costly, and take time to implement, or require expansion of school staff, for which there may be no budget.”

In addition, “[n]ot all students are likely to comply with masking, distance, and hand-washing recommendations. One student who is noncompliant will be able to infect many other students and staff, as has been seen in other countries.” Also, parental attitudes toward control measures are likely to affect student attitudes, he noted.

“I have interviewed many families at recent checkups, and most have felt that the rush to remote learning that occurred at the end of the last school year resulted in fairly disorganized instruction,” Dr. Smart said. “They are hoping that, having had the summer to plan ahead, the remote teaching will be handled better. Remote learning will certainly work best for self-motivated, organized students with good family support, as noted in the Black, Ferdig, and Thompson article,” he said.

Pediatricians can support the schools by being a source of evidence-based information for parents, Dr. Smart said. “Pediatricians with time and energy might want to volunteer to hold informational video conferences for parents and/or school personnel if they feel they are up to date on current COVID-19 science and want to handle potentially contentious questions.”

The decision parents make to send their children back to school comes down to a risk-benefit calculation. “In some communities this may be left to parents, while in other communities this will a public health decision,” he said. “It is still not clear whether having students attend school in person will result in increased spread of COVID-19 among the students, or in their communities. Although some evidence from early in the pandemic suggests that children may not spread the virus as much as adults, more recent evidence suggests that children 10 years and older do transmit the virus at least as much as adults.”

“The risk to the students and the community, therefore, is unknown,” and difficult to compare with the benefit of in-person schooling, Dr. Smart noted.

“We will learn quite a bit from communities where students do go back to in-person class, as we follow the progression of COVID-19 over the weeks following the resumption of instruction.” Ultimately, advice to parents will need to be tailored to the current conditions of COVID-19 transmission in the community, he concluded.
 

It’s not just about education

“The AAP released its guidance to ensure that as school districts were contemplating reopening they were considering the full array of risks for children and adolescents. These risks included not only those related to COVID-19, but also those related to the impact of not reopening in-person,” Nathaniel Beers, MD, president of the HSC Health Care System in Washington, said in an interview.

“Students and families are dependent on schools for much more than just an education, and those [elements] need to be factored into the decisions to reopen,” the pediatrician said.

However, “[t]he major barrier for schools is resources to safely reopen,” said Dr. Beers. “The additional staffing and supplies will require additional funding. There are increased demands regardless of whether students are learning in-person or virtually or through hybrid models.”

“Another significant barrier is ensuring that parents and staff are actively engaged in planning for the type of model being used,” he said.

“All of the models require buy-in by staff and parents. This will require significant outreach and strong communication plans. Schools also need to ensure they are planning not just for how to return students to schools, but what will happen when staff or students test positive for COVID-19. Students, families, and staff all will need to know what these plans are up front to feel confident in returning to school,” he emphasized.

“There are students who can thrive in a virtual learning environment,” Dr. Beers said. “There are also students who benefit from the virtual learning environment because of their own risk, or because of a family member’s risk for COVID-19 or the complications from it.”

“However, many children with disabilities have struggled in a virtual environment,” he said. “These students struggle to access the educational services without the adequate supports at home. They often receive additional services in school, such as speech, occupational therapy or physical therapy, or nursing services, that may not have transitioned to home but are critical for their health and development. Many students with disabilities are dependent on family members to successfully access the educational services they need.”

“Pediatricians can play a role in providing feedback on recommendations related to physical distancing and face coverings in particular,” said Dr. Beers. “In addition, they can be helpful in developing plans for children with disabilities as well as what the response plan should be for students who become sick during the school day.”

The Centers for Disease Control and Prevention released a decision tool for parents who are considering whether to send their child to in-person school, and pediatricians can help parents walk through these questions, Dr. Beers noted. “In addition, pediatricians play an important role in helping patients and families think about the risks of COVID for the patient and other family members, and this can be helpful in addressing the anxiety that parents and patients may be experiencing.”

Further information can be found in Return to School During COVID-19, which can be located at HealthyChildren.org, by the American Academy of Pediatrics.

The authors of the viewpoints had no relevant financial disclosures. Dr. Smart, a member of the Pediatric News editorial advisory board, had no relevant financial disclosures. Dr. Beers has served on the editorial advisory board of Pediatric News in the past, but had no relevant financial disclosures.

SOURCES: Black E, Ferdig R, Thompson LA. JAMA Pediatr. 2020 Aug 11. doi: 10.1001/jamapediatrics.2020.3800. Wang CJ and Bair H. JAMA Pediatr. Aug 11. doi: 10.1001/jamapediatrics.2020.3871.
 

The abrupt transition to online learning for American children in kindergarten through 12th grade has left educators and parents unprepared, but virtual learning can be a successful part of education going forward, according to a viewpoint published in JAMA Pediatrics. However, schools also can reopen safely if precautions are taken, and students would benefit in many ways, according to a second viewpoint.

monkeybusinessimages/Thinkstock

“As policy makers, health care professionals, and parents prepare for the fall semester and as public and private schools grapple with how to make that possible, a better understanding of K-12 virtual learning options and outcomes may facilitate those difficult decisions,” wrote Erik Black, PhD, of the University of Florida, Gainesville; Richard Ferdig, PhD, of Kent State University, Ohio; and Lindsay A. Thompson, MD, of the University of Florida, Gainesville.

“Importantly, K-12 virtual schooling is not suited for all students or all families.”

In a viewpoint published in JAMA Pediatrics, the authors noted that virtual schooling has existed in the United States in various forms for some time. “Just like the myriad options that are available for face-to-face schooling in the U.S., virtual schooling exists in a complex landscape of for-profit, charter, and public options.”
 

Not all virtual schools are equal

Consequently, not all virtual schools are created equal, they emphasized. Virtual education can be successful for many students when presented by trained online instructors using a curriculum designed to be effective in an online venue.

“Parents need to seek reviews and ask for educational outcomes from each virtual school system to assess the quality of the provided education,” Dr. Black, Dr. Ferdig, and Dr. Thompson emphasized.

Key questions for parents to consider when faced with online learning include the type of technology needed to participate; whether their child can maintain a study schedule and complete assignments with limited supervision; whether their child could ask for help and communicate with teachers through technology including phone, text, email, or video; and whether their child has the basic reading, math, and computer literacy skills to engage in online learning, the authors said. Other questions include the school’s expectations for parents and caregivers, how student information may be shared, and how the virtual school lines up with state standards for K-12 educators (in the case of options outside the public school system).

“The COVID-19 pandemic offers a unique challenge for educators, policymakers, and health care professionals to partner with parents to make the best local and individual decisions for children,” Dr. Black, Dr. Ferdig, and Dr. Thompson concluded.
 

Schools may be able to open safely

Children continue to make up a low percentage of COVID-19 cases and appear less likely to experience illness, wrote C. Jason Wang, MD, PhD, and Henry Bair, BS, of Stanford (Calif.) University in a second viewpoint also published in JAMA Pediatrics. The impact of long-term school closures extends beyond education and can “exacerbate socioeconomic disparities, amplify existing educational inequalities, and aggravate food insecurity, domestic violence, and mental health disorders,” they wrote.

Dr. Wang and Mr. Bair proposed that school districts “engage key stakeholders to establish a COVID-19 task force, composed of the superintendent, members of the school board, teachers, parents, and health care professionals to develop policies and procedures,” that would allow schools to open safely.

The authors outlined strategies including adapting teaching spaces to accommodate physical distance, with the addition of temporary modular buildings if needed. They advised assigned seating on school buses, and acknowledged the need for the availability of protective equipment, including hand sanitizer and masks, as well as the possible use of transparent barriers on the sides of student desks.

“As the AAP [American Academy of Pediatrics] guidance suggests, teachers who must work closely with students with special needs or with students who are unable to wear masks should wear N95 masks if possible or wear face shields in addition to surgical masks,” Dr. Wang and Mr. Bair noted. Other elements of the AAP guidance include the creation of fixed cohorts of students and teachers to limit virus exposure.

“Even with all the precautions in place, COVID-19 outbreaks within schools are still likely,” they said. “Therefore, schools will need to remain flexible and consider temporary closures if there is an outbreak involving multiple students and/or staff and be ready to transition to online education.”

The AAP guidance does not address operational approaches to identifying signs and symptoms of COVID-19, the authors noted. “To address this, we recommend that schools implement multilevel screening for students and staff.”

“In summary, to maximize health and educational outcomes, school districts should adopt some or all of the measures of the AAP guidance and prioritize them after considering local COVID-19 incidence, key stakeholder input, and budgetary constraints,” Dr. Wang and Mr. Bair concluded.
 

Schools opening is a regional decision

“The mission of the AAP is to attain optimal physical, mental, and social health and well-being for all infants, children, adolescents, and young adults,” Howard Smart, MD, said in an interview. The question of school reopening “is of national importance, and the AAP has a national role in making recommendations regarding national policy affecting the health of the children.”

“The decision to open schools will be made regionally, but it is important for a nonpolitical national voice to make expert recommendations,” he emphasized.

“Many of the recommendations are ideal goals,” noted Dr. Smart, chairman of the department of pediatrics at the Sharp Rees-Stealy Medical Group in San Diego. “It will be difficult, for example, to implement symptom screening every day before school, no matter where it is performed. Some of the measures may be quite costly, and take time to implement, or require expansion of school staff, for which there may be no budget.”

In addition, “[n]ot all students are likely to comply with masking, distance, and hand-washing recommendations. One student who is noncompliant will be able to infect many other students and staff, as has been seen in other countries.” Also, parental attitudes toward control measures are likely to affect student attitudes, he noted.

“I have interviewed many families at recent checkups, and most have felt that the rush to remote learning that occurred at the end of the last school year resulted in fairly disorganized instruction,” Dr. Smart said. “They are hoping that, having had the summer to plan ahead, the remote teaching will be handled better. Remote learning will certainly work best for self-motivated, organized students with good family support, as noted in the Black, Ferdig, and Thompson article,” he said.

Pediatricians can support the schools by being a source of evidence-based information for parents, Dr. Smart said. “Pediatricians with time and energy might want to volunteer to hold informational video conferences for parents and/or school personnel if they feel they are up to date on current COVID-19 science and want to handle potentially contentious questions.”

The decision parents make to send their children back to school comes down to a risk-benefit calculation. “In some communities this may be left to parents, while in other communities this will a public health decision,” he said. “It is still not clear whether having students attend school in person will result in increased spread of COVID-19 among the students, or in their communities. Although some evidence from early in the pandemic suggests that children may not spread the virus as much as adults, more recent evidence suggests that children 10 years and older do transmit the virus at least as much as adults.”

“The risk to the students and the community, therefore, is unknown,” and difficult to compare with the benefit of in-person schooling, Dr. Smart noted.

“We will learn quite a bit from communities where students do go back to in-person class, as we follow the progression of COVID-19 over the weeks following the resumption of instruction.” Ultimately, advice to parents will need to be tailored to the current conditions of COVID-19 transmission in the community, he concluded.
 

It’s not just about education

“The AAP released its guidance to ensure that as school districts were contemplating reopening they were considering the full array of risks for children and adolescents. These risks included not only those related to COVID-19, but also those related to the impact of not reopening in-person,” Nathaniel Beers, MD, president of the HSC Health Care System in Washington, said in an interview.

“Students and families are dependent on schools for much more than just an education, and those [elements] need to be factored into the decisions to reopen,” the pediatrician said.

However, “[t]he major barrier for schools is resources to safely reopen,” said Dr. Beers. “The additional staffing and supplies will require additional funding. There are increased demands regardless of whether students are learning in-person or virtually or through hybrid models.”

“Another significant barrier is ensuring that parents and staff are actively engaged in planning for the type of model being used,” he said.

“All of the models require buy-in by staff and parents. This will require significant outreach and strong communication plans. Schools also need to ensure they are planning not just for how to return students to schools, but what will happen when staff or students test positive for COVID-19. Students, families, and staff all will need to know what these plans are up front to feel confident in returning to school,” he emphasized.

“There are students who can thrive in a virtual learning environment,” Dr. Beers said. “There are also students who benefit from the virtual learning environment because of their own risk, or because of a family member’s risk for COVID-19 or the complications from it.”

“However, many children with disabilities have struggled in a virtual environment,” he said. “These students struggle to access the educational services without the adequate supports at home. They often receive additional services in school, such as speech, occupational therapy or physical therapy, or nursing services, that may not have transitioned to home but are critical for their health and development. Many students with disabilities are dependent on family members to successfully access the educational services they need.”

“Pediatricians can play a role in providing feedback on recommendations related to physical distancing and face coverings in particular,” said Dr. Beers. “In addition, they can be helpful in developing plans for children with disabilities as well as what the response plan should be for students who become sick during the school day.”

The Centers for Disease Control and Prevention released a decision tool for parents who are considering whether to send their child to in-person school, and pediatricians can help parents walk through these questions, Dr. Beers noted. “In addition, pediatricians play an important role in helping patients and families think about the risks of COVID for the patient and other family members, and this can be helpful in addressing the anxiety that parents and patients may be experiencing.”

Further information can be found in Return to School During COVID-19, which can be located at HealthyChildren.org, by the American Academy of Pediatrics.

The authors of the viewpoints had no relevant financial disclosures. Dr. Smart, a member of the Pediatric News editorial advisory board, had no relevant financial disclosures. Dr. Beers has served on the editorial advisory board of Pediatric News in the past, but had no relevant financial disclosures.

SOURCES: Black E, Ferdig R, Thompson LA. JAMA Pediatr. 2020 Aug 11. doi: 10.1001/jamapediatrics.2020.3800. Wang CJ and Bair H. JAMA Pediatr. Aug 11. doi: 10.1001/jamapediatrics.2020.3871.
 

The abrupt transition to online learning for American children in kindergarten through 12th grade has left educators and parents unprepared, but virtual learning can be a successful part of education going forward, according to a viewpoint published in JAMA Pediatrics. However, schools also can reopen safely if precautions are taken, and students would benefit in many ways, according to a second viewpoint.

monkeybusinessimages/Thinkstock

“As policy makers, health care professionals, and parents prepare for the fall semester and as public and private schools grapple with how to make that possible, a better understanding of K-12 virtual learning options and outcomes may facilitate those difficult decisions,” wrote Erik Black, PhD, of the University of Florida, Gainesville; Richard Ferdig, PhD, of Kent State University, Ohio; and Lindsay A. Thompson, MD, of the University of Florida, Gainesville.

“Importantly, K-12 virtual schooling is not suited for all students or all families.”

In a viewpoint published in JAMA Pediatrics, the authors noted that virtual schooling has existed in the United States in various forms for some time. “Just like the myriad options that are available for face-to-face schooling in the U.S., virtual schooling exists in a complex landscape of for-profit, charter, and public options.”
 

Not all virtual schools are equal

Consequently, not all virtual schools are created equal, they emphasized. Virtual education can be successful for many students when presented by trained online instructors using a curriculum designed to be effective in an online venue.

“Parents need to seek reviews and ask for educational outcomes from each virtual school system to assess the quality of the provided education,” Dr. Black, Dr. Ferdig, and Dr. Thompson emphasized.

Key questions for parents to consider when faced with online learning include the type of technology needed to participate; whether their child can maintain a study schedule and complete assignments with limited supervision; whether their child could ask for help and communicate with teachers through technology including phone, text, email, or video; and whether their child has the basic reading, math, and computer literacy skills to engage in online learning, the authors said. Other questions include the school’s expectations for parents and caregivers, how student information may be shared, and how the virtual school lines up with state standards for K-12 educators (in the case of options outside the public school system).

“The COVID-19 pandemic offers a unique challenge for educators, policymakers, and health care professionals to partner with parents to make the best local and individual decisions for children,” Dr. Black, Dr. Ferdig, and Dr. Thompson concluded.
 

Schools may be able to open safely

Children continue to make up a low percentage of COVID-19 cases and appear less likely to experience illness, wrote C. Jason Wang, MD, PhD, and Henry Bair, BS, of Stanford (Calif.) University in a second viewpoint also published in JAMA Pediatrics. The impact of long-term school closures extends beyond education and can “exacerbate socioeconomic disparities, amplify existing educational inequalities, and aggravate food insecurity, domestic violence, and mental health disorders,” they wrote.

Dr. Wang and Mr. Bair proposed that school districts “engage key stakeholders to establish a COVID-19 task force, composed of the superintendent, members of the school board, teachers, parents, and health care professionals to develop policies and procedures,” that would allow schools to open safely.

The authors outlined strategies including adapting teaching spaces to accommodate physical distance, with the addition of temporary modular buildings if needed. They advised assigned seating on school buses, and acknowledged the need for the availability of protective equipment, including hand sanitizer and masks, as well as the possible use of transparent barriers on the sides of student desks.

“As the AAP [American Academy of Pediatrics] guidance suggests, teachers who must work closely with students with special needs or with students who are unable to wear masks should wear N95 masks if possible or wear face shields in addition to surgical masks,” Dr. Wang and Mr. Bair noted. Other elements of the AAP guidance include the creation of fixed cohorts of students and teachers to limit virus exposure.

“Even with all the precautions in place, COVID-19 outbreaks within schools are still likely,” they said. “Therefore, schools will need to remain flexible and consider temporary closures if there is an outbreak involving multiple students and/or staff and be ready to transition to online education.”

The AAP guidance does not address operational approaches to identifying signs and symptoms of COVID-19, the authors noted. “To address this, we recommend that schools implement multilevel screening for students and staff.”

“In summary, to maximize health and educational outcomes, school districts should adopt some or all of the measures of the AAP guidance and prioritize them after considering local COVID-19 incidence, key stakeholder input, and budgetary constraints,” Dr. Wang and Mr. Bair concluded.
 

Schools opening is a regional decision

“The mission of the AAP is to attain optimal physical, mental, and social health and well-being for all infants, children, adolescents, and young adults,” Howard Smart, MD, said in an interview. The question of school reopening “is of national importance, and the AAP has a national role in making recommendations regarding national policy affecting the health of the children.”

“The decision to open schools will be made regionally, but it is important for a nonpolitical national voice to make expert recommendations,” he emphasized.

“Many of the recommendations are ideal goals,” noted Dr. Smart, chairman of the department of pediatrics at the Sharp Rees-Stealy Medical Group in San Diego. “It will be difficult, for example, to implement symptom screening every day before school, no matter where it is performed. Some of the measures may be quite costly, and take time to implement, or require expansion of school staff, for which there may be no budget.”

In addition, “[n]ot all students are likely to comply with masking, distance, and hand-washing recommendations. One student who is noncompliant will be able to infect many other students and staff, as has been seen in other countries.” Also, parental attitudes toward control measures are likely to affect student attitudes, he noted.

“I have interviewed many families at recent checkups, and most have felt that the rush to remote learning that occurred at the end of the last school year resulted in fairly disorganized instruction,” Dr. Smart said. “They are hoping that, having had the summer to plan ahead, the remote teaching will be handled better. Remote learning will certainly work best for self-motivated, organized students with good family support, as noted in the Black, Ferdig, and Thompson article,” he said.

Pediatricians can support the schools by being a source of evidence-based information for parents, Dr. Smart said. “Pediatricians with time and energy might want to volunteer to hold informational video conferences for parents and/or school personnel if they feel they are up to date on current COVID-19 science and want to handle potentially contentious questions.”

The decision parents make to send their children back to school comes down to a risk-benefit calculation. “In some communities this may be left to parents, while in other communities this will a public health decision,” he said. “It is still not clear whether having students attend school in person will result in increased spread of COVID-19 among the students, or in their communities. Although some evidence from early in the pandemic suggests that children may not spread the virus as much as adults, more recent evidence suggests that children 10 years and older do transmit the virus at least as much as adults.”

“The risk to the students and the community, therefore, is unknown,” and difficult to compare with the benefit of in-person schooling, Dr. Smart noted.

“We will learn quite a bit from communities where students do go back to in-person class, as we follow the progression of COVID-19 over the weeks following the resumption of instruction.” Ultimately, advice to parents will need to be tailored to the current conditions of COVID-19 transmission in the community, he concluded.
 

It’s not just about education

“The AAP released its guidance to ensure that as school districts were contemplating reopening they were considering the full array of risks for children and adolescents. These risks included not only those related to COVID-19, but also those related to the impact of not reopening in-person,” Nathaniel Beers, MD, president of the HSC Health Care System in Washington, said in an interview.

“Students and families are dependent on schools for much more than just an education, and those [elements] need to be factored into the decisions to reopen,” the pediatrician said.

However, “[t]he major barrier for schools is resources to safely reopen,” said Dr. Beers. “The additional staffing and supplies will require additional funding. There are increased demands regardless of whether students are learning in-person or virtually or through hybrid models.”

“Another significant barrier is ensuring that parents and staff are actively engaged in planning for the type of model being used,” he said.

“All of the models require buy-in by staff and parents. This will require significant outreach and strong communication plans. Schools also need to ensure they are planning not just for how to return students to schools, but what will happen when staff or students test positive for COVID-19. Students, families, and staff all will need to know what these plans are up front to feel confident in returning to school,” he emphasized.

“There are students who can thrive in a virtual learning environment,” Dr. Beers said. “There are also students who benefit from the virtual learning environment because of their own risk, or because of a family member’s risk for COVID-19 or the complications from it.”

“However, many children with disabilities have struggled in a virtual environment,” he said. “These students struggle to access the educational services without the adequate supports at home. They often receive additional services in school, such as speech, occupational therapy or physical therapy, or nursing services, that may not have transitioned to home but are critical for their health and development. Many students with disabilities are dependent on family members to successfully access the educational services they need.”

“Pediatricians can play a role in providing feedback on recommendations related to physical distancing and face coverings in particular,” said Dr. Beers. “In addition, they can be helpful in developing plans for children with disabilities as well as what the response plan should be for students who become sick during the school day.”

The Centers for Disease Control and Prevention released a decision tool for parents who are considering whether to send their child to in-person school, and pediatricians can help parents walk through these questions, Dr. Beers noted. “In addition, pediatricians play an important role in helping patients and families think about the risks of COVID for the patient and other family members, and this can be helpful in addressing the anxiety that parents and patients may be experiencing.”

Further information can be found in Return to School During COVID-19, which can be located at HealthyChildren.org, by the American Academy of Pediatrics.

The authors of the viewpoints had no relevant financial disclosures. Dr. Smart, a member of the Pediatric News editorial advisory board, had no relevant financial disclosures. Dr. Beers has served on the editorial advisory board of Pediatric News in the past, but had no relevant financial disclosures.

SOURCES: Black E, Ferdig R, Thompson LA. JAMA Pediatr. 2020 Aug 11. doi: 10.1001/jamapediatrics.2020.3800. Wang CJ and Bair H. JAMA Pediatr. Aug 11. doi: 10.1001/jamapediatrics.2020.3871.
 

Delirium is the most common postsurgical complication for older adults, with incidence of 15%-54%, depending on surgery type.¹ Increasing numbers of older adults are undergoing surgery²; and those who develop delirium experience negative consequences including longer lengths of stay, higher likelihood of institutional discharge, and increased morbidity and mortality.³ The American Geriatrics Society Expert Panel on Postoperative Delirium in Older Adults and the European Society of Anaesthesiology⁴ recommend routine screening for delirium in those at risk.

Ultrabrief screens are designed to rule out delirium quickly and identify a subset of patients who require further testing.⁵ Our group, and others, have previously published ultrabrief screens for the general medicine, nonsurgical population and for patients with dementia.^5,6 The UB-2 is an ultrabrief screen consisting of “Months of the year backward” (MOYB) and “What day of the week is it?”, which has a sensitivity of 93% and specificity of 64% in hospitalized older adults and takes less than 40 seconds to administer.⁵ However, no such screens for delirium have been developed for the group with relatively high cognitive and physical functioning undergoing scheduled major surgery in which delirium may present differently. Thus, the purpose of this study was to develop an ultrabrief screen for postoperative delirium using data from a large study of delirium in cognitively intact, older adults undergoing scheduled major noncardiac surgery.

We performed a secondary data analysis on 560 patients enrolled between June 18, 2010, and August 8, 2013, in the Successful Aging After Elective Surgery (SAGES) study,⁷ an ongoing prospective cohort study of older adults undergoing major elective surgeries (eg, total hip or knee replacement; lumbar, cervical, or sacral laminectomy; lower extremity arterial bypass surgery; open abdominal aortic aneurysm repair; and open or laparoscopic colectomy). Exclusion criteria included evidence of dementia, delirium, prior hospitalization within 3 months, legal blindness, severe deafness, terminal condition, history of schizophrenia or psychosis, and history of alcohol abuse or withdrawal. The Institutional Review Boards of Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, and Hebrew SeniorLife, all in Boston, Massachusetts, approved the study.

SAGES Delirium Assessment and Additional Variables

The presence or absence of delirium was based on daily in-hospital assessments by trained research staff using the Confusion Assessment Method (CAM)⁸ long form. The Delirium Symptom Interview (DSI)⁹ and information related to acute changes in mental status were also included as provided by nursing staff and/or family. Delirium severity was determined using the CAM-S.¹⁰ Participants in The SAGES Study had an initial baseline, presurgical assessment in their homes. Cognitive and physical functioning, depression, comorbidities, laboratory, and self-reported demographic data were collected.

Statistical Analyses

We included CAM delirium data from postoperative days (POD) 1 and 2 for each participant, if available; postoperative day 0 was not included because of potential residual anesthetic effects. We chose these days because most delirium began on POD1 or 2, and patients started being discharged on POD3. We considered all one-, two-, and three-item combinations of the 12 cognitive items of the 3D-CAM¹¹ because of their demonstrated high information content for CAM diagnostic features per Item Response Theory.¹² There were 12 possible one-item screens, 66 two-item screens, and 220 three-item screens. Sensitivity, specificity, and 95% confidence intervals for each were compared with CAM delirium determination. An ideal ultrabrief screen for delirium has high sensitivity with moderate specificity; general guidelines considered based on investigator consensus included screens with a sensitivity higher than 0.90 and specificity greater than 0.70. Because these screens are used to quickly rule out delirium, we also present the percent positive screen among the entire population (whether delirium is present or not). Screens with a positive screen rate of more than 50% are unlikely to be helpful in ruling out delirium quickly in a large enough fraction of the population. We also required that in multiple item screens, no two items should assess the same CAM feature. For instance, we would eliminate a two-item screen with MOYB and four-digit span since both items measure CAM Feature 2 (Inattention). Finally, we evaluated screen performance separately on POD1 and POD2. Switching screens by POD can be confusing, so we chose a single best screen that retained excellent performance over both days. Data analyses used SAS version 9.4 (SAS Institute, Cary, North Carolina).

The dataset included 560 adults who had an average age of 76.6 years (SD = 5.2), were 58% women, and were highly educated (15.0 years; SD = 2.9; Table). Postoperative delirium occurred during one or more days in 134 individuals (24%). A total of 1,100 delirium assessments were used, with 113 that were CAM positive (10.3%). For POD1, we used 551 assessments, 61 of which were positive (11.1%); for POD2, 549 assessments were used, with 51 positive (9.3%). Appendix Tables present the positive screen rates, sensitivities, specificities, and 95% confidence intervals of all 12 one-item screens and the 12 best performing two- and three-item screens in order of decreasing sensitivity.

The best ultrabrief screen from POD1 included the following three items: “Does the patient report feeling confused?”, MOYB, and “Does the patient appear sleepy?”, with a sensitivity of 0.95 (95% CI, 0.87-0.99) and specificity of 0.73 (95% CI, 0.69-0.77). The same combination of items has a sensitivity of 0.88 (95% CI, 0.77-0.96) and a specificity of 0.70 (95% CI, 0.66-0.74) on POD2. When POD1 and POD2 are combined, the sensitivity is 0.92 (95% CI, 0.85-0.96) and specificity is 0.72 (95% CI, 0.69-0.74). We consider this to be our best screen overall.

We identified a three-item screen for delirium after elective surgery consisting of “Does the patient report feeling confused?”, MOYB, and “Does the patient appear sleepy?” In our own prior work, we identified a two-item screen consisting of MOYB and “What is the day of the week?” as the best ultrabrief screen for delirium in general medicine populations (termed the “UB-2”)⁵ and a subsequent screen for patients with delirium superimposed on dementia (DSD) including “What type of place is this?”, Days of the Week Backward, and “Does the patient appear sleepy?”⁶ All three contain a test of attention (a cardinal feature of delirium) and a test of orientation, although the specific test for that varies. Both the surgical and DSD screens include “Does the patient appear sleepy?”, which addresses a reduced level of consciousness. This might be particularly important in the postoperative setting because of residual effects of anesthesia and/or postoperative analgesic medications contributing to delirium. Work done by others confirms our current findings, which is that MOYB is the best single item for most groups. Belleli et al¹³ and Han et al¹⁴ included MOYB as the single attentional item in the 4AT and B-CAM, respectively. The Nu-DESC has been used as a screen in surgical patients; however, it involves only nursing observations and no direct questioning of the patient.¹⁵

The Figure describes how our “best screen” could be integrated into clinical care. One or more “positive” or incorrect responses on these three items constitutes a positive screen that should be further evaluated with the CAM or 3D-CAM. If all three items are correct or negative, this effectively rules out delirium; however, continued periodic screening on a daily (or per shift) basis is indicated. On repeat testing, if any of the previously negative or correct items becomes positive or incorrect, this would be evidence for Acute Change, CAM Feature 1. Finally, it should be noted that, if all three items in our best screen are positive, full CAM criteria for delirium diagnosis are met within the screen itself, and no further testing is required. We envision this process being facilitated by use of an app-based program that generates optimal screening items based on patient and setting characteristics.

There are several limitations that must be noted. First, our three-item screen may not generalize to nonsurgical candidates or those undergoing emergent surgery and should be tested in these groups. Second, the SAGES sample is relatively homogenous with respect to racial and ethnic diversity and was highly educated with little functional impairment and no dementia. Therefore, results may not be generalizable to populations with lower educational attainment and/or preexisting mental and physical disabilities. A third limitation is that screen items were included in the reference standard delirium assessment, leading to a potential bias toward increased sensitivity. Finally, all screens were derived from secondary data analysis and further research will be needed to prospectively validate the results. Despite these limitations, this study has several strengths including the use of a well-characterized surgical population and a rigorous approach to delirium measurement. It is one of the first studies to identify a screening tool targeted to identifying delirium in postoperative older adults.

Future research should prospectively validate our screening tool and test its implementation in a real-world clinical environment. As part of this process, clinicians should document barriers and facilitators to widespread implementation. The goal of such screens is to facilitate early identification of postoperative delirium, which will allow timely intervention to address underlying causes and prevent adverse consequences, thereby improving the outcomes of vulnerable older surgical patients.

Delirium is the most common postsurgical complication for older adults, with incidence of 15%-54%, depending on surgery type.¹ Increasing numbers of older adults are undergoing surgery²; and those who develop delirium experience negative consequences including longer lengths of stay, higher likelihood of institutional discharge, and increased morbidity and mortality.³ The American Geriatrics Society Expert Panel on Postoperative Delirium in Older Adults and the European Society of Anaesthesiology⁴ recommend routine screening for delirium in those at risk.

Ultrabrief screens are designed to rule out delirium quickly and identify a subset of patients who require further testing.⁵ Our group, and others, have previously published ultrabrief screens for the general medicine, nonsurgical population and for patients with dementia.^5,6 The UB-2 is an ultrabrief screen consisting of “Months of the year backward” (MOYB) and “What day of the week is it?”, which has a sensitivity of 93% and specificity of 64% in hospitalized older adults and takes less than 40 seconds to administer.⁵ However, no such screens for delirium have been developed for the group with relatively high cognitive and physical functioning undergoing scheduled major surgery in which delirium may present differently. Thus, the purpose of this study was to develop an ultrabrief screen for postoperative delirium using data from a large study of delirium in cognitively intact, older adults undergoing scheduled major noncardiac surgery.

We performed a secondary data analysis on 560 patients enrolled between June 18, 2010, and August 8, 2013, in the Successful Aging After Elective Surgery (SAGES) study,⁷ an ongoing prospective cohort study of older adults undergoing major elective surgeries (eg, total hip or knee replacement; lumbar, cervical, or sacral laminectomy; lower extremity arterial bypass surgery; open abdominal aortic aneurysm repair; and open or laparoscopic colectomy). Exclusion criteria included evidence of dementia, delirium, prior hospitalization within 3 months, legal blindness, severe deafness, terminal condition, history of schizophrenia or psychosis, and history of alcohol abuse or withdrawal. The Institutional Review Boards of Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, and Hebrew SeniorLife, all in Boston, Massachusetts, approved the study.

SAGES Delirium Assessment and Additional Variables

The presence or absence of delirium was based on daily in-hospital assessments by trained research staff using the Confusion Assessment Method (CAM)⁸ long form. The Delirium Symptom Interview (DSI)⁹ and information related to acute changes in mental status were also included as provided by nursing staff and/or family. Delirium severity was determined using the CAM-S.¹⁰ Participants in The SAGES Study had an initial baseline, presurgical assessment in their homes. Cognitive and physical functioning, depression, comorbidities, laboratory, and self-reported demographic data were collected.

Statistical Analyses

We included CAM delirium data from postoperative days (POD) 1 and 2 for each participant, if available; postoperative day 0 was not included because of potential residual anesthetic effects. We chose these days because most delirium began on POD1 or 2, and patients started being discharged on POD3. We considered all one-, two-, and three-item combinations of the 12 cognitive items of the 3D-CAM¹¹ because of their demonstrated high information content for CAM diagnostic features per Item Response Theory.¹² There were 12 possible one-item screens, 66 two-item screens, and 220 three-item screens. Sensitivity, specificity, and 95% confidence intervals for each were compared with CAM delirium determination. An ideal ultrabrief screen for delirium has high sensitivity with moderate specificity; general guidelines considered based on investigator consensus included screens with a sensitivity higher than 0.90 and specificity greater than 0.70. Because these screens are used to quickly rule out delirium, we also present the percent positive screen among the entire population (whether delirium is present or not). Screens with a positive screen rate of more than 50% are unlikely to be helpful in ruling out delirium quickly in a large enough fraction of the population. We also required that in multiple item screens, no two items should assess the same CAM feature. For instance, we would eliminate a two-item screen with MOYB and four-digit span since both items measure CAM Feature 2 (Inattention). Finally, we evaluated screen performance separately on POD1 and POD2. Switching screens by POD can be confusing, so we chose a single best screen that retained excellent performance over both days. Data analyses used SAS version 9.4 (SAS Institute, Cary, North Carolina).

The dataset included 560 adults who had an average age of 76.6 years (SD = 5.2), were 58% women, and were highly educated (15.0 years; SD = 2.9; Table). Postoperative delirium occurred during one or more days in 134 individuals (24%). A total of 1,100 delirium assessments were used, with 113 that were CAM positive (10.3%). For POD1, we used 551 assessments, 61 of which were positive (11.1%); for POD2, 549 assessments were used, with 51 positive (9.3%). Appendix Tables present the positive screen rates, sensitivities, specificities, and 95% confidence intervals of all 12 one-item screens and the 12 best performing two- and three-item screens in order of decreasing sensitivity.

The best ultrabrief screen from POD1 included the following three items: “Does the patient report feeling confused?”, MOYB, and “Does the patient appear sleepy?”, with a sensitivity of 0.95 (95% CI, 0.87-0.99) and specificity of 0.73 (95% CI, 0.69-0.77). The same combination of items has a sensitivity of 0.88 (95% CI, 0.77-0.96) and a specificity of 0.70 (95% CI, 0.66-0.74) on POD2. When POD1 and POD2 are combined, the sensitivity is 0.92 (95% CI, 0.85-0.96) and specificity is 0.72 (95% CI, 0.69-0.74). We consider this to be our best screen overall.

We identified a three-item screen for delirium after elective surgery consisting of “Does the patient report feeling confused?”, MOYB, and “Does the patient appear sleepy?” In our own prior work, we identified a two-item screen consisting of MOYB and “What is the day of the week?” as the best ultrabrief screen for delirium in general medicine populations (termed the “UB-2”)⁵ and a subsequent screen for patients with delirium superimposed on dementia (DSD) including “What type of place is this?”, Days of the Week Backward, and “Does the patient appear sleepy?”⁶ All three contain a test of attention (a cardinal feature of delirium) and a test of orientation, although the specific test for that varies. Both the surgical and DSD screens include “Does the patient appear sleepy?”, which addresses a reduced level of consciousness. This might be particularly important in the postoperative setting because of residual effects of anesthesia and/or postoperative analgesic medications contributing to delirium. Work done by others confirms our current findings, which is that MOYB is the best single item for most groups. Belleli et al¹³ and Han et al¹⁴ included MOYB as the single attentional item in the 4AT and B-CAM, respectively. The Nu-DESC has been used as a screen in surgical patients; however, it involves only nursing observations and no direct questioning of the patient.¹⁵

The Figure describes how our “best screen” could be integrated into clinical care. One or more “positive” or incorrect responses on these three items constitutes a positive screen that should be further evaluated with the CAM or 3D-CAM. If all three items are correct or negative, this effectively rules out delirium; however, continued periodic screening on a daily (or per shift) basis is indicated. On repeat testing, if any of the previously negative or correct items becomes positive or incorrect, this would be evidence for Acute Change, CAM Feature 1. Finally, it should be noted that, if all three items in our best screen are positive, full CAM criteria for delirium diagnosis are met within the screen itself, and no further testing is required. We envision this process being facilitated by use of an app-based program that generates optimal screening items based on patient and setting characteristics.

There are several limitations that must be noted. First, our three-item screen may not generalize to nonsurgical candidates or those undergoing emergent surgery and should be tested in these groups. Second, the SAGES sample is relatively homogenous with respect to racial and ethnic diversity and was highly educated with little functional impairment and no dementia. Therefore, results may not be generalizable to populations with lower educational attainment and/or preexisting mental and physical disabilities. A third limitation is that screen items were included in the reference standard delirium assessment, leading to a potential bias toward increased sensitivity. Finally, all screens were derived from secondary data analysis and further research will be needed to prospectively validate the results. Despite these limitations, this study has several strengths including the use of a well-characterized surgical population and a rigorous approach to delirium measurement. It is one of the first studies to identify a screening tool targeted to identifying delirium in postoperative older adults.

Future research should prospectively validate our screening tool and test its implementation in a real-world clinical environment. As part of this process, clinicians should document barriers and facilitators to widespread implementation. The goal of such screens is to facilitate early identification of postoperative delirium, which will allow timely intervention to address underlying causes and prevent adverse consequences, thereby improving the outcomes of vulnerable older surgical patients.

Delirium is the most common postsurgical complication for older adults, with incidence of 15%-54%, depending on surgery type.¹ Increasing numbers of older adults are undergoing surgery²; and those who develop delirium experience negative consequences including longer lengths of stay, higher likelihood of institutional discharge, and increased morbidity and mortality.³ The American Geriatrics Society Expert Panel on Postoperative Delirium in Older Adults and the European Society of Anaesthesiology⁴ recommend routine screening for delirium in those at risk.

Ultrabrief screens are designed to rule out delirium quickly and identify a subset of patients who require further testing.⁵ Our group, and others, have previously published ultrabrief screens for the general medicine, nonsurgical population and for patients with dementia.^5,6 The UB-2 is an ultrabrief screen consisting of “Months of the year backward” (MOYB) and “What day of the week is it?”, which has a sensitivity of 93% and specificity of 64% in hospitalized older adults and takes less than 40 seconds to administer.⁵ However, no such screens for delirium have been developed for the group with relatively high cognitive and physical functioning undergoing scheduled major surgery in which delirium may present differently. Thus, the purpose of this study was to develop an ultrabrief screen for postoperative delirium using data from a large study of delirium in cognitively intact, older adults undergoing scheduled major noncardiac surgery.

We performed a secondary data analysis on 560 patients enrolled between June 18, 2010, and August 8, 2013, in the Successful Aging After Elective Surgery (SAGES) study,⁷ an ongoing prospective cohort study of older adults undergoing major elective surgeries (eg, total hip or knee replacement; lumbar, cervical, or sacral laminectomy; lower extremity arterial bypass surgery; open abdominal aortic aneurysm repair; and open or laparoscopic colectomy). Exclusion criteria included evidence of dementia, delirium, prior hospitalization within 3 months, legal blindness, severe deafness, terminal condition, history of schizophrenia or psychosis, and history of alcohol abuse or withdrawal. The Institutional Review Boards of Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, and Hebrew SeniorLife, all in Boston, Massachusetts, approved the study.

SAGES Delirium Assessment and Additional Variables

The presence or absence of delirium was based on daily in-hospital assessments by trained research staff using the Confusion Assessment Method (CAM)⁸ long form. The Delirium Symptom Interview (DSI)⁹ and information related to acute changes in mental status were also included as provided by nursing staff and/or family. Delirium severity was determined using the CAM-S.¹⁰ Participants in The SAGES Study had an initial baseline, presurgical assessment in their homes. Cognitive and physical functioning, depression, comorbidities, laboratory, and self-reported demographic data were collected.

Statistical Analyses

We included CAM delirium data from postoperative days (POD) 1 and 2 for each participant, if available; postoperative day 0 was not included because of potential residual anesthetic effects. We chose these days because most delirium began on POD1 or 2, and patients started being discharged on POD3. We considered all one-, two-, and three-item combinations of the 12 cognitive items of the 3D-CAM¹¹ because of their demonstrated high information content for CAM diagnostic features per Item Response Theory.¹² There were 12 possible one-item screens, 66 two-item screens, and 220 three-item screens. Sensitivity, specificity, and 95% confidence intervals for each were compared with CAM delirium determination. An ideal ultrabrief screen for delirium has high sensitivity with moderate specificity; general guidelines considered based on investigator consensus included screens with a sensitivity higher than 0.90 and specificity greater than 0.70. Because these screens are used to quickly rule out delirium, we also present the percent positive screen among the entire population (whether delirium is present or not). Screens with a positive screen rate of more than 50% are unlikely to be helpful in ruling out delirium quickly in a large enough fraction of the population. We also required that in multiple item screens, no two items should assess the same CAM feature. For instance, we would eliminate a two-item screen with MOYB and four-digit span since both items measure CAM Feature 2 (Inattention). Finally, we evaluated screen performance separately on POD1 and POD2. Switching screens by POD can be confusing, so we chose a single best screen that retained excellent performance over both days. Data analyses used SAS version 9.4 (SAS Institute, Cary, North Carolina).

The dataset included 560 adults who had an average age of 76.6 years (SD = 5.2), were 58% women, and were highly educated (15.0 years; SD = 2.9; Table). Postoperative delirium occurred during one or more days in 134 individuals (24%). A total of 1,100 delirium assessments were used, with 113 that were CAM positive (10.3%). For POD1, we used 551 assessments, 61 of which were positive (11.1%); for POD2, 549 assessments were used, with 51 positive (9.3%). Appendix Tables present the positive screen rates, sensitivities, specificities, and 95% confidence intervals of all 12 one-item screens and the 12 best performing two- and three-item screens in order of decreasing sensitivity.

The best ultrabrief screen from POD1 included the following three items: “Does the patient report feeling confused?”, MOYB, and “Does the patient appear sleepy?”, with a sensitivity of 0.95 (95% CI, 0.87-0.99) and specificity of 0.73 (95% CI, 0.69-0.77). The same combination of items has a sensitivity of 0.88 (95% CI, 0.77-0.96) and a specificity of 0.70 (95% CI, 0.66-0.74) on POD2. When POD1 and POD2 are combined, the sensitivity is 0.92 (95% CI, 0.85-0.96) and specificity is 0.72 (95% CI, 0.69-0.74). We consider this to be our best screen overall.

We identified a three-item screen for delirium after elective surgery consisting of “Does the patient report feeling confused?”, MOYB, and “Does the patient appear sleepy?” In our own prior work, we identified a two-item screen consisting of MOYB and “What is the day of the week?” as the best ultrabrief screen for delirium in general medicine populations (termed the “UB-2”)⁵ and a subsequent screen for patients with delirium superimposed on dementia (DSD) including “What type of place is this?”, Days of the Week Backward, and “Does the patient appear sleepy?”⁶ All three contain a test of attention (a cardinal feature of delirium) and a test of orientation, although the specific test for that varies. Both the surgical and DSD screens include “Does the patient appear sleepy?”, which addresses a reduced level of consciousness. This might be particularly important in the postoperative setting because of residual effects of anesthesia and/or postoperative analgesic medications contributing to delirium. Work done by others confirms our current findings, which is that MOYB is the best single item for most groups. Belleli et al¹³ and Han et al¹⁴ included MOYB as the single attentional item in the 4AT and B-CAM, respectively. The Nu-DESC has been used as a screen in surgical patients; however, it involves only nursing observations and no direct questioning of the patient.¹⁵

The Figure describes how our “best screen” could be integrated into clinical care. One or more “positive” or incorrect responses on these three items constitutes a positive screen that should be further evaluated with the CAM or 3D-CAM. If all three items are correct or negative, this effectively rules out delirium; however, continued periodic screening on a daily (or per shift) basis is indicated. On repeat testing, if any of the previously negative or correct items becomes positive or incorrect, this would be evidence for Acute Change, CAM Feature 1. Finally, it should be noted that, if all three items in our best screen are positive, full CAM criteria for delirium diagnosis are met within the screen itself, and no further testing is required. We envision this process being facilitated by use of an app-based program that generates optimal screening items based on patient and setting characteristics.

There are several limitations that must be noted. First, our three-item screen may not generalize to nonsurgical candidates or those undergoing emergent surgery and should be tested in these groups. Second, the SAGES sample is relatively homogenous with respect to racial and ethnic diversity and was highly educated with little functional impairment and no dementia. Therefore, results may not be generalizable to populations with lower educational attainment and/or preexisting mental and physical disabilities. A third limitation is that screen items were included in the reference standard delirium assessment, leading to a potential bias toward increased sensitivity. Finally, all screens were derived from secondary data analysis and further research will be needed to prospectively validate the results. Despite these limitations, this study has several strengths including the use of a well-characterized surgical population and a rigorous approach to delirium measurement. It is one of the first studies to identify a screening tool targeted to identifying delirium in postoperative older adults.

Future research should prospectively validate our screening tool and test its implementation in a real-world clinical environment. As part of this process, clinicians should document barriers and facilitators to widespread implementation. The goal of such screens is to facilitate early identification of postoperative delirium, which will allow timely intervention to address underlying causes and prevent adverse consequences, thereby improving the outcomes of vulnerable older surgical patients.

Reduction in serious pediatric medical errors has been achieved through sharing of best practices and structured collaboration.¹ However, limited progress has been made in reducing complex, multifactorial events such as unrecognized and undertreated patient deterioration events.² To address this critical gap, interventions to improve clinician situation awareness (SA) have increasingly been applied.³

SA is the ability to recognize and monitor cues regarding what is happening, create a comprehensive picture with available information, and extrapolate whether it indicates adverse developments either immediately or in the near future.⁴ Methods such as care team huddling^5-8 and using standardized patient acuity scoring instruments⁹ increase SA shared across care team roles. Shared SA is the degree to which each team member possesses a common understanding of what is going on. A team is considered to have shared SA when all the individuals agree on both what is happening (accurate perception and comprehension) and what is going to happen in the future (correct projection). Shared SA for high-risk patients in the pediatric intensive care unit (PICU) has not previously been described and may be an opportunity to improve interprofessional team communication for the sickest patients. Shared SA for high-risk patient status is only one aspect of SA, but it facilitates team-based mitigation planning and is an important starting place for understanding opportunities to improve SA. The primary objective of this study was to measure and compare SA among care team roles regarding patients with high-risk status in the PICU.

We conducted a prospective, cross-sectional study from March 2018 to July 2019 examining the individual and shared SA of patient care team trios: the nurse, respiratory therapist (RT), and pediatric resident. The Institutional Review Board at Cincinnati Children’s Hospital Medical Center (CCHMC) determined this study to be non–human-subjects research.

Setting

Research was conducted in the 35-bed PICU of CCHMC, a 500-bed academic free-standing quaternary care children’s hospital.

Participants

We conducted independent surveys of the nurse, RT, and pediatric resident (care team trio) caring for each patient regarding the patient’s clinical deterioration risk status. No patients or care team trios were excluded.

Reference Standard

In 2016, a local panel of experts derived clinical criteria to determine high-risk status for PICU patients, the definition of which, as well as other study terms, appears in Table 1. A PICU attending or fellow identifies a patient as “high risk” when these clinical criteria are met. A plan for prevention and mitigation is formulated and documented for high-risk patients by the PICU attending or fellow at two preexisting daily SA huddles. This plan includes prevention measures to take immediately, specific vital sign thresholds for early identification of deterioration, and guidance on which emergency medication order sets should be utilized to expedite treatment in the event of clinical decline. Dissemination of the care team’s plan is the responsibility of the PICU fellow with additional follow-up by the charge nurse to improve reliability. Identification of high-risk status and development of the prevention and mitigation plan, as completed by the PICU fellow or attending, served as the reference standard for this study.

Survey Instrument Development

The locally developed survey tool was modeled after a validated handoff communication instrument.¹⁰ The tool covered the patient’s risk status, which high-risk clinical criteria were met, the presence and content of a mitigation plan, and planned patient interventions (Appendix).

Data Collection

Care team trios were sampled weekly on weekdays during day and night shifts within 4 to 6 hours of the SA huddle by a core group of three research assistants. Care team trios for one group of five to nine patients within a small geographically isolated pod were surveyed each time. The care team trio was surveyed individually regarding the patient’s risk status, the high-risk clinical criteria met, the presence and content of a mitigation plan, and planned patient interventions. The responses were compared for accuracy against the reference standard, which was defined as identification of high-risk patient status and development of the prevention and mitigation plan as completed by the PICU fellow or attending.

Data Analysis

Rates of agreement between the reference standard and individual members of the care team trio were evaluated via a calculation of proportions by care team role. The agreement between each care team trio member and the reference standard was compared with the nurse role performance using chi-square tests. Rates of concordance within the members of the care team trio were calculated via Light’s kappa for determination of high-risk status.¹¹ Assuming a correct assessment of high-risk status of 62%,¹² with a difference between groups of 10%, a sample size of 400 bedside provider trios gives a power of 85% at the P < .05 significance level for a two-sided chi-square test.

Between March 1, 2018, and July 11, 2019, 400 care team trios were surveyed. Seventy-three trios cared for patients designated high risk (Table 2 for N and proportions). Among all surveyed trios, 94% of nurses (reference), 95% of RTs (P = .4), and 87% of residents (P = .002) identified patient’s risk status correctly. Care trio member concordance for high-risk status was moderate agreement as assessed by a kappa of 0.57 (95% CI, 0.25-0.90).

Of the 73 high-risk patients, nurses correctly identified risk status for 82% (reference), RTs 85% (P = .7), and residents 67% (P = .04). For high-risk patients, nurses identified the presence of a mitigation plan for 98% of patients (reference), RTs 90% (P = .06), and residents 88% (P = .03). Among the care team members who correctly identified the presence of a mitigation plan, nurses were able to specify the correct plan for 83% of patients (reference), RTs for 68% (P = .09), and residents for 70% (P = .11; Figure).

When shared SA for high-risk patients was examined more closely, all three care team roles correctly identified the clinical reason for high-risk status for 32% of patients, with only one or two clinicians being correct for 53%. All three care team clinicians were incorrect for 15% of high-risk patients. Among trios with partial accuracy in which two of three care team members correctly identified a patient as high risk, we examined which care-member was most likely to be incorrect. Nurses incorrectly identified risk for 17% of patients (reference), RTs 19% (P = .8), and residents 64% (P < .0001).

Examining 400 care team trios, we found lower individual SA for residents, compared with nurses, regarding high-risk status, the reason for this status, and the presence of a mitigation plan. In all reported measures except for the content of mitigation plans, residents were significantly less correct than the bedside nurses while RTs performed similarly to bedside nurses throughout. In addition, there was only moderate agreement between care team roles, which shows further opportunities for improvement in shared SA. The disparities between care team roles are consistent with studies that suggest certain factors grounded in institutional culture and interpersonal dynamics, such as poor communication, can lead to breakdowns in shared knowledge.^13,14 Communication issues demonstrate differences across care team roles¹⁴ and may provide insight into barriers to individual and shared SA throughout the care team.

In addition, the effects of patient load on SA needs further study. While our PICU nurses are commonly assigned to 1 to 2 patients, RTs care for 7 to 11 patients, and an on-call resident may be covering 15 to 20 patients during a high-census season. The increased patient load cannot serve as an excuse for the knowledge gap regarding high-risk status and mitigation plan, but may provide an opportunity to support residents and other medical providers through the use of clinical decision-­support tools that indicate high-risk status and represent mitigation plans.¹²

This study has multiple limitations. First, while we based our survey tool on a communication assessment tool with prior validity evidence,^10,12 our tool has not been used prior to this study. The adapted tool contained relevant categorizations of patient information, including explicit statement of patient status and planned treatment consistent with study definitions of SA, and has been used in the critical care setting previously.¹¹ The survey tool used to measure SA in this study was locally designed and implemented only within the study unit, which could lead to decreased reliability and generalizability of the results to other units and institutions at large. Second, while the sample size for the primary measure (N = 400) was adequately powered because our baseline SA was higher than estimated, we had insufficient power for some subgroup analyses that can lead to type II errors. Third, care team trios may have been surveyed repeatedly on the same patient without adjustment in the results for repeated measures. However, as we surveyed on average only once a week and alternated areas of the PICU surveyed, it is unlikely that it affected results given that the most lengths of stay within the PICU range from 3 to 4 days. Finally, individual characteristics of patients were not collected for this work, and therefore, no adjustments or further analysis can be made on the effect of the patient characteristic on the care team role SA.

This study is the first to assess differences in individual and shared SA within a PICU by care team role. Efforts to expand on these findings should include investigation into the causes for the disparities in SA among care team roles for individual patients and among the care teams of high-risk and normal-risk patients. Given the association between increased SA and improved patient outcomes,⁴ future efforts should be structured to address care team role–specific gaps in SA because these may advance the quality of care in the pediatric inpatient setting.

Reduction in serious pediatric medical errors has been achieved through sharing of best practices and structured collaboration.¹ However, limited progress has been made in reducing complex, multifactorial events such as unrecognized and undertreated patient deterioration events.² To address this critical gap, interventions to improve clinician situation awareness (SA) have increasingly been applied.³

SA is the ability to recognize and monitor cues regarding what is happening, create a comprehensive picture with available information, and extrapolate whether it indicates adverse developments either immediately or in the near future.⁴ Methods such as care team huddling^5-8 and using standardized patient acuity scoring instruments⁹ increase SA shared across care team roles. Shared SA is the degree to which each team member possesses a common understanding of what is going on. A team is considered to have shared SA when all the individuals agree on both what is happening (accurate perception and comprehension) and what is going to happen in the future (correct projection). Shared SA for high-risk patients in the pediatric intensive care unit (PICU) has not previously been described and may be an opportunity to improve interprofessional team communication for the sickest patients. Shared SA for high-risk patient status is only one aspect of SA, but it facilitates team-based mitigation planning and is an important starting place for understanding opportunities to improve SA. The primary objective of this study was to measure and compare SA among care team roles regarding patients with high-risk status in the PICU.

We conducted a prospective, cross-sectional study from March 2018 to July 2019 examining the individual and shared SA of patient care team trios: the nurse, respiratory therapist (RT), and pediatric resident. The Institutional Review Board at Cincinnati Children’s Hospital Medical Center (CCHMC) determined this study to be non–human-subjects research.

Setting

Research was conducted in the 35-bed PICU of CCHMC, a 500-bed academic free-standing quaternary care children’s hospital.

Participants

We conducted independent surveys of the nurse, RT, and pediatric resident (care team trio) caring for each patient regarding the patient’s clinical deterioration risk status. No patients or care team trios were excluded.

Reference Standard

In 2016, a local panel of experts derived clinical criteria to determine high-risk status for PICU patients, the definition of which, as well as other study terms, appears in Table 1. A PICU attending or fellow identifies a patient as “high risk” when these clinical criteria are met. A plan for prevention and mitigation is formulated and documented for high-risk patients by the PICU attending or fellow at two preexisting daily SA huddles. This plan includes prevention measures to take immediately, specific vital sign thresholds for early identification of deterioration, and guidance on which emergency medication order sets should be utilized to expedite treatment in the event of clinical decline. Dissemination of the care team’s plan is the responsibility of the PICU fellow with additional follow-up by the charge nurse to improve reliability. Identification of high-risk status and development of the prevention and mitigation plan, as completed by the PICU fellow or attending, served as the reference standard for this study.

Survey Instrument Development

The locally developed survey tool was modeled after a validated handoff communication instrument.¹⁰ The tool covered the patient’s risk status, which high-risk clinical criteria were met, the presence and content of a mitigation plan, and planned patient interventions (Appendix).

Data Collection

Care team trios were sampled weekly on weekdays during day and night shifts within 4 to 6 hours of the SA huddle by a core group of three research assistants. Care team trios for one group of five to nine patients within a small geographically isolated pod were surveyed each time. The care team trio was surveyed individually regarding the patient’s risk status, the high-risk clinical criteria met, the presence and content of a mitigation plan, and planned patient interventions. The responses were compared for accuracy against the reference standard, which was defined as identification of high-risk patient status and development of the prevention and mitigation plan as completed by the PICU fellow or attending.

Data Analysis

Rates of agreement between the reference standard and individual members of the care team trio were evaluated via a calculation of proportions by care team role. The agreement between each care team trio member and the reference standard was compared with the nurse role performance using chi-square tests. Rates of concordance within the members of the care team trio were calculated via Light’s kappa for determination of high-risk status.¹¹ Assuming a correct assessment of high-risk status of 62%,¹² with a difference between groups of 10%, a sample size of 400 bedside provider trios gives a power of 85% at the P < .05 significance level for a two-sided chi-square test.

Between March 1, 2018, and July 11, 2019, 400 care team trios were surveyed. Seventy-three trios cared for patients designated high risk (Table 2 for N and proportions). Among all surveyed trios, 94% of nurses (reference), 95% of RTs (P = .4), and 87% of residents (P = .002) identified patient’s risk status correctly. Care trio member concordance for high-risk status was moderate agreement as assessed by a kappa of 0.57 (95% CI, 0.25-0.90).

Of the 73 high-risk patients, nurses correctly identified risk status for 82% (reference), RTs 85% (P = .7), and residents 67% (P = .04). For high-risk patients, nurses identified the presence of a mitigation plan for 98% of patients (reference), RTs 90% (P = .06), and residents 88% (P = .03). Among the care team members who correctly identified the presence of a mitigation plan, nurses were able to specify the correct plan for 83% of patients (reference), RTs for 68% (P = .09), and residents for 70% (P = .11; Figure).

When shared SA for high-risk patients was examined more closely, all three care team roles correctly identified the clinical reason for high-risk status for 32% of patients, with only one or two clinicians being correct for 53%. All three care team clinicians were incorrect for 15% of high-risk patients. Among trios with partial accuracy in which two of three care team members correctly identified a patient as high risk, we examined which care-member was most likely to be incorrect. Nurses incorrectly identified risk for 17% of patients (reference), RTs 19% (P = .8), and residents 64% (P < .0001).

Examining 400 care team trios, we found lower individual SA for residents, compared with nurses, regarding high-risk status, the reason for this status, and the presence of a mitigation plan. In all reported measures except for the content of mitigation plans, residents were significantly less correct than the bedside nurses while RTs performed similarly to bedside nurses throughout. In addition, there was only moderate agreement between care team roles, which shows further opportunities for improvement in shared SA. The disparities between care team roles are consistent with studies that suggest certain factors grounded in institutional culture and interpersonal dynamics, such as poor communication, can lead to breakdowns in shared knowledge.^13,14 Communication issues demonstrate differences across care team roles¹⁴ and may provide insight into barriers to individual and shared SA throughout the care team.

In addition, the effects of patient load on SA needs further study. While our PICU nurses are commonly assigned to 1 to 2 patients, RTs care for 7 to 11 patients, and an on-call resident may be covering 15 to 20 patients during a high-census season. The increased patient load cannot serve as an excuse for the knowledge gap regarding high-risk status and mitigation plan, but may provide an opportunity to support residents and other medical providers through the use of clinical decision-­support tools that indicate high-risk status and represent mitigation plans.¹²

This study has multiple limitations. First, while we based our survey tool on a communication assessment tool with prior validity evidence,^10,12 our tool has not been used prior to this study. The adapted tool contained relevant categorizations of patient information, including explicit statement of patient status and planned treatment consistent with study definitions of SA, and has been used in the critical care setting previously.¹¹ The survey tool used to measure SA in this study was locally designed and implemented only within the study unit, which could lead to decreased reliability and generalizability of the results to other units and institutions at large. Second, while the sample size for the primary measure (N = 400) was adequately powered because our baseline SA was higher than estimated, we had insufficient power for some subgroup analyses that can lead to type II errors. Third, care team trios may have been surveyed repeatedly on the same patient without adjustment in the results for repeated measures. However, as we surveyed on average only once a week and alternated areas of the PICU surveyed, it is unlikely that it affected results given that the most lengths of stay within the PICU range from 3 to 4 days. Finally, individual characteristics of patients were not collected for this work, and therefore, no adjustments or further analysis can be made on the effect of the patient characteristic on the care team role SA.

This study is the first to assess differences in individual and shared SA within a PICU by care team role. Efforts to expand on these findings should include investigation into the causes for the disparities in SA among care team roles for individual patients and among the care teams of high-risk and normal-risk patients. Given the association between increased SA and improved patient outcomes,⁴ future efforts should be structured to address care team role–specific gaps in SA because these may advance the quality of care in the pediatric inpatient setting.

Reduction in serious pediatric medical errors has been achieved through sharing of best practices and structured collaboration.¹ However, limited progress has been made in reducing complex, multifactorial events such as unrecognized and undertreated patient deterioration events.² To address this critical gap, interventions to improve clinician situation awareness (SA) have increasingly been applied.³

SA is the ability to recognize and monitor cues regarding what is happening, create a comprehensive picture with available information, and extrapolate whether it indicates adverse developments either immediately or in the near future.⁴ Methods such as care team huddling^5-8 and using standardized patient acuity scoring instruments⁹ increase SA shared across care team roles. Shared SA is the degree to which each team member possesses a common understanding of what is going on. A team is considered to have shared SA when all the individuals agree on both what is happening (accurate perception and comprehension) and what is going to happen in the future (correct projection). Shared SA for high-risk patients in the pediatric intensive care unit (PICU) has not previously been described and may be an opportunity to improve interprofessional team communication for the sickest patients. Shared SA for high-risk patient status is only one aspect of SA, but it facilitates team-based mitigation planning and is an important starting place for understanding opportunities to improve SA. The primary objective of this study was to measure and compare SA among care team roles regarding patients with high-risk status in the PICU.

We conducted a prospective, cross-sectional study from March 2018 to July 2019 examining the individual and shared SA of patient care team trios: the nurse, respiratory therapist (RT), and pediatric resident. The Institutional Review Board at Cincinnati Children’s Hospital Medical Center (CCHMC) determined this study to be non–human-subjects research.

Setting

Research was conducted in the 35-bed PICU of CCHMC, a 500-bed academic free-standing quaternary care children’s hospital.

Participants

We conducted independent surveys of the nurse, RT, and pediatric resident (care team trio) caring for each patient regarding the patient’s clinical deterioration risk status. No patients or care team trios were excluded.

Reference Standard

In 2016, a local panel of experts derived clinical criteria to determine high-risk status for PICU patients, the definition of which, as well as other study terms, appears in Table 1. A PICU attending or fellow identifies a patient as “high risk” when these clinical criteria are met. A plan for prevention and mitigation is formulated and documented for high-risk patients by the PICU attending or fellow at two preexisting daily SA huddles. This plan includes prevention measures to take immediately, specific vital sign thresholds for early identification of deterioration, and guidance on which emergency medication order sets should be utilized to expedite treatment in the event of clinical decline. Dissemination of the care team’s plan is the responsibility of the PICU fellow with additional follow-up by the charge nurse to improve reliability. Identification of high-risk status and development of the prevention and mitigation plan, as completed by the PICU fellow or attending, served as the reference standard for this study.

Survey Instrument Development

The locally developed survey tool was modeled after a validated handoff communication instrument.¹⁰ The tool covered the patient’s risk status, which high-risk clinical criteria were met, the presence and content of a mitigation plan, and planned patient interventions (Appendix).

Data Collection

Care team trios were sampled weekly on weekdays during day and night shifts within 4 to 6 hours of the SA huddle by a core group of three research assistants. Care team trios for one group of five to nine patients within a small geographically isolated pod were surveyed each time. The care team trio was surveyed individually regarding the patient’s risk status, the high-risk clinical criteria met, the presence and content of a mitigation plan, and planned patient interventions. The responses were compared for accuracy against the reference standard, which was defined as identification of high-risk patient status and development of the prevention and mitigation plan as completed by the PICU fellow or attending.

Data Analysis

Rates of agreement between the reference standard and individual members of the care team trio were evaluated via a calculation of proportions by care team role. The agreement between each care team trio member and the reference standard was compared with the nurse role performance using chi-square tests. Rates of concordance within the members of the care team trio were calculated via Light’s kappa for determination of high-risk status.¹¹ Assuming a correct assessment of high-risk status of 62%,¹² with a difference between groups of 10%, a sample size of 400 bedside provider trios gives a power of 85% at the P < .05 significance level for a two-sided chi-square test.

Between March 1, 2018, and July 11, 2019, 400 care team trios were surveyed. Seventy-three trios cared for patients designated high risk (Table 2 for N and proportions). Among all surveyed trios, 94% of nurses (reference), 95% of RTs (P = .4), and 87% of residents (P = .002) identified patient’s risk status correctly. Care trio member concordance for high-risk status was moderate agreement as assessed by a kappa of 0.57 (95% CI, 0.25-0.90).

Of the 73 high-risk patients, nurses correctly identified risk status for 82% (reference), RTs 85% (P = .7), and residents 67% (P = .04). For high-risk patients, nurses identified the presence of a mitigation plan for 98% of patients (reference), RTs 90% (P = .06), and residents 88% (P = .03). Among the care team members who correctly identified the presence of a mitigation plan, nurses were able to specify the correct plan for 83% of patients (reference), RTs for 68% (P = .09), and residents for 70% (P = .11; Figure).

When shared SA for high-risk patients was examined more closely, all three care team roles correctly identified the clinical reason for high-risk status for 32% of patients, with only one or two clinicians being correct for 53%. All three care team clinicians were incorrect for 15% of high-risk patients. Among trios with partial accuracy in which two of three care team members correctly identified a patient as high risk, we examined which care-member was most likely to be incorrect. Nurses incorrectly identified risk for 17% of patients (reference), RTs 19% (P = .8), and residents 64% (P < .0001).

Examining 400 care team trios, we found lower individual SA for residents, compared with nurses, regarding high-risk status, the reason for this status, and the presence of a mitigation plan. In all reported measures except for the content of mitigation plans, residents were significantly less correct than the bedside nurses while RTs performed similarly to bedside nurses throughout. In addition, there was only moderate agreement between care team roles, which shows further opportunities for improvement in shared SA. The disparities between care team roles are consistent with studies that suggest certain factors grounded in institutional culture and interpersonal dynamics, such as poor communication, can lead to breakdowns in shared knowledge.^13,14 Communication issues demonstrate differences across care team roles¹⁴ and may provide insight into barriers to individual and shared SA throughout the care team.

In addition, the effects of patient load on SA needs further study. While our PICU nurses are commonly assigned to 1 to 2 patients, RTs care for 7 to 11 patients, and an on-call resident may be covering 15 to 20 patients during a high-census season. The increased patient load cannot serve as an excuse for the knowledge gap regarding high-risk status and mitigation plan, but may provide an opportunity to support residents and other medical providers through the use of clinical decision-­support tools that indicate high-risk status and represent mitigation plans.¹²

This study has multiple limitations. First, while we based our survey tool on a communication assessment tool with prior validity evidence,^10,12 our tool has not been used prior to this study. The adapted tool contained relevant categorizations of patient information, including explicit statement of patient status and planned treatment consistent with study definitions of SA, and has been used in the critical care setting previously.¹¹ The survey tool used to measure SA in this study was locally designed and implemented only within the study unit, which could lead to decreased reliability and generalizability of the results to other units and institutions at large. Second, while the sample size for the primary measure (N = 400) was adequately powered because our baseline SA was higher than estimated, we had insufficient power for some subgroup analyses that can lead to type II errors. Third, care team trios may have been surveyed repeatedly on the same patient without adjustment in the results for repeated measures. However, as we surveyed on average only once a week and alternated areas of the PICU surveyed, it is unlikely that it affected results given that the most lengths of stay within the PICU range from 3 to 4 days. Finally, individual characteristics of patients were not collected for this work, and therefore, no adjustments or further analysis can be made on the effect of the patient characteristic on the care team role SA.

This study is the first to assess differences in individual and shared SA within a PICU by care team role. Efforts to expand on these findings should include investigation into the causes for the disparities in SA among care team roles for individual patients and among the care teams of high-risk and normal-risk patients. Given the association between increased SA and improved patient outcomes,⁴ future efforts should be structured to address care team role–specific gaps in SA because these may advance the quality of care in the pediatric inpatient setting.

Community-acquired pneumonia (CAP) is the second most common cause of hospitalization in the United States, with over 1.5 million unique hospitalizations annually.¹ CAP is also the most common infectious cause of death in US adults.² The 2019 CAP guideline from the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) provides recommendations on the diagnosis and management of CAP. The guideline provides 16 recommendations, which we have consolidated to highlight practice changing updates in diagnostic testing, risk stratification, and treatment.

Diagnostic Testing

Recommendation 1. In patients with CAP, routine blood cultures, sputum cultures, and urinary antigen tests are not routinely recommended unless severe CAP (Table), history of methicillin-resistant Staphylococcus aureus (MRSA) and/or Pseudomonas infection, or prior hospitalization for which intravenous antibiotics were administered. (Strong recommendation; very low quality of evidence)

The guideline emphasizes that the diagnostic yield of blood/sputum cultures and urinary antigen testing is low. Additionally, high-quality data showing improved clinical outcomes with routine testing of blood cultures and urinary antigens are lacking. Instead, the guideline suggests obtaining blood cultures, urinary antigens, and sputum gram stain and culture only for patients with severe CAP and those being treated for or having prior infection with MRSA or P aeruginosa. They recommend narrowing therapy as appropriate if cultures are negative for either of these two organisms or previous hospitalization with intravenous antibiotics.

Recommendation 2. In patients with CAP, Pneumonia Severity Index (PSI) or CURB-65 (tool based on confusion, urea level, respiratory rate, blood pressure, and age 65 years or older) scores should not be used to determine general medical ward vs intensive care unit care (ICU). (Strong recommendation; low quality of evidence)

The PSI and CURB-65 scores are not validated to determine location of hospital care. Multiple prognostic models have been studied to predict the need for ICU-level care including SMART-COP (systolic blood pressure, multilobar chest radiography involvement, albumin level, respiratory rate, tachycardia, confusion, oxygenation, and arterial pH), SCAPA (Study of Community Acquired Pneumonia Aetiology), and the ATS/IDSA criteria (Table). The positive and negative likelihood ratios for needing ICU admission in CAP with either one major or three or more minor ATS/IDSA criteria are 3.28 and 0.21, respectively.

Treatment

Recommendation 3a. In patients with nonsevere CAP and no risk factors for MRSA or Pseudomonas infection, empiric treatment with a ß-lactam plus macrolide or monotherapy with fluoroquinolones is recommended. (Strong recommendation; high quality of evidence)

Recommendation 3b. In patients with severe CAP and no risk factors for MRSA or Pseudomonas infection, empiric treatment with a ß-lactam plus either a macrolide or fluoroquinolone is recommended. (Strong recommendation; low to moderate quality of evidence)

Microbiologic risk assessment is critical. Risk factors for MRSA or P aeruginosa pneumonia include isolation of these agents in culture and recent hospitalization with receipt of parenteral antibiotics. ß-Lactam monotherapy is not recommended because previous randomized clinical trials (RCTs) demonstrated inferiority of ß-lactam monotherapy to combination therapy for resolution of CAP. The recommended combination therapy for patients with severe CAP without risk factors for MRSA or P aeruginosa infection is a ß-lactam plus either a macrolide or a respiratory fluoroquinolone.

Recommendation 4. In patients with suspected aspiration pneumonia, additional anaerobic coverage is not routinely recommended. (Conditional recommendation; very low quality of evidence)

Aspiration often causes a self-limited pneumonitis that will resolve in 24 to 48 hours with supportive care. Use of additional anaerobic coverage in these patients increases risk for complications (eg, Clostridioides difficile infection) without improving outcomes.

Recommendation 5. In patients with nonsevere CAP, corticosteroids are not routinely recommended. (Conditional recommendation; moderate quality of evidence)

There is no direct evidence that steroids reduce mortality or organ failure in nonsevere CAP. Additionally, the use of steroids in CAP can come with considerable risks (eg, secondary infection, hyperglycemia).

Recommendation 6. In hospitalized patients with CAP, empiric coverage for MRSA or P aeruginosa should be limited to patients meeting specific criteria. (Strong recommendation; moderate quality of evidence)

The guideline highlights the current overuse of extended spectrum antibiotics in patients meeting the previous definition of healthcare-associated pneumonia (HCAP). HCAP was defined by the presence of new chest x-ray infiltrates in patients with various exposures to healthcare settings (eg, chronic dialysis, infusion centers, emergency rooms). Antimicrobial therapy covering MRSA or P aeruginosa should be reserved for patients at risk for MRSA or P aeruginosa infection unless microbiologic testing is negative. Empiric antibiotic selection should incorporate local resistance patterns guided by hospital antibiograms.

Recommendation 7. In adults with CAP, antibiotics should be continued for no less than 5 days with documented clinical stability. (Strong recommendation; moderate quality of evidence)

Hospitalists often determine the length of antibiotic therapy for CAP. Recent studies show extended antibiotic treatment for pneumonia increases risk for adverse events without improving outcomes. Studies also demonstrate patients who receive 5 days of antibiotics total after achieving clinical stability by day 3 do no worse than patients receiving 8 or more days of antibiotics.

This guideline was created by a panel of pulmonologists, infectious disease specialists, general internists, and methodologists using the GRADE (Grading of Recommendations Assessment, Development and Evaluations) approach to draft recommendations. Conflicts of interest were disclosed by all panel members according to the ATS and IDSA policies, and ultimately, two panel members recused themselves owing to conflicts of interest. The inclusion of a large number of RCTs, observational studies, and meta-analyses provides for good generalizability of the guideline published by this group.

Equal support was given in the guideline to all ß-lactams listed, including ampicillin/sulbactam, cefotaxime, ceftriaxone, and ceftaroline, regardless of MRSA risk factors. As the authors explicitly state in the guideline, one of the major reasons for abandoning the HCAP classification was to correct the overuse of anti-MRSA and antipseudomonal therapy.³ It is surprising, then, that the authors would include ceftaroline, a broad-spectrum cephalosporin that covers MRSA, as first-line therapy for patients without risk factors for MRSA.

The guideline also supported the use of a respiratory fluoroquinolone or a ß-lactam with macrolide equally. Although most RCTs have found equal efficacy between these two regimens,⁴ there is growing concern about the safety of fluoroquinolones.⁵ While the authors do encourage clinicians to consider these side effects in the main body of the text, a stronger statement could have been made more prominently to warn clinicians of safety concerns with fluoroquinolones.

Finally, while monotherapy with a ß-lactam was supported for the treatment of nonsevere outpatient CAP, it was not included in the recommendations for the treatment of hospitalized patients. There is conflicting data on this topic. One RCT failed to show noninferiority of monotherapy, but this was most pronounced among patients with severe pneumonia (PSI category IV) or cases with proven atypical infections.⁶ Another RCT found monotherapy to be noninferior to combination therapy for hospitalized patients not admitted to the ICU.⁷ There is also evidence suggesting that many patients hospitalized with pneumonia have viral rather than bacterial infections,⁸ which brings into question the need for antibiotics in this subset entirely. When these findings are considered from a stewardship perspective and patient safety profile, monotherapy with a ß-lactam for hospitalized patients without severe pneumonia could have been considered.

Future research should track the effects of this guideline’s recommendation to narrow empiric therapy on patients empirically treated for MRSA or P aeruginosa infection once sputum and blood cultures are negative, particularly with respect to reduction of time on broad spectrum antimicrobials and clinical outcomes. Similarly, better definitions of which patients require empiric MRSA and P aeruginosa antimicrobial coverage are needed. Ideally, further research will facilitate rapid, cost-­effective, and individualized therapy, particularly with growing concerns for antimicrobial resistance and safety.

The authors have no relevant financial conflicts of interest to disclose.

Community-acquired pneumonia (CAP) is the second most common cause of hospitalization in the United States, with over 1.5 million unique hospitalizations annually.¹ CAP is also the most common infectious cause of death in US adults.² The 2019 CAP guideline from the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) provides recommendations on the diagnosis and management of CAP. The guideline provides 16 recommendations, which we have consolidated to highlight practice changing updates in diagnostic testing, risk stratification, and treatment.

Diagnostic Testing

Recommendation 1. In patients with CAP, routine blood cultures, sputum cultures, and urinary antigen tests are not routinely recommended unless severe CAP (Table), history of methicillin-resistant Staphylococcus aureus (MRSA) and/or Pseudomonas infection, or prior hospitalization for which intravenous antibiotics were administered. (Strong recommendation; very low quality of evidence)

The guideline emphasizes that the diagnostic yield of blood/sputum cultures and urinary antigen testing is low. Additionally, high-quality data showing improved clinical outcomes with routine testing of blood cultures and urinary antigens are lacking. Instead, the guideline suggests obtaining blood cultures, urinary antigens, and sputum gram stain and culture only for patients with severe CAP and those being treated for or having prior infection with MRSA or P aeruginosa. They recommend narrowing therapy as appropriate if cultures are negative for either of these two organisms or previous hospitalization with intravenous antibiotics.

Recommendation 2. In patients with CAP, Pneumonia Severity Index (PSI) or CURB-65 (tool based on confusion, urea level, respiratory rate, blood pressure, and age 65 years or older) scores should not be used to determine general medical ward vs intensive care unit care (ICU). (Strong recommendation; low quality of evidence)

The PSI and CURB-65 scores are not validated to determine location of hospital care. Multiple prognostic models have been studied to predict the need for ICU-level care including SMART-COP (systolic blood pressure, multilobar chest radiography involvement, albumin level, respiratory rate, tachycardia, confusion, oxygenation, and arterial pH), SCAPA (Study of Community Acquired Pneumonia Aetiology), and the ATS/IDSA criteria (Table). The positive and negative likelihood ratios for needing ICU admission in CAP with either one major or three or more minor ATS/IDSA criteria are 3.28 and 0.21, respectively.

Treatment

Recommendation 3a. In patients with nonsevere CAP and no risk factors for MRSA or Pseudomonas infection, empiric treatment with a ß-lactam plus macrolide or monotherapy with fluoroquinolones is recommended. (Strong recommendation; high quality of evidence)

Recommendation 3b. In patients with severe CAP and no risk factors for MRSA or Pseudomonas infection, empiric treatment with a ß-lactam plus either a macrolide or fluoroquinolone is recommended. (Strong recommendation; low to moderate quality of evidence)

Microbiologic risk assessment is critical. Risk factors for MRSA or P aeruginosa pneumonia include isolation of these agents in culture and recent hospitalization with receipt of parenteral antibiotics. ß-Lactam monotherapy is not recommended because previous randomized clinical trials (RCTs) demonstrated inferiority of ß-lactam monotherapy to combination therapy for resolution of CAP. The recommended combination therapy for patients with severe CAP without risk factors for MRSA or P aeruginosa infection is a ß-lactam plus either a macrolide or a respiratory fluoroquinolone.

Recommendation 4. In patients with suspected aspiration pneumonia, additional anaerobic coverage is not routinely recommended. (Conditional recommendation; very low quality of evidence)

Aspiration often causes a self-limited pneumonitis that will resolve in 24 to 48 hours with supportive care. Use of additional anaerobic coverage in these patients increases risk for complications (eg, Clostridioides difficile infection) without improving outcomes.

Recommendation 5. In patients with nonsevere CAP, corticosteroids are not routinely recommended. (Conditional recommendation; moderate quality of evidence)

There is no direct evidence that steroids reduce mortality or organ failure in nonsevere CAP. Additionally, the use of steroids in CAP can come with considerable risks (eg, secondary infection, hyperglycemia).

Recommendation 6. In hospitalized patients with CAP, empiric coverage for MRSA or P aeruginosa should be limited to patients meeting specific criteria. (Strong recommendation; moderate quality of evidence)

The guideline highlights the current overuse of extended spectrum antibiotics in patients meeting the previous definition of healthcare-associated pneumonia (HCAP). HCAP was defined by the presence of new chest x-ray infiltrates in patients with various exposures to healthcare settings (eg, chronic dialysis, infusion centers, emergency rooms). Antimicrobial therapy covering MRSA or P aeruginosa should be reserved for patients at risk for MRSA or P aeruginosa infection unless microbiologic testing is negative. Empiric antibiotic selection should incorporate local resistance patterns guided by hospital antibiograms.

Recommendation 7. In adults with CAP, antibiotics should be continued for no less than 5 days with documented clinical stability. (Strong recommendation; moderate quality of evidence)

Hospitalists often determine the length of antibiotic therapy for CAP. Recent studies show extended antibiotic treatment for pneumonia increases risk for adverse events without improving outcomes. Studies also demonstrate patients who receive 5 days of antibiotics total after achieving clinical stability by day 3 do no worse than patients receiving 8 or more days of antibiotics.

This guideline was created by a panel of pulmonologists, infectious disease specialists, general internists, and methodologists using the GRADE (Grading of Recommendations Assessment, Development and Evaluations) approach to draft recommendations. Conflicts of interest were disclosed by all panel members according to the ATS and IDSA policies, and ultimately, two panel members recused themselves owing to conflicts of interest. The inclusion of a large number of RCTs, observational studies, and meta-analyses provides for good generalizability of the guideline published by this group.

Equal support was given in the guideline to all ß-lactams listed, including ampicillin/sulbactam, cefotaxime, ceftriaxone, and ceftaroline, regardless of MRSA risk factors. As the authors explicitly state in the guideline, one of the major reasons for abandoning the HCAP classification was to correct the overuse of anti-MRSA and antipseudomonal therapy.³ It is surprising, then, that the authors would include ceftaroline, a broad-spectrum cephalosporin that covers MRSA, as first-line therapy for patients without risk factors for MRSA.

The guideline also supported the use of a respiratory fluoroquinolone or a ß-lactam with macrolide equally. Although most RCTs have found equal efficacy between these two regimens,⁴ there is growing concern about the safety of fluoroquinolones.⁵ While the authors do encourage clinicians to consider these side effects in the main body of the text, a stronger statement could have been made more prominently to warn clinicians of safety concerns with fluoroquinolones.

Finally, while monotherapy with a ß-lactam was supported for the treatment of nonsevere outpatient CAP, it was not included in the recommendations for the treatment of hospitalized patients. There is conflicting data on this topic. One RCT failed to show noninferiority of monotherapy, but this was most pronounced among patients with severe pneumonia (PSI category IV) or cases with proven atypical infections.⁶ Another RCT found monotherapy to be noninferior to combination therapy for hospitalized patients not admitted to the ICU.⁷ There is also evidence suggesting that many patients hospitalized with pneumonia have viral rather than bacterial infections,⁸ which brings into question the need for antibiotics in this subset entirely. When these findings are considered from a stewardship perspective and patient safety profile, monotherapy with a ß-lactam for hospitalized patients without severe pneumonia could have been considered.

Future research should track the effects of this guideline’s recommendation to narrow empiric therapy on patients empirically treated for MRSA or P aeruginosa infection once sputum and blood cultures are negative, particularly with respect to reduction of time on broad spectrum antimicrobials and clinical outcomes. Similarly, better definitions of which patients require empiric MRSA and P aeruginosa antimicrobial coverage are needed. Ideally, further research will facilitate rapid, cost-­effective, and individualized therapy, particularly with growing concerns for antimicrobial resistance and safety.

The authors have no relevant financial conflicts of interest to disclose.

Community-acquired pneumonia (CAP) is the second most common cause of hospitalization in the United States, with over 1.5 million unique hospitalizations annually.¹ CAP is also the most common infectious cause of death in US adults.² The 2019 CAP guideline from the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) provides recommendations on the diagnosis and management of CAP. The guideline provides 16 recommendations, which we have consolidated to highlight practice changing updates in diagnostic testing, risk stratification, and treatment.

Diagnostic Testing

Recommendation 1. In patients with CAP, routine blood cultures, sputum cultures, and urinary antigen tests are not routinely recommended unless severe CAP (Table), history of methicillin-resistant Staphylococcus aureus (MRSA) and/or Pseudomonas infection, or prior hospitalization for which intravenous antibiotics were administered. (Strong recommendation; very low quality of evidence)

The guideline emphasizes that the diagnostic yield of blood/sputum cultures and urinary antigen testing is low. Additionally, high-quality data showing improved clinical outcomes with routine testing of blood cultures and urinary antigens are lacking. Instead, the guideline suggests obtaining blood cultures, urinary antigens, and sputum gram stain and culture only for patients with severe CAP and those being treated for or having prior infection with MRSA or P aeruginosa. They recommend narrowing therapy as appropriate if cultures are negative for either of these two organisms or previous hospitalization with intravenous antibiotics.

Recommendation 2. In patients with CAP, Pneumonia Severity Index (PSI) or CURB-65 (tool based on confusion, urea level, respiratory rate, blood pressure, and age 65 years or older) scores should not be used to determine general medical ward vs intensive care unit care (ICU). (Strong recommendation; low quality of evidence)

The PSI and CURB-65 scores are not validated to determine location of hospital care. Multiple prognostic models have been studied to predict the need for ICU-level care including SMART-COP (systolic blood pressure, multilobar chest radiography involvement, albumin level, respiratory rate, tachycardia, confusion, oxygenation, and arterial pH), SCAPA (Study of Community Acquired Pneumonia Aetiology), and the ATS/IDSA criteria (Table). The positive and negative likelihood ratios for needing ICU admission in CAP with either one major or three or more minor ATS/IDSA criteria are 3.28 and 0.21, respectively.

Treatment

Recommendation 3a. In patients with nonsevere CAP and no risk factors for MRSA or Pseudomonas infection, empiric treatment with a ß-lactam plus macrolide or monotherapy with fluoroquinolones is recommended. (Strong recommendation; high quality of evidence)

Recommendation 3b. In patients with severe CAP and no risk factors for MRSA or Pseudomonas infection, empiric treatment with a ß-lactam plus either a macrolide or fluoroquinolone is recommended. (Strong recommendation; low to moderate quality of evidence)

Microbiologic risk assessment is critical. Risk factors for MRSA or P aeruginosa pneumonia include isolation of these agents in culture and recent hospitalization with receipt of parenteral antibiotics. ß-Lactam monotherapy is not recommended because previous randomized clinical trials (RCTs) demonstrated inferiority of ß-lactam monotherapy to combination therapy for resolution of CAP. The recommended combination therapy for patients with severe CAP without risk factors for MRSA or P aeruginosa infection is a ß-lactam plus either a macrolide or a respiratory fluoroquinolone.

Recommendation 4. In patients with suspected aspiration pneumonia, additional anaerobic coverage is not routinely recommended. (Conditional recommendation; very low quality of evidence)

Aspiration often causes a self-limited pneumonitis that will resolve in 24 to 48 hours with supportive care. Use of additional anaerobic coverage in these patients increases risk for complications (eg, Clostridioides difficile infection) without improving outcomes.

Recommendation 5. In patients with nonsevere CAP, corticosteroids are not routinely recommended. (Conditional recommendation; moderate quality of evidence)

There is no direct evidence that steroids reduce mortality or organ failure in nonsevere CAP. Additionally, the use of steroids in CAP can come with considerable risks (eg, secondary infection, hyperglycemia).

Recommendation 6. In hospitalized patients with CAP, empiric coverage for MRSA or P aeruginosa should be limited to patients meeting specific criteria. (Strong recommendation; moderate quality of evidence)

The guideline highlights the current overuse of extended spectrum antibiotics in patients meeting the previous definition of healthcare-associated pneumonia (HCAP). HCAP was defined by the presence of new chest x-ray infiltrates in patients with various exposures to healthcare settings (eg, chronic dialysis, infusion centers, emergency rooms). Antimicrobial therapy covering MRSA or P aeruginosa should be reserved for patients at risk for MRSA or P aeruginosa infection unless microbiologic testing is negative. Empiric antibiotic selection should incorporate local resistance patterns guided by hospital antibiograms.

Recommendation 7. In adults with CAP, antibiotics should be continued for no less than 5 days with documented clinical stability. (Strong recommendation; moderate quality of evidence)

Hospitalists often determine the length of antibiotic therapy for CAP. Recent studies show extended antibiotic treatment for pneumonia increases risk for adverse events without improving outcomes. Studies also demonstrate patients who receive 5 days of antibiotics total after achieving clinical stability by day 3 do no worse than patients receiving 8 or more days of antibiotics.

This guideline was created by a panel of pulmonologists, infectious disease specialists, general internists, and methodologists using the GRADE (Grading of Recommendations Assessment, Development and Evaluations) approach to draft recommendations. Conflicts of interest were disclosed by all panel members according to the ATS and IDSA policies, and ultimately, two panel members recused themselves owing to conflicts of interest. The inclusion of a large number of RCTs, observational studies, and meta-analyses provides for good generalizability of the guideline published by this group.

Equal support was given in the guideline to all ß-lactams listed, including ampicillin/sulbactam, cefotaxime, ceftriaxone, and ceftaroline, regardless of MRSA risk factors. As the authors explicitly state in the guideline, one of the major reasons for abandoning the HCAP classification was to correct the overuse of anti-MRSA and antipseudomonal therapy.³ It is surprising, then, that the authors would include ceftaroline, a broad-spectrum cephalosporin that covers MRSA, as first-line therapy for patients without risk factors for MRSA.

The guideline also supported the use of a respiratory fluoroquinolone or a ß-lactam with macrolide equally. Although most RCTs have found equal efficacy between these two regimens,⁴ there is growing concern about the safety of fluoroquinolones.⁵ While the authors do encourage clinicians to consider these side effects in the main body of the text, a stronger statement could have been made more prominently to warn clinicians of safety concerns with fluoroquinolones.

Finally, while monotherapy with a ß-lactam was supported for the treatment of nonsevere outpatient CAP, it was not included in the recommendations for the treatment of hospitalized patients. There is conflicting data on this topic. One RCT failed to show noninferiority of monotherapy, but this was most pronounced among patients with severe pneumonia (PSI category IV) or cases with proven atypical infections.⁶ Another RCT found monotherapy to be noninferior to combination therapy for hospitalized patients not admitted to the ICU.⁷ There is also evidence suggesting that many patients hospitalized with pneumonia have viral rather than bacterial infections,⁸ which brings into question the need for antibiotics in this subset entirely. When these findings are considered from a stewardship perspective and patient safety profile, monotherapy with a ß-lactam for hospitalized patients without severe pneumonia could have been considered.

Future research should track the effects of this guideline’s recommendation to narrow empiric therapy on patients empirically treated for MRSA or P aeruginosa infection once sputum and blood cultures are negative, particularly with respect to reduction of time on broad spectrum antimicrobials and clinical outcomes. Similarly, better definitions of which patients require empiric MRSA and P aeruginosa antimicrobial coverage are needed. Ideally, further research will facilitate rapid, cost-­effective, and individualized therapy, particularly with growing concerns for antimicrobial resistance and safety.

The authors have no relevant financial conflicts of interest to disclose.

According to the most recent Annual Report of the American Association of Poison Control Centers’ National Poison Data System, there were 51,081 patient exposures to acetaminophen or acetaminophen-­containing products treated in a healthcare facility in 2018.¹ The toxicity of acetaminophen is mediated by its metabolism into the electrophile N-acetyl-p-benzoquinone imine (NAPQI).² If the amount of acetaminophen ingested is higher than recommended dosages, glutathione stores may become depleted as the liver tries to detoxify NAPQI and may no longer able to keep up with the demand. As the patient progresses 24 to 36 hours after ingestion, the onset of hepatic injury becomes apparent with elevations in aspartate aminotransferase (AST). AST elevations, should they occur, are almost always present by 36 hours.² Maximum hepatic dysfunction, as well as elevations in prothrombin time, bilirubin, and serum creatinine, occurs 72 to 96 hours after a toxic ingestion. As a result of marked age-associated differences in the process of conjugating acetaminophen metabolites, infants and young children may be less susceptible to acetaminophen-associated hepatotoxicity, compared with their adult counterparts.^3,4

This clinical progress note addresses acetaminophen toxicity treatment, focusing on N-acetylcysteine (NAC) dosing protocols and the 2017 American College of Medical Toxicology (ACMT) position statement, Duration of Intravenous Acetylcysteine Therapy Following Acetaminophen Overdose.⁵ We conducted a literature search via the PubMed database. The authors began by using the following Medical Subject Headings terms “acetaminophen overdose [title],” which yielded 299 articles, “acetaminophen hepatotoxicity [title],” which yielded 283 articles, and “acetaminophen N-acetylcysteine [title],” which yielded 335 titles. Variations of these terms were used to ensure exhaustive search results. The search results were reviewed for applicability to acetaminophen poisoning and especially goal-directed N-acetylcysteine treatment strategies.

Clarifying a patient’s history of ingestion is a crucial first step to the diagnosis and risk evaluation of acetaminophen-poisoned patients. The initial laboratory workup should include, at minimum, measurement (at 4 or more hours after ingestion) of serum acetaminophen level, AST and alanine aminotransferase (ALT), bilirubin, alkaline phosphatase, creatinine, prothrombin time and international normalized ratio (PT/INR), lactate, and ethanol levels. Gastric decontamination is not appropriate in most cases because of the rapid absorption of acetaminophen.² Activated charcoal is most effective when given within the first 2 hours following ingestion. For acetaminophen-­poisoned patients with severe hepatic toxicity, treating clinicians should consider consultation with a medical toxicologist, an individual with expertise, or the local Poison Control Center.⁵

The Rumack-Matthew nomogram provides guidance on the initiation of antidotal treatment for patients with acetaminophen overdose. This nomogram was developed to exhibit high sensitivity in patients at risk for hepatic damage from acetaminophen overdose.⁶ The mainstay for treatment of acetaminophen poisonings is NAC. Early administration of NAC can replenish depleted hepatic glutathione stores, which restores the liver’s ability to detoxify the toxic metabolite NAPQI. When administered within 6 to 8 hours following ingestion, NAC is nearly universally effective at preventing the subsequent hepatic damage from NAPQI.⁷ Consideration of individualized factors should lead the treating clinician to use the Rumack-Matthew nomogram within the appropriate contexts. Factors such as an unreliable timeline of ingestion by patients, concomitantly ingested medications, and patient-specific factors that might alter the absorption of acetaminophen or impact serum acetaminophen concentrations should be considered. While this nomogram is helpful for decision-making pertaining to the initiation of NAC, further management and continuation of treatment must be patient specific and determined by the treating clinician.

In the United States, intravenous and oral formulations of NAC are available for treatment of acetaminophen toxicity. These formulations are equally efficacious in treating acetaminophen toxicity, with the exception of established hepatic failure, for which only the intravenous route has been studied.⁸ Oral administration results in vomiting in approximately 20% of patients, while intravenous administration may uncommonly result in severe anaphylactoid reactions. Three scenarios exist in which the intravenous route is preferred over the oral route: acetaminophen toxicity in pregnant women, acetaminophen-­induced hepatic failure, and intractable vomiting preventing treatment with oral therapy.² The intravenous formulation is Food and Drug Administration–approved for a 21-hour treatment duration, while the oral formulation is traditionally administered for a 72-hour duration.^9,10

Treatment of acetaminophen poisoning must be tailored on an individual basis and should not follow predetermined durations of treatment. Not only might the FDA-approved 21-hour course of intravenous NAC be inadequate, but the standard 72-hour oral regimen duration may be excessive for many patients. Both the 21-hour and 72-hour protocols were developed based on the half-life and expected elimination of acetaminophen from the body. The traditional 72-hour oral protocol used in the United States was approved in 1985 and was based on the observation that, in patients who developed acetaminophen-induced fatal hepatotoxicity, the acetaminophen half-life was 12 hours, requiring five half-lives to eliminate the drug, for a total of 60 hours.¹¹ The FDA then added an additional 12 hours to provide an additional margin of safety. Researchers in the United Kingdom developed an intravenous treatment protocol based on a shorter 4-hour acetaminophen half-life, calculated from observations of a larger pool of acetaminophen-poisoned patients and not just those with fatal hepatotoxicity.¹² This 21-hour protocol—slightly longer than the five 4-hour half-lives needed—was subsequently approved in the United States as the intravenous formulation’s duration in 2004.

Case reports of hepatic failure have described treatment failures of intravenous NAC after the completion of the standard 21 hour treatment regimen.¹³ In a case report by Smith et al, a patient with significant single ingestion is described who ultimately developed hepatotoxicity despite receiving the FDA-­approved 21-hour infusion.¹³ This patient ingested approximately 96 immediate-release, 500-mg acetaminophen tablets over approximately 1 hour. The initial acetaminophen concentration was 264 mcg/mL at 2.25 hours after ingestion. At 21 hours after ingestion, the patient’s acetaminophen levels remained elevated at 116 mcg/mL, but therapy with NAC was discontinued per protocol because AST and ALT levels were normal. A second peak in serum acetaminophen levels occurred after discontinuation of NAC, with levels reaching 228 mcg/mL approximately 48 hours after ingestion. Liver function worsened over the next few days with elevations in AST of greater than 4,000 U/L, PT of 51.4 seconds, and ammonia of 165 mcg/dL. Intravenous NAC was restarted and hepatic function improved gradually. The patient was ultimately discharged from the hospital. This case and others highlight the possible pitfalls of applying a protocolized, fixed treatment duration of NAC to all patients.

Based on individual ingestion timing, quantities, and pharmacokinetics, patients should have pertinent laboratory markers monitored at least every 24 hours from presentation. The clinician may then consider the need to continue or discontinue NAC treatment every 24 hours from the initiation of NAC. Although notable limitations exist for both intravenous and oral treatment regimens, the literature uniformly recommends treating until serum acetaminophen levels are undetectable, regardless of NAC administration route. Based on the metabolism of acetaminophen, as long as serum concentrations of acetaminophen persist, further metabolism to the toxic NAPQI metabolite is possible. The ACMT addressed these concerns with the 2017 position paper, which strongly recommends all of the following criteria to be present prior to discontinuation of intravenous NAC: undetectable acetaminophen concentration, improving hepatic aminotransferases, and improving prognostic markers, including creatinine, lactate, pH, PT/INR, and phosphate.⁵ In cases in which laboratory and clinical parameters are abnormal, continued treatment beyond the established standard NAC treatment durations is warranted. However, once NAC treatment is extended beyond established protocol lengths, the subsequent dosing regimens that should be employed in these patients are not well studied. The ACMT Position Statement states the administration of an additional NAC bolus or extending the duration of the 6.25 mg/kg per hour maintenance infusion may be appropriate in this subset of patients requiring continued treatment.

Based on the positive outcomes in most patients receiving the 21-hour intravenous NAC protocol, the necessity of an additional 2 days of NAC treatment with the 72-hour oral regimen is uncertain. The ACMT Position Statement states “evidence supports using shorter oral NAC courses, provided that liver enzymes and synthetic function are normal or improving, and plasma acetaminophen concentration is undetectable.”⁵ Based on this and available literature, patients with a lower risk for developing hepatotoxicity may have oral NAC therapy discontinued after 24 to 48 hours of treatment if specific lab and patient parameters are within defined criteria.

The ACMT does not differentiate between adult and pediatric recommendations. However, the data used to develop the ACMT goal-directed treatment recommendations included both adult and pediatric patients.^14,15 The same goal-­directed treatment principles may be applied to pediatric patients, though studies have not specifically addressed pediatric goal-directed treatment of acetaminophen poisoning.

Acetaminophen-poisoned patients require evaluation not just prior to initiation of treatment, but also when deciding to discontinue NAC therapy. New literature supports reconsideration of standardized 21- and 72-hour NAC treatment protocols, as well as the notion that treatment duration should be guided by laboratory parameters rather than by route of NAC administration. Goal-directed or patient-tailored treatment is also supported by the ACMT.⁵ Treatment with NAC should continue in patients displaying hepatic toxicity or persistent elevations in acetaminophen levels. In these cases, the optimal treatment regimen in these cases remains unknown and further research into this area is merited.

According to the most recent Annual Report of the American Association of Poison Control Centers’ National Poison Data System, there were 51,081 patient exposures to acetaminophen or acetaminophen-­containing products treated in a healthcare facility in 2018.¹ The toxicity of acetaminophen is mediated by its metabolism into the electrophile N-acetyl-p-benzoquinone imine (NAPQI).² If the amount of acetaminophen ingested is higher than recommended dosages, glutathione stores may become depleted as the liver tries to detoxify NAPQI and may no longer able to keep up with the demand. As the patient progresses 24 to 36 hours after ingestion, the onset of hepatic injury becomes apparent with elevations in aspartate aminotransferase (AST). AST elevations, should they occur, are almost always present by 36 hours.² Maximum hepatic dysfunction, as well as elevations in prothrombin time, bilirubin, and serum creatinine, occurs 72 to 96 hours after a toxic ingestion. As a result of marked age-associated differences in the process of conjugating acetaminophen metabolites, infants and young children may be less susceptible to acetaminophen-associated hepatotoxicity, compared with their adult counterparts.^3,4

This clinical progress note addresses acetaminophen toxicity treatment, focusing on N-acetylcysteine (NAC) dosing protocols and the 2017 American College of Medical Toxicology (ACMT) position statement, Duration of Intravenous Acetylcysteine Therapy Following Acetaminophen Overdose.⁵ We conducted a literature search via the PubMed database. The authors began by using the following Medical Subject Headings terms “acetaminophen overdose [title],” which yielded 299 articles, “acetaminophen hepatotoxicity [title],” which yielded 283 articles, and “acetaminophen N-acetylcysteine [title],” which yielded 335 titles. Variations of these terms were used to ensure exhaustive search results. The search results were reviewed for applicability to acetaminophen poisoning and especially goal-directed N-acetylcysteine treatment strategies.

Clarifying a patient’s history of ingestion is a crucial first step to the diagnosis and risk evaluation of acetaminophen-poisoned patients. The initial laboratory workup should include, at minimum, measurement (at 4 or more hours after ingestion) of serum acetaminophen level, AST and alanine aminotransferase (ALT), bilirubin, alkaline phosphatase, creatinine, prothrombin time and international normalized ratio (PT/INR), lactate, and ethanol levels. Gastric decontamination is not appropriate in most cases because of the rapid absorption of acetaminophen.² Activated charcoal is most effective when given within the first 2 hours following ingestion. For acetaminophen-­poisoned patients with severe hepatic toxicity, treating clinicians should consider consultation with a medical toxicologist, an individual with expertise, or the local Poison Control Center.⁵

The Rumack-Matthew nomogram provides guidance on the initiation of antidotal treatment for patients with acetaminophen overdose. This nomogram was developed to exhibit high sensitivity in patients at risk for hepatic damage from acetaminophen overdose.⁶ The mainstay for treatment of acetaminophen poisonings is NAC. Early administration of NAC can replenish depleted hepatic glutathione stores, which restores the liver’s ability to detoxify the toxic metabolite NAPQI. When administered within 6 to 8 hours following ingestion, NAC is nearly universally effective at preventing the subsequent hepatic damage from NAPQI.⁷ Consideration of individualized factors should lead the treating clinician to use the Rumack-Matthew nomogram within the appropriate contexts. Factors such as an unreliable timeline of ingestion by patients, concomitantly ingested medications, and patient-specific factors that might alter the absorption of acetaminophen or impact serum acetaminophen concentrations should be considered. While this nomogram is helpful for decision-making pertaining to the initiation of NAC, further management and continuation of treatment must be patient specific and determined by the treating clinician.

In the United States, intravenous and oral formulations of NAC are available for treatment of acetaminophen toxicity. These formulations are equally efficacious in treating acetaminophen toxicity, with the exception of established hepatic failure, for which only the intravenous route has been studied.⁸ Oral administration results in vomiting in approximately 20% of patients, while intravenous administration may uncommonly result in severe anaphylactoid reactions. Three scenarios exist in which the intravenous route is preferred over the oral route: acetaminophen toxicity in pregnant women, acetaminophen-­induced hepatic failure, and intractable vomiting preventing treatment with oral therapy.² The intravenous formulation is Food and Drug Administration–approved for a 21-hour treatment duration, while the oral formulation is traditionally administered for a 72-hour duration.^9,10

Treatment of acetaminophen poisoning must be tailored on an individual basis and should not follow predetermined durations of treatment. Not only might the FDA-approved 21-hour course of intravenous NAC be inadequate, but the standard 72-hour oral regimen duration may be excessive for many patients. Both the 21-hour and 72-hour protocols were developed based on the half-life and expected elimination of acetaminophen from the body. The traditional 72-hour oral protocol used in the United States was approved in 1985 and was based on the observation that, in patients who developed acetaminophen-induced fatal hepatotoxicity, the acetaminophen half-life was 12 hours, requiring five half-lives to eliminate the drug, for a total of 60 hours.¹¹ The FDA then added an additional 12 hours to provide an additional margin of safety. Researchers in the United Kingdom developed an intravenous treatment protocol based on a shorter 4-hour acetaminophen half-life, calculated from observations of a larger pool of acetaminophen-poisoned patients and not just those with fatal hepatotoxicity.¹² This 21-hour protocol—slightly longer than the five 4-hour half-lives needed—was subsequently approved in the United States as the intravenous formulation’s duration in 2004.

Case reports of hepatic failure have described treatment failures of intravenous NAC after the completion of the standard 21 hour treatment regimen.¹³ In a case report by Smith et al, a patient with significant single ingestion is described who ultimately developed hepatotoxicity despite receiving the FDA-­approved 21-hour infusion.¹³ This patient ingested approximately 96 immediate-release, 500-mg acetaminophen tablets over approximately 1 hour. The initial acetaminophen concentration was 264 mcg/mL at 2.25 hours after ingestion. At 21 hours after ingestion, the patient’s acetaminophen levels remained elevated at 116 mcg/mL, but therapy with NAC was discontinued per protocol because AST and ALT levels were normal. A second peak in serum acetaminophen levels occurred after discontinuation of NAC, with levels reaching 228 mcg/mL approximately 48 hours after ingestion. Liver function worsened over the next few days with elevations in AST of greater than 4,000 U/L, PT of 51.4 seconds, and ammonia of 165 mcg/dL. Intravenous NAC was restarted and hepatic function improved gradually. The patient was ultimately discharged from the hospital. This case and others highlight the possible pitfalls of applying a protocolized, fixed treatment duration of NAC to all patients.

Based on individual ingestion timing, quantities, and pharmacokinetics, patients should have pertinent laboratory markers monitored at least every 24 hours from presentation. The clinician may then consider the need to continue or discontinue NAC treatment every 24 hours from the initiation of NAC. Although notable limitations exist for both intravenous and oral treatment regimens, the literature uniformly recommends treating until serum acetaminophen levels are undetectable, regardless of NAC administration route. Based on the metabolism of acetaminophen, as long as serum concentrations of acetaminophen persist, further metabolism to the toxic NAPQI metabolite is possible. The ACMT addressed these concerns with the 2017 position paper, which strongly recommends all of the following criteria to be present prior to discontinuation of intravenous NAC: undetectable acetaminophen concentration, improving hepatic aminotransferases, and improving prognostic markers, including creatinine, lactate, pH, PT/INR, and phosphate.⁵ In cases in which laboratory and clinical parameters are abnormal, continued treatment beyond the established standard NAC treatment durations is warranted. However, once NAC treatment is extended beyond established protocol lengths, the subsequent dosing regimens that should be employed in these patients are not well studied. The ACMT Position Statement states the administration of an additional NAC bolus or extending the duration of the 6.25 mg/kg per hour maintenance infusion may be appropriate in this subset of patients requiring continued treatment.

Based on the positive outcomes in most patients receiving the 21-hour intravenous NAC protocol, the necessity of an additional 2 days of NAC treatment with the 72-hour oral regimen is uncertain. The ACMT Position Statement states “evidence supports using shorter oral NAC courses, provided that liver enzymes and synthetic function are normal or improving, and plasma acetaminophen concentration is undetectable.”⁵ Based on this and available literature, patients with a lower risk for developing hepatotoxicity may have oral NAC therapy discontinued after 24 to 48 hours of treatment if specific lab and patient parameters are within defined criteria.

The ACMT does not differentiate between adult and pediatric recommendations. However, the data used to develop the ACMT goal-directed treatment recommendations included both adult and pediatric patients.^14,15 The same goal-­directed treatment principles may be applied to pediatric patients, though studies have not specifically addressed pediatric goal-directed treatment of acetaminophen poisoning.

Acetaminophen-poisoned patients require evaluation not just prior to initiation of treatment, but also when deciding to discontinue NAC therapy. New literature supports reconsideration of standardized 21- and 72-hour NAC treatment protocols, as well as the notion that treatment duration should be guided by laboratory parameters rather than by route of NAC administration. Goal-directed or patient-tailored treatment is also supported by the ACMT.⁵ Treatment with NAC should continue in patients displaying hepatic toxicity or persistent elevations in acetaminophen levels. In these cases, the optimal treatment regimen in these cases remains unknown and further research into this area is merited.

According to the most recent Annual Report of the American Association of Poison Control Centers’ National Poison Data System, there were 51,081 patient exposures to acetaminophen or acetaminophen-­containing products treated in a healthcare facility in 2018.¹ The toxicity of acetaminophen is mediated by its metabolism into the electrophile N-acetyl-p-benzoquinone imine (NAPQI).² If the amount of acetaminophen ingested is higher than recommended dosages, glutathione stores may become depleted as the liver tries to detoxify NAPQI and may no longer able to keep up with the demand. As the patient progresses 24 to 36 hours after ingestion, the onset of hepatic injury becomes apparent with elevations in aspartate aminotransferase (AST). AST elevations, should they occur, are almost always present by 36 hours.² Maximum hepatic dysfunction, as well as elevations in prothrombin time, bilirubin, and serum creatinine, occurs 72 to 96 hours after a toxic ingestion. As a result of marked age-associated differences in the process of conjugating acetaminophen metabolites, infants and young children may be less susceptible to acetaminophen-associated hepatotoxicity, compared with their adult counterparts.^3,4

This clinical progress note addresses acetaminophen toxicity treatment, focusing on N-acetylcysteine (NAC) dosing protocols and the 2017 American College of Medical Toxicology (ACMT) position statement, Duration of Intravenous Acetylcysteine Therapy Following Acetaminophen Overdose.⁵ We conducted a literature search via the PubMed database. The authors began by using the following Medical Subject Headings terms “acetaminophen overdose [title],” which yielded 299 articles, “acetaminophen hepatotoxicity [title],” which yielded 283 articles, and “acetaminophen N-acetylcysteine [title],” which yielded 335 titles. Variations of these terms were used to ensure exhaustive search results. The search results were reviewed for applicability to acetaminophen poisoning and especially goal-directed N-acetylcysteine treatment strategies.

Clarifying a patient’s history of ingestion is a crucial first step to the diagnosis and risk evaluation of acetaminophen-poisoned patients. The initial laboratory workup should include, at minimum, measurement (at 4 or more hours after ingestion) of serum acetaminophen level, AST and alanine aminotransferase (ALT), bilirubin, alkaline phosphatase, creatinine, prothrombin time and international normalized ratio (PT/INR), lactate, and ethanol levels. Gastric decontamination is not appropriate in most cases because of the rapid absorption of acetaminophen.² Activated charcoal is most effective when given within the first 2 hours following ingestion. For acetaminophen-­poisoned patients with severe hepatic toxicity, treating clinicians should consider consultation with a medical toxicologist, an individual with expertise, or the local Poison Control Center.⁵

The Rumack-Matthew nomogram provides guidance on the initiation of antidotal treatment for patients with acetaminophen overdose. This nomogram was developed to exhibit high sensitivity in patients at risk for hepatic damage from acetaminophen overdose.⁶ The mainstay for treatment of acetaminophen poisonings is NAC. Early administration of NAC can replenish depleted hepatic glutathione stores, which restores the liver’s ability to detoxify the toxic metabolite NAPQI. When administered within 6 to 8 hours following ingestion, NAC is nearly universally effective at preventing the subsequent hepatic damage from NAPQI.⁷ Consideration of individualized factors should lead the treating clinician to use the Rumack-Matthew nomogram within the appropriate contexts. Factors such as an unreliable timeline of ingestion by patients, concomitantly ingested medications, and patient-specific factors that might alter the absorption of acetaminophen or impact serum acetaminophen concentrations should be considered. While this nomogram is helpful for decision-making pertaining to the initiation of NAC, further management and continuation of treatment must be patient specific and determined by the treating clinician.

In the United States, intravenous and oral formulations of NAC are available for treatment of acetaminophen toxicity. These formulations are equally efficacious in treating acetaminophen toxicity, with the exception of established hepatic failure, for which only the intravenous route has been studied.⁸ Oral administration results in vomiting in approximately 20% of patients, while intravenous administration may uncommonly result in severe anaphylactoid reactions. Three scenarios exist in which the intravenous route is preferred over the oral route: acetaminophen toxicity in pregnant women, acetaminophen-­induced hepatic failure, and intractable vomiting preventing treatment with oral therapy.² The intravenous formulation is Food and Drug Administration–approved for a 21-hour treatment duration, while the oral formulation is traditionally administered for a 72-hour duration.^9,10

Treatment of acetaminophen poisoning must be tailored on an individual basis and should not follow predetermined durations of treatment. Not only might the FDA-approved 21-hour course of intravenous NAC be inadequate, but the standard 72-hour oral regimen duration may be excessive for many patients. Both the 21-hour and 72-hour protocols were developed based on the half-life and expected elimination of acetaminophen from the body. The traditional 72-hour oral protocol used in the United States was approved in 1985 and was based on the observation that, in patients who developed acetaminophen-induced fatal hepatotoxicity, the acetaminophen half-life was 12 hours, requiring five half-lives to eliminate the drug, for a total of 60 hours.¹¹ The FDA then added an additional 12 hours to provide an additional margin of safety. Researchers in the United Kingdom developed an intravenous treatment protocol based on a shorter 4-hour acetaminophen half-life, calculated from observations of a larger pool of acetaminophen-poisoned patients and not just those with fatal hepatotoxicity.¹² This 21-hour protocol—slightly longer than the five 4-hour half-lives needed—was subsequently approved in the United States as the intravenous formulation’s duration in 2004.

Case reports of hepatic failure have described treatment failures of intravenous NAC after the completion of the standard 21 hour treatment regimen.¹³ In a case report by Smith et al, a patient with significant single ingestion is described who ultimately developed hepatotoxicity despite receiving the FDA-­approved 21-hour infusion.¹³ This patient ingested approximately 96 immediate-release, 500-mg acetaminophen tablets over approximately 1 hour. The initial acetaminophen concentration was 264 mcg/mL at 2.25 hours after ingestion. At 21 hours after ingestion, the patient’s acetaminophen levels remained elevated at 116 mcg/mL, but therapy with NAC was discontinued per protocol because AST and ALT levels were normal. A second peak in serum acetaminophen levels occurred after discontinuation of NAC, with levels reaching 228 mcg/mL approximately 48 hours after ingestion. Liver function worsened over the next few days with elevations in AST of greater than 4,000 U/L, PT of 51.4 seconds, and ammonia of 165 mcg/dL. Intravenous NAC was restarted and hepatic function improved gradually. The patient was ultimately discharged from the hospital. This case and others highlight the possible pitfalls of applying a protocolized, fixed treatment duration of NAC to all patients.

Based on individual ingestion timing, quantities, and pharmacokinetics, patients should have pertinent laboratory markers monitored at least every 24 hours from presentation. The clinician may then consider the need to continue or discontinue NAC treatment every 24 hours from the initiation of NAC. Although notable limitations exist for both intravenous and oral treatment regimens, the literature uniformly recommends treating until serum acetaminophen levels are undetectable, regardless of NAC administration route. Based on the metabolism of acetaminophen, as long as serum concentrations of acetaminophen persist, further metabolism to the toxic NAPQI metabolite is possible. The ACMT addressed these concerns with the 2017 position paper, which strongly recommends all of the following criteria to be present prior to discontinuation of intravenous NAC: undetectable acetaminophen concentration, improving hepatic aminotransferases, and improving prognostic markers, including creatinine, lactate, pH, PT/INR, and phosphate.⁵ In cases in which laboratory and clinical parameters are abnormal, continued treatment beyond the established standard NAC treatment durations is warranted. However, once NAC treatment is extended beyond established protocol lengths, the subsequent dosing regimens that should be employed in these patients are not well studied. The ACMT Position Statement states the administration of an additional NAC bolus or extending the duration of the 6.25 mg/kg per hour maintenance infusion may be appropriate in this subset of patients requiring continued treatment.

Based on the positive outcomes in most patients receiving the 21-hour intravenous NAC protocol, the necessity of an additional 2 days of NAC treatment with the 72-hour oral regimen is uncertain. The ACMT Position Statement states “evidence supports using shorter oral NAC courses, provided that liver enzymes and synthetic function are normal or improving, and plasma acetaminophen concentration is undetectable.”⁵ Based on this and available literature, patients with a lower risk for developing hepatotoxicity may have oral NAC therapy discontinued after 24 to 48 hours of treatment if specific lab and patient parameters are within defined criteria.

The ACMT does not differentiate between adult and pediatric recommendations. However, the data used to develop the ACMT goal-directed treatment recommendations included both adult and pediatric patients.^14,15 The same goal-­directed treatment principles may be applied to pediatric patients, though studies have not specifically addressed pediatric goal-directed treatment of acetaminophen poisoning.

Acetaminophen-poisoned patients require evaluation not just prior to initiation of treatment, but also when deciding to discontinue NAC therapy. New literature supports reconsideration of standardized 21- and 72-hour NAC treatment protocols, as well as the notion that treatment duration should be guided by laboratory parameters rather than by route of NAC administration. Goal-directed or patient-tailored treatment is also supported by the ACMT.⁵ Treatment with NAC should continue in patients displaying hepatic toxicity or persistent elevations in acetaminophen levels. In these cases, the optimal treatment regimen in these cases remains unknown and further research into this area is merited.

Uncomplicated bacteremia, while not precisely defined in the literature, generally implies bacteremia in the absence of a persistent or difficult-to-eradicate infectious source. Bacteremia secondary to focal infections such as skin and soft-tissue infection, pneumonia, pyelonephritis, or urinary tract infection (UTI) accounts for up to 25% of bloodstream infections (BSIs) and usually resolves with prompt and appropriate antimicrobial therapy.^1,2 Current practice guidelines do not adequately address key aspects of the optimal management of gram-negative (GN)–BSI commonly encountered in hospital care.^3-7 Notably, antimicrobial duration, criteria to transition from intravenous (IV) to oral step-down therapy, choice of oral antimicrobials, and reassessment of follow-up blood cultures have not been addressed. In the absence of consensus guidelines, clinicians rely on “conventional wisdom” and clinical experience, which may not be supported by scientific rigor. A growing body of research now challenges some long-standing practices once thought to be standard of care.

In this narrative review, we aim to examine and synthesize emerging information to provide an evidence-based framework in the management of hospitalized patients with GN-BSI. We highlight the unintended consequences and potential harms of excessive antimicrobial exposure and focus on areas in the fundamental approach to duration of therapy, the role of oral antimicrobials, and usefulness of follow-up blood cultures. A comprehensive search of the published literature was performed in PubMed with an emphasis on articles published during 2015-2019 with use of search terms including gram-negative bacteremia, duration, antibiotics, adverse effects, intravascular catheter, and follow-up blood cultures.

Antimicrobial overuse is common and may be driven by concerns for undertreatment. Clinicians may believe that prolonged antimicrobial therapy maximizes cure rates, with treatment duration often defined arbitrarily by a fixed number of “Constantine-units” (dating back to the ancient Roman emperor’s decree of 7 days in a week).^8-10 Recent publications refute this notion and point out that the harms of overprescribing outweigh the perceived benefits of longer treatment duration.

Antimicrobials are lifesaving but not benign; adverse effects are common and costly to our patients and healthcare system. Among 1,488 hospitalized adults who received at least 24 hours of systemic antimicrobials, 20% had an antimicrobial-­associated adverse event, mostly gastrointestinal, renal, or hematologic in nature.¹¹ Prolonged duration of antimicrobials is further associated with adverse effects such as antimicrobial-associated diarrhea, increased rates of Clostridioides difficile infection (CDI), emergence of antimicrobial resistance, and longer hospital length of stay (LOS).^11-15 Vaughn and colleagues conducted the largest observational study to date, evaluating antimicrobial prescriptions for the treatment of nearly 6,500 adults with community-acquired pneumonia in a 43-hospital consortium in Michigan.¹⁴ More than two-thirds of patients received antimicrobial courses (median 8 days) that exceeded guideline-­recommended duration. Patients who received longer antimicrobial courses did not have reduced mortality, readmission, or emergency department visits. More importantly, each excess day of treatment was associated with a relative 5% increase in the odds of antimicrobial-associated adverse effects reported by patients. This is further supported by national and state hospital data that antimicrobial-associated adverse events are an independent predictor of longer LOS.¹²

CDI is commonly linked to destructive changes to the indigenous microbiota of the intestinal flora caused by antimicrobial administration. Stevens and colleagues identified 7,792 hospitalized patients who received at least 2 consecutive days of antimicrobial therapy¹³; comparing 241 cases of CDI with the control group, they observed a dose-dependent risk of CDI associated with increasing cumulative dose, number of antimicrobials, and days of antimicrobial exposure. Compared with patients who received fewer than 4 days of antimicrobials, the adjusted hazard ratios (aHR) for those who received 4-7 days or 8-18 days of therapy were 1.4 (95% CI, 0.8-2.4) and 3.0 (95% CI, 1.9-5.0), respectively. This correlates to a threefold increase in CDI risk for patients who received more than 7 days of antimicrobials. More specifically, the empiric use of antipseudomonal ß-lactams (APBL) for more than 48 hours was also found to be an independent risk factor for CDI among 808 patients with Enterobacteriaceae BSI.¹⁶ The risk of CDI within 90 days of BSI was higher among those who received >48 hours of APBL than it was among those who received ≤48 hours (HR, 3.6; 95% CI, 1.5-9.9).

While C difficile may be the most well-known pathogen implicated in antimicrobial usage, the incidence of multidrug-­resistant (MDR) organisms, either as infectious or colonizing pathogens, is also tied to antimicrobial exposure. Among patients receiving systemic antimicrobials, 6% developed an MDR infection within 90 days.¹¹ Over a 5-year period, Teshome and colleagues evaluated 7,118 critically ill patients and demonstrated that prolonged exposures to APBLs increased the risk of new antimicrobial resistance within 60 days.¹⁵ This resistance pattern was not an institutional or environmental finding but a patient-level finding. For each additional day of cefepime or piperacillin/tazobactam received, the risk of new antimicrobial resistance was increased by 8%. The authors concluded that defining a piperacillin/tazobactam course as 10 vs 7 days would result in a 24% higher relative risk of resistance per patient related to those 3 additional days of antimicrobial exposure.

Catheter complications including thrombophlebitis, infiltration, and infection are serious and frequent problems associated with IV medication administration.¹⁷ Even with short-term use, peripherally inserted central catheters (PICCs) carry a substantial risk of venous thrombosis (superficial and deep veins). The incidence of deep vein thrombosis (DVT) for PICCs is estimated between 5% and 15% for hospitalized patients and 2% and 5% for ambulatory patients.¹⁸ A recent randomized controlled trial (RCT) of oral vs IV antimicrobials for bone and joint infections reported that, compared with patients randomized to oral antimicrobials, those randomized to IV antimicrobials were more likely to have catheter complications (9.4% vs 1.0%; P < .001) and to discontinue therapy earlier (18.9% vs 12.8%; P = .006).¹⁹ Median hospital stay was also significantly longer in the IV group (14 days vs 11 days; P < .001).

Optimization of antimicrobial duration has long been recognized as one of the key strategies in reducing unnecessary antimicrobial exposure, yet high-quality evidence on comparative effectiveness of duration in the setting of bacteremia has been limited until recently.²⁰ The presence of bacteremia is often used as a justification for prolonged courses of antimicrobial regardless of infection source or clinical response. The Infectious Diseases Society of America guidelines suggest 7 to 14 days of treatment for intravascular catheter-associated gram-negative bacteremia, but the optimal duration for non–catheter-related gram-negative bacteremia is not addressed.²¹ This lack of clear guidance and the historical scarcity of robust data make it difficult to inform best practices, which leads to wide variability in clinical practice and 14 days being the most prescribed duration.^22,23

Pooled clinical trials’ data from subsets of patients with bacteremia and those from observational studies have been the best available evidence for the treatment duration of GN-BSI until recently (Table 1).^24-32 Two meta-analyses evaluating RCTs of adult and pediatric patients with pyelonephritis, UTI, peritonitis, and pneumonia found no differences in clinical failure, microbiologic cure, or survival between short and long courses of therapy in the subset of patient with associated bacteremia.^24,25 Six heterogeneous RCTs of short vs long courses of therapy for complicated UTI or pyelonephritis reported no differences in clinical cure rates in the subset of patients with associated GN-BSI.² The observational studies outlined in Table 1 are also consistent with RCT results supporting noninferiority in clinical cure and mortality outcomes between short and long courses of therapy.^26-32 These findings may also be extrapolated to immunocompromised hosts given a considerable representation of 10% to 47% of the study population with immunosuppressive conditions.

Nelson and colleagues conducted the only retrospective study to date reporting conflicting results of higher risk of treatment failure (defined as composite endpoint of mortality or recurrent infection within 90 days of index BSI) in patients receiving a short course of therapy.²⁷ However, the difference was driven by 90-day mortality (8.2% vs 3.3%; P = .04) not recurrent infection (6.7% vs 6.5%; P = 0.93). Giannella and colleagues also evaluated 90-day mortality as a primary endpoint in a much larger cohort of over 850 patients in Italy and found no difference in mortality rates between short and long courses of antimicrobials.³⁰

Yahav and colleagues conducted the first well-designed open-label RCT comparing short and long courses of antimicrobials in uncomplicated GN-BSI.³³ This noninferiority study randomized more than 600 hospitalized patients with adequate source control who were afebrile and hemodynamically stable for ≥48 hours to receive either 7 days or 14 days of therapy. The source of infections was predominantly urinary (68%), and the causative pathogens were 90% Enterobacteriacae, including 20% MDR strains. The primary outcome was a composite of 90-day all-cause mortality or clinical failure defined as either relapse of bacteremia, local or distant complications, readmission, or extended hospital stay >14 days. The authors reported no statistically significant differences in the primary outcome between short (45.8%) and long (48.3%) courses of treatment. In the prespecified post hoc analysis designed to evaluate infection-­related outcomes at an earlier time frame, there were no observed differences in complications, relapses, or mortality between study groups at 14 and 28 days. Further subgroup analysis demonstrated similar results among patients with MDR pathogens, primarily extended-spectrum ß-lactamases (ESBL). Interestingly, there was a more rapid return to baseline activity and functional capacity among patients randomized to a short course of therapy. The authors acknowledged that the patients’ perception of illness while taking antimicrobials may have influenced self-reported well-being and functional performance. In exploratory analysis, prolonged hospitalization and readmission were excluded from the primary study endpoint to mirror outcomes assessed by Nelson and colleagues. There were no statistically significant differences in death, relapses, or complications between groups randomized to short (18.6%) or long (15.1%) courses of therapy, with a risk difference of 3.5% (95% CI, –2.5% to 9.5%) in this study population.

Patients with Pseudomonas aeruginosa BSI often have more chronic medical comorbidities, immunocompromised conditions, higher severity of illness, and more indwelling catheters than do patients with Enterobacteriaceae BSI.³² It is uncertain whether shorter duration of therapy is generalizable to this population, given that Pseudomonas accounted for a relatively low number (8%) of infections in the published RCT.³³ Fabre and colleagues included high-risk patients with >65% of the cohort with severe immunocompromised conditions consisting of stem cell transplantation, recent chemotherapy, or neutropenia, and they reported no difference in 30-day mortality or recurrent infections among patients with pseudomonal BSI regardless of duration of therapy.³²

It is a well-accepted standard of practice that BSI are treated with upfront IV antimicrobials that can rapidly achieve therapeutic serum concentration. Whether IV administration is warranted for the entire duration of therapy, though, remains controversial. Even in an era of highly bioavailable oral antimicrobials, clinicians often assume that IV antimicrobials are more potent and efficacious than oral antimicrobials.^8,9 This belief has contributed to the dogma that IV therapy is necessary irrespective of the associated risks and costs. Oral antimicrobials are often overlooked as alternatives despite established benefits in avoiding complications associated with IV catheters, decreasing hospital LOS, and improving quality of life.³⁴ There are promising clinical data in support of the efficacy and safety of transitioning from sequential-IV to highly bioavailable oral agents for the treatment of uncomplicated bacteremia caused by both gram-positive and gram-negative pathogens.^2,35 Highly bioavailable oral antimicrobials are also increasingly integrated as sequential therapy for deep-seated infections in bone and joint infections, such as vertebral osteomyelitis.^19,36 These findings have been confirmed in a recent RCT demonstrating noninferiority of oral antimicrobial combinations after satisfactory clinical responses to at least 10 days of IV therapy, compared with continued IV regimens, in left-­sided infective endocarditis.³⁶ While not a prespecified endpoint, hospital LOS was shorter among patients randomized to oral antimicrobials.

Although there are no large-scale RCTs sufficiently powered to address the role of oral antimicrobials in the treatment of uncomplicated GN-BSI, some insights can be gleaned from the existing literature (Table 2). In the RCT establishing noninferiority of short vs long courses of antimicrobials for uncomplicated GN-BSI, the majority of patients randomized to 7 days vs 14 days of therapy, 64% and 81%, respectively, were de-escalated to oral antimicrobials, with fluoroquinolones (FQs) being the predominant (>70%) oral regimen, followed by trimethoprim/sulfamethoxazole (T/S) and oral ß-lactams.³³

Despite the Food and Drug Administration warnings of the potentially permanent adverse effects involving tendons, muscles, joints, nerves, and most recently, aortic aneurysms and ruptures,³⁷ FQs remain a unique class of drugs with favorable pharmacodynamic and pharmacokinetic properties that achieve approximately equivalent serum and tissue concentration when administered either intravenously or orally. This advantage was recognized early on as a potential IV-sparing therapeutic option. A prospective RCT that evaluated oral vs IV ciprofloxacin as initial empiric therapy among 141 patients with pyelonephritis or complicated UTI (38% with secondary BSI) reported no significant differences in microbiological failure or clinical response between the two treatment groups.³⁸ Two small RCTs have also demonstrated the safety and effectiveness of sequential-IV antimicrobial to oral FQs in the setting of GN-BSI secondary to urinary source and cholangitis.^39,40 Oral ß-lactams, however, achieve substantially lower serum concentration than do their IV counterparts and, accordingly, may be less reliably effective.²

Five retrospective cohort studies have more directly investigated the role of oral antimicrobials in the setting of GN-BSI secondary to common focal infections (Table 2 and Table 3).^41-45 Two observational studies reported no difference of treatment failure among patients who received IV-only therapy vs those who were switched to oral therapy in bacteremia secondary to UTIs.^41,42 Catheter-associated complications were higher in the IV cohort (6.1% vs 0.4%; P = .03).⁴² In the largest multicenter cohort study to date, which included 1,478 patients with Enterobacteriaceae bacteremia, there was no difference in 30-day mortality or recurrent bacteremia between patients converted to oral step-down therapy and patients who received the full course of IV antimicrobials.⁴³ Furthermore, the median hospital LOS was shorter (5 days vs 7 days; P < .001) among patients who were transitioned to oral therapy, a finding that is consistent with other studies.^39-42 In their analysis, the oral antimicrobials were categorized as low-bioavailability (ß-lactams) or high-bioavailability (FQ and T/S), and there was no difference in outcomes when results were stratified by bioavailability. Mercuro and colleagues reported similar clinical success among patients who received oral ß-lactams and those who received FQs as step-down therapy.⁴⁴ Notably, patients were more likely to tolerate ß-lactams without experiencing adverse effects than were those who received FQs (91.7% vs 82.1%; P = .049). In contrast, Kutob and colleagues compared step-down oral antimicrobials categorized as low bioavailability (ß-lactams), moderate bioavailability (ciprofloxacin and T/S), and high bioavailability (levofloxacin). They reported that treatment failures were significantly higher among patients who received low-bioavailability (14%) and moderate-­bioavailability (12%) antimicrobials, compared with those who received the high-bioavailability agent (2%; P = .02).⁴⁵ Interestingly, the bioavailability of ciprofloxacin reaches 85% and T/S approaches 90%, and they are often categorized as highly bioavailable agents in other studies.^43,46 If they were reclassified as highly bioavailable agents, the study conclusions might differ. Nevertheless, the reported success with oral step-down therapy exceeded 85% in all five studies.^41-45

It is important to acknowledge the possibility of unmeasured confounders in these retrospective, observational studies despite statistical adjustments and that they are likely underpowered to determine the clinical significance of oral bioavailability of antimicrobials. In a meta-analysis of published studies and abstracts that included 2,289 patients with Enterobacteriaceae bacteremia, all-cause mortality was similar between patients de-escalated to an oral FQ, T/S, or ß-lactam.⁴⁶ Overall recurrence of infection (bacteremia or primary site) occurred more frequently in patients transitioned to oral ß-lactams than FQs, but relapse of bacteremia was not statistically different between comparator groups. Bioavailability of the oral agents may not be the sole determinant of higher recurrence; adherence may be poor because of the more frequent dosing required for oral ß-lactams to achieve targeted pharmacokinetics. Additionally, suboptimal dosing of oral ß-lactams noted in the studies may have also contributed to the increased recurrences.

After source control has been achieved and bacterial inoculum burden is sufficiently reduced with appropriate upfront IV therapy, the bioavailability of oral antimicrobials may become less important. However, existing observational data indicate clinical experience is most established with highly bioavailable oral agents, particularly FQs, though the risks vs benefits require careful consideration. For now, the preferred oral agent remains uncertain and selections should be individualized based on susceptibility, patient factors, and other clinical considerations. More importantly, if there are no contraindications or concerns of malabsorption, oral step-down therapy should be initiated as soon as source control and good clinical responses have been achieved.

Routine follow-up blood cultures (FUBCs) are strongly recommended in Staphylococcus aureus bacteremia because of the propensity for endovascular and metastatic infection, which dictates clinical decision-making regarding duration of therapy. In contrast, GN-BSI secondary to focal infections is usually transient, and the need for confirmation of blood culture clearance is less clear. The low yield of FUBC in many clinical settings suggests that it may not be helpful.^47-50 Despite the questionable impact on the clinical management of GN-BSI, FUBCs are routinely ordered in the hospital.^1,47 Although there is no high-quality evidence addressing the utility of FUBC, several observational studies suggest clinicians should reconsider routinely ordering FUBC.

Canzoneri and colleagues retrospectively evaluated 383 episodes of bacteremia with at least one FUBC drawn after the initial blood culture.⁴⁸ On average, 2.32 FUBC were performed per patient for GN-BSI episode, and only 8 patients (5.7%) had persistent bacteremia. Specifically, only 3% had documented positive FUBC among patients with urinary tract source of infection. It was estimated that 17 FUBCs are needed to yield one positive result for GN-BSI. This finding is consistent with results from another study that examined 1,801 episodes of bacteremia, 901 of which were gram-negative organisms, predominantly (67%) Escherichia coli and Klebsiella spp.⁴⁹ Among GN-BSI episodes, FUBCs were performed in 247 cases, with 27 (10.9%) cases demonstrating persistent bacteremia. A nested case-­control analysis between patients with cleared or persistent bacteremia found a lower yield in FUBC with gram-negative organisms and a genitourinary source of infection. Moreover, persistent bacteremia did not influence a change in antimicrobial regimen. Kang and colleagues investigated 1,068 episodes of Klebsiella pneumoniae bacteremia, with FUBCs performed in 862 (80.7%) cases despite only a 7.2% incidence of persistent bacteremia.⁵⁰ The independent risk factors associated with persistent bacteremia were intra-abdominal infection, solid organ transplantation, high Charlson comorbidity index score, and unfavorable treatment responses, which suggests the need for FUBC may be individualized rather than routine.

In the setting of GN-BSI in which the probability of persistent bacteremia is relatively low, especially in genitourinary sources of infection, FUBCs are not warranted. It is uncomfortable for patients and exposes them to harms of false-positive results, leading to antimicrobial administration with possible adverse effects, which can be further compounded by unnecessary testing, potentially missed alternative diagnosis, and increasing hospital LOS.^1,51 Given the low yield of FUBC in GN-BSI, and the lack of association of persistent bacteremia with change in antimicrobial therapy or clinical outcomes, we recommend avoiding FUBC as a test of cure. Documentation of gram-negative blood culture clearance should be reserved for situations in which there is concern for deeper or otherwise uncontrolled source of infection.

The optimal management of gram-negative bacteremia in hospitalized patients is evolving. There is a growing body of evidence supporting shorter duration for a total of 7 days with oral step-down therapy as safe and effective for patients with uncomplicated Enterobacteriaceae bacteremia who have achieved adequate source control and demonstrated clinical stability and improvement. Although comparative data regarding the optimal duration of therapy in the setting of MDR strains such as ESBL Enterobacteriaceae and pseudomonal BSI are limited, available data appear promising in favor of shorter treatment duration with oral step-down therapy. Routine follow-up blood culture is not cost-effective and may result in unnecessary healthcare resource utilization and inappropriate use of antimicrobials. Table 4 provides a framework for the clinical management of GN-BSI in the hospital. Taken together, these steps will facilitate antimicrobial stewardship, limit unnecessary antimicrobial exposure, and improve quality of patient care.

The authors have no conflicts of interest to disclose.

Uncomplicated bacteremia, while not precisely defined in the literature, generally implies bacteremia in the absence of a persistent or difficult-to-eradicate infectious source. Bacteremia secondary to focal infections such as skin and soft-tissue infection, pneumonia, pyelonephritis, or urinary tract infection (UTI) accounts for up to 25% of bloodstream infections (BSIs) and usually resolves with prompt and appropriate antimicrobial therapy.^1,2 Current practice guidelines do not adequately address key aspects of the optimal management of gram-negative (GN)–BSI commonly encountered in hospital care.^3-7 Notably, antimicrobial duration, criteria to transition from intravenous (IV) to oral step-down therapy, choice of oral antimicrobials, and reassessment of follow-up blood cultures have not been addressed. In the absence of consensus guidelines, clinicians rely on “conventional wisdom” and clinical experience, which may not be supported by scientific rigor. A growing body of research now challenges some long-standing practices once thought to be standard of care.

In this narrative review, we aim to examine and synthesize emerging information to provide an evidence-based framework in the management of hospitalized patients with GN-BSI. We highlight the unintended consequences and potential harms of excessive antimicrobial exposure and focus on areas in the fundamental approach to duration of therapy, the role of oral antimicrobials, and usefulness of follow-up blood cultures. A comprehensive search of the published literature was performed in PubMed with an emphasis on articles published during 2015-2019 with use of search terms including gram-negative bacteremia, duration, antibiotics, adverse effects, intravascular catheter, and follow-up blood cultures.

Antimicrobial overuse is common and may be driven by concerns for undertreatment. Clinicians may believe that prolonged antimicrobial therapy maximizes cure rates, with treatment duration often defined arbitrarily by a fixed number of “Constantine-units” (dating back to the ancient Roman emperor’s decree of 7 days in a week).^8-10 Recent publications refute this notion and point out that the harms of overprescribing outweigh the perceived benefits of longer treatment duration.

Antimicrobials are lifesaving but not benign; adverse effects are common and costly to our patients and healthcare system. Among 1,488 hospitalized adults who received at least 24 hours of systemic antimicrobials, 20% had an antimicrobial-­associated adverse event, mostly gastrointestinal, renal, or hematologic in nature.¹¹ Prolonged duration of antimicrobials is further associated with adverse effects such as antimicrobial-associated diarrhea, increased rates of Clostridioides difficile infection (CDI), emergence of antimicrobial resistance, and longer hospital length of stay (LOS).^11-15 Vaughn and colleagues conducted the largest observational study to date, evaluating antimicrobial prescriptions for the treatment of nearly 6,500 adults with community-acquired pneumonia in a 43-hospital consortium in Michigan.¹⁴ More than two-thirds of patients received antimicrobial courses (median 8 days) that exceeded guideline-­recommended duration. Patients who received longer antimicrobial courses did not have reduced mortality, readmission, or emergency department visits. More importantly, each excess day of treatment was associated with a relative 5% increase in the odds of antimicrobial-associated adverse effects reported by patients. This is further supported by national and state hospital data that antimicrobial-associated adverse events are an independent predictor of longer LOS.¹²

CDI is commonly linked to destructive changes to the indigenous microbiota of the intestinal flora caused by antimicrobial administration. Stevens and colleagues identified 7,792 hospitalized patients who received at least 2 consecutive days of antimicrobial therapy¹³; comparing 241 cases of CDI with the control group, they observed a dose-dependent risk of CDI associated with increasing cumulative dose, number of antimicrobials, and days of antimicrobial exposure. Compared with patients who received fewer than 4 days of antimicrobials, the adjusted hazard ratios (aHR) for those who received 4-7 days or 8-18 days of therapy were 1.4 (95% CI, 0.8-2.4) and 3.0 (95% CI, 1.9-5.0), respectively. This correlates to a threefold increase in CDI risk for patients who received more than 7 days of antimicrobials. More specifically, the empiric use of antipseudomonal ß-lactams (APBL) for more than 48 hours was also found to be an independent risk factor for CDI among 808 patients with Enterobacteriaceae BSI.¹⁶ The risk of CDI within 90 days of BSI was higher among those who received >48 hours of APBL than it was among those who received ≤48 hours (HR, 3.6; 95% CI, 1.5-9.9).

While C difficile may be the most well-known pathogen implicated in antimicrobial usage, the incidence of multidrug-­resistant (MDR) organisms, either as infectious or colonizing pathogens, is also tied to antimicrobial exposure. Among patients receiving systemic antimicrobials, 6% developed an MDR infection within 90 days.¹¹ Over a 5-year period, Teshome and colleagues evaluated 7,118 critically ill patients and demonstrated that prolonged exposures to APBLs increased the risk of new antimicrobial resistance within 60 days.¹⁵ This resistance pattern was not an institutional or environmental finding but a patient-level finding. For each additional day of cefepime or piperacillin/tazobactam received, the risk of new antimicrobial resistance was increased by 8%. The authors concluded that defining a piperacillin/tazobactam course as 10 vs 7 days would result in a 24% higher relative risk of resistance per patient related to those 3 additional days of antimicrobial exposure.

Catheter complications including thrombophlebitis, infiltration, and infection are serious and frequent problems associated with IV medication administration.¹⁷ Even with short-term use, peripherally inserted central catheters (PICCs) carry a substantial risk of venous thrombosis (superficial and deep veins). The incidence of deep vein thrombosis (DVT) for PICCs is estimated between 5% and 15% for hospitalized patients and 2% and 5% for ambulatory patients.¹⁸ A recent randomized controlled trial (RCT) of oral vs IV antimicrobials for bone and joint infections reported that, compared with patients randomized to oral antimicrobials, those randomized to IV antimicrobials were more likely to have catheter complications (9.4% vs 1.0%; P < .001) and to discontinue therapy earlier (18.9% vs 12.8%; P = .006).¹⁹ Median hospital stay was also significantly longer in the IV group (14 days vs 11 days; P < .001).

Optimization of antimicrobial duration has long been recognized as one of the key strategies in reducing unnecessary antimicrobial exposure, yet high-quality evidence on comparative effectiveness of duration in the setting of bacteremia has been limited until recently.²⁰ The presence of bacteremia is often used as a justification for prolonged courses of antimicrobial regardless of infection source or clinical response. The Infectious Diseases Society of America guidelines suggest 7 to 14 days of treatment for intravascular catheter-associated gram-negative bacteremia, but the optimal duration for non–catheter-related gram-negative bacteremia is not addressed.²¹ This lack of clear guidance and the historical scarcity of robust data make it difficult to inform best practices, which leads to wide variability in clinical practice and 14 days being the most prescribed duration.^22,23

Pooled clinical trials’ data from subsets of patients with bacteremia and those from observational studies have been the best available evidence for the treatment duration of GN-BSI until recently (Table 1).^24-32 Two meta-analyses evaluating RCTs of adult and pediatric patients with pyelonephritis, UTI, peritonitis, and pneumonia found no differences in clinical failure, microbiologic cure, or survival between short and long courses of therapy in the subset of patient with associated bacteremia.^24,25 Six heterogeneous RCTs of short vs long courses of therapy for complicated UTI or pyelonephritis reported no differences in clinical cure rates in the subset of patients with associated GN-BSI.² The observational studies outlined in Table 1 are also consistent with RCT results supporting noninferiority in clinical cure and mortality outcomes between short and long courses of therapy.^26-32 These findings may also be extrapolated to immunocompromised hosts given a considerable representation of 10% to 47% of the study population with immunosuppressive conditions.

Nelson and colleagues conducted the only retrospective study to date reporting conflicting results of higher risk of treatment failure (defined as composite endpoint of mortality or recurrent infection within 90 days of index BSI) in patients receiving a short course of therapy.²⁷ However, the difference was driven by 90-day mortality (8.2% vs 3.3%; P = .04) not recurrent infection (6.7% vs 6.5%; P = 0.93). Giannella and colleagues also evaluated 90-day mortality as a primary endpoint in a much larger cohort of over 850 patients in Italy and found no difference in mortality rates between short and long courses of antimicrobials.³⁰

Yahav and colleagues conducted the first well-designed open-label RCT comparing short and long courses of antimicrobials in uncomplicated GN-BSI.³³ This noninferiority study randomized more than 600 hospitalized patients with adequate source control who were afebrile and hemodynamically stable for ≥48 hours to receive either 7 days or 14 days of therapy. The source of infections was predominantly urinary (68%), and the causative pathogens were 90% Enterobacteriacae, including 20% MDR strains. The primary outcome was a composite of 90-day all-cause mortality or clinical failure defined as either relapse of bacteremia, local or distant complications, readmission, or extended hospital stay >14 days. The authors reported no statistically significant differences in the primary outcome between short (45.8%) and long (48.3%) courses of treatment. In the prespecified post hoc analysis designed to evaluate infection-­related outcomes at an earlier time frame, there were no observed differences in complications, relapses, or mortality between study groups at 14 and 28 days. Further subgroup analysis demonstrated similar results among patients with MDR pathogens, primarily extended-spectrum ß-lactamases (ESBL). Interestingly, there was a more rapid return to baseline activity and functional capacity among patients randomized to a short course of therapy. The authors acknowledged that the patients’ perception of illness while taking antimicrobials may have influenced self-reported well-being and functional performance. In exploratory analysis, prolonged hospitalization and readmission were excluded from the primary study endpoint to mirror outcomes assessed by Nelson and colleagues. There were no statistically significant differences in death, relapses, or complications between groups randomized to short (18.6%) or long (15.1%) courses of therapy, with a risk difference of 3.5% (95% CI, –2.5% to 9.5%) in this study population.

Patients with Pseudomonas aeruginosa BSI often have more chronic medical comorbidities, immunocompromised conditions, higher severity of illness, and more indwelling catheters than do patients with Enterobacteriaceae BSI.³² It is uncertain whether shorter duration of therapy is generalizable to this population, given that Pseudomonas accounted for a relatively low number (8%) of infections in the published RCT.³³ Fabre and colleagues included high-risk patients with >65% of the cohort with severe immunocompromised conditions consisting of stem cell transplantation, recent chemotherapy, or neutropenia, and they reported no difference in 30-day mortality or recurrent infections among patients with pseudomonal BSI regardless of duration of therapy.³²

It is a well-accepted standard of practice that BSI are treated with upfront IV antimicrobials that can rapidly achieve therapeutic serum concentration. Whether IV administration is warranted for the entire duration of therapy, though, remains controversial. Even in an era of highly bioavailable oral antimicrobials, clinicians often assume that IV antimicrobials are more potent and efficacious than oral antimicrobials.^8,9 This belief has contributed to the dogma that IV therapy is necessary irrespective of the associated risks and costs. Oral antimicrobials are often overlooked as alternatives despite established benefits in avoiding complications associated with IV catheters, decreasing hospital LOS, and improving quality of life.³⁴ There are promising clinical data in support of the efficacy and safety of transitioning from sequential-IV to highly bioavailable oral agents for the treatment of uncomplicated bacteremia caused by both gram-positive and gram-negative pathogens.^2,35 Highly bioavailable oral antimicrobials are also increasingly integrated as sequential therapy for deep-seated infections in bone and joint infections, such as vertebral osteomyelitis.^19,36 These findings have been confirmed in a recent RCT demonstrating noninferiority of oral antimicrobial combinations after satisfactory clinical responses to at least 10 days of IV therapy, compared with continued IV regimens, in left-­sided infective endocarditis.³⁶ While not a prespecified endpoint, hospital LOS was shorter among patients randomized to oral antimicrobials.

Although there are no large-scale RCTs sufficiently powered to address the role of oral antimicrobials in the treatment of uncomplicated GN-BSI, some insights can be gleaned from the existing literature (Table 2). In the RCT establishing noninferiority of short vs long courses of antimicrobials for uncomplicated GN-BSI, the majority of patients randomized to 7 days vs 14 days of therapy, 64% and 81%, respectively, were de-escalated to oral antimicrobials, with fluoroquinolones (FQs) being the predominant (>70%) oral regimen, followed by trimethoprim/sulfamethoxazole (T/S) and oral ß-lactams.³³

Despite the Food and Drug Administration warnings of the potentially permanent adverse effects involving tendons, muscles, joints, nerves, and most recently, aortic aneurysms and ruptures,³⁷ FQs remain a unique class of drugs with favorable pharmacodynamic and pharmacokinetic properties that achieve approximately equivalent serum and tissue concentration when administered either intravenously or orally. This advantage was recognized early on as a potential IV-sparing therapeutic option. A prospective RCT that evaluated oral vs IV ciprofloxacin as initial empiric therapy among 141 patients with pyelonephritis or complicated UTI (38% with secondary BSI) reported no significant differences in microbiological failure or clinical response between the two treatment groups.³⁸ Two small RCTs have also demonstrated the safety and effectiveness of sequential-IV antimicrobial to oral FQs in the setting of GN-BSI secondary to urinary source and cholangitis.^39,40 Oral ß-lactams, however, achieve substantially lower serum concentration than do their IV counterparts and, accordingly, may be less reliably effective.²

Five retrospective cohort studies have more directly investigated the role of oral antimicrobials in the setting of GN-BSI secondary to common focal infections (Table 2 and Table 3).^41-45 Two observational studies reported no difference of treatment failure among patients who received IV-only therapy vs those who were switched to oral therapy in bacteremia secondary to UTIs.^41,42 Catheter-associated complications were higher in the IV cohort (6.1% vs 0.4%; P = .03).⁴² In the largest multicenter cohort study to date, which included 1,478 patients with Enterobacteriaceae bacteremia, there was no difference in 30-day mortality or recurrent bacteremia between patients converted to oral step-down therapy and patients who received the full course of IV antimicrobials.⁴³ Furthermore, the median hospital LOS was shorter (5 days vs 7 days; P < .001) among patients who were transitioned to oral therapy, a finding that is consistent with other studies.^39-42 In their analysis, the oral antimicrobials were categorized as low-bioavailability (ß-lactams) or high-bioavailability (FQ and T/S), and there was no difference in outcomes when results were stratified by bioavailability. Mercuro and colleagues reported similar clinical success among patients who received oral ß-lactams and those who received FQs as step-down therapy.⁴⁴ Notably, patients were more likely to tolerate ß-lactams without experiencing adverse effects than were those who received FQs (91.7% vs 82.1%; P = .049). In contrast, Kutob and colleagues compared step-down oral antimicrobials categorized as low bioavailability (ß-lactams), moderate bioavailability (ciprofloxacin and T/S), and high bioavailability (levofloxacin). They reported that treatment failures were significantly higher among patients who received low-bioavailability (14%) and moderate-­bioavailability (12%) antimicrobials, compared with those who received the high-bioavailability agent (2%; P = .02).⁴⁵ Interestingly, the bioavailability of ciprofloxacin reaches 85% and T/S approaches 90%, and they are often categorized as highly bioavailable agents in other studies.^43,46 If they were reclassified as highly bioavailable agents, the study conclusions might differ. Nevertheless, the reported success with oral step-down therapy exceeded 85% in all five studies.^41-45

It is important to acknowledge the possibility of unmeasured confounders in these retrospective, observational studies despite statistical adjustments and that they are likely underpowered to determine the clinical significance of oral bioavailability of antimicrobials. In a meta-analysis of published studies and abstracts that included 2,289 patients with Enterobacteriaceae bacteremia, all-cause mortality was similar between patients de-escalated to an oral FQ, T/S, or ß-lactam.⁴⁶ Overall recurrence of infection (bacteremia or primary site) occurred more frequently in patients transitioned to oral ß-lactams than FQs, but relapse of bacteremia was not statistically different between comparator groups. Bioavailability of the oral agents may not be the sole determinant of higher recurrence; adherence may be poor because of the more frequent dosing required for oral ß-lactams to achieve targeted pharmacokinetics. Additionally, suboptimal dosing of oral ß-lactams noted in the studies may have also contributed to the increased recurrences.

After source control has been achieved and bacterial inoculum burden is sufficiently reduced with appropriate upfront IV therapy, the bioavailability of oral antimicrobials may become less important. However, existing observational data indicate clinical experience is most established with highly bioavailable oral agents, particularly FQs, though the risks vs benefits require careful consideration. For now, the preferred oral agent remains uncertain and selections should be individualized based on susceptibility, patient factors, and other clinical considerations. More importantly, if there are no contraindications or concerns of malabsorption, oral step-down therapy should be initiated as soon as source control and good clinical responses have been achieved.

Routine follow-up blood cultures (FUBCs) are strongly recommended in Staphylococcus aureus bacteremia because of the propensity for endovascular and metastatic infection, which dictates clinical decision-making regarding duration of therapy. In contrast, GN-BSI secondary to focal infections is usually transient, and the need for confirmation of blood culture clearance is less clear. The low yield of FUBC in many clinical settings suggests that it may not be helpful.^47-50 Despite the questionable impact on the clinical management of GN-BSI, FUBCs are routinely ordered in the hospital.^1,47 Although there is no high-quality evidence addressing the utility of FUBC, several observational studies suggest clinicians should reconsider routinely ordering FUBC.

Canzoneri and colleagues retrospectively evaluated 383 episodes of bacteremia with at least one FUBC drawn after the initial blood culture.⁴⁸ On average, 2.32 FUBC were performed per patient for GN-BSI episode, and only 8 patients (5.7%) had persistent bacteremia. Specifically, only 3% had documented positive FUBC among patients with urinary tract source of infection. It was estimated that 17 FUBCs are needed to yield one positive result for GN-BSI. This finding is consistent with results from another study that examined 1,801 episodes of bacteremia, 901 of which were gram-negative organisms, predominantly (67%) Escherichia coli and Klebsiella spp.⁴⁹ Among GN-BSI episodes, FUBCs were performed in 247 cases, with 27 (10.9%) cases demonstrating persistent bacteremia. A nested case-­control analysis between patients with cleared or persistent bacteremia found a lower yield in FUBC with gram-negative organisms and a genitourinary source of infection. Moreover, persistent bacteremia did not influence a change in antimicrobial regimen. Kang and colleagues investigated 1,068 episodes of Klebsiella pneumoniae bacteremia, with FUBCs performed in 862 (80.7%) cases despite only a 7.2% incidence of persistent bacteremia.⁵⁰ The independent risk factors associated with persistent bacteremia were intra-abdominal infection, solid organ transplantation, high Charlson comorbidity index score, and unfavorable treatment responses, which suggests the need for FUBC may be individualized rather than routine.

In the setting of GN-BSI in which the probability of persistent bacteremia is relatively low, especially in genitourinary sources of infection, FUBCs are not warranted. It is uncomfortable for patients and exposes them to harms of false-positive results, leading to antimicrobial administration with possible adverse effects, which can be further compounded by unnecessary testing, potentially missed alternative diagnosis, and increasing hospital LOS.^1,51 Given the low yield of FUBC in GN-BSI, and the lack of association of persistent bacteremia with change in antimicrobial therapy or clinical outcomes, we recommend avoiding FUBC as a test of cure. Documentation of gram-negative blood culture clearance should be reserved for situations in which there is concern for deeper or otherwise uncontrolled source of infection.

The optimal management of gram-negative bacteremia in hospitalized patients is evolving. There is a growing body of evidence supporting shorter duration for a total of 7 days with oral step-down therapy as safe and effective for patients with uncomplicated Enterobacteriaceae bacteremia who have achieved adequate source control and demonstrated clinical stability and improvement. Although comparative data regarding the optimal duration of therapy in the setting of MDR strains such as ESBL Enterobacteriaceae and pseudomonal BSI are limited, available data appear promising in favor of shorter treatment duration with oral step-down therapy. Routine follow-up blood culture is not cost-effective and may result in unnecessary healthcare resource utilization and inappropriate use of antimicrobials. Table 4 provides a framework for the clinical management of GN-BSI in the hospital. Taken together, these steps will facilitate antimicrobial stewardship, limit unnecessary antimicrobial exposure, and improve quality of patient care.

The authors have no conflicts of interest to disclose.

Uncomplicated bacteremia, while not precisely defined in the literature, generally implies bacteremia in the absence of a persistent or difficult-to-eradicate infectious source. Bacteremia secondary to focal infections such as skin and soft-tissue infection, pneumonia, pyelonephritis, or urinary tract infection (UTI) accounts for up to 25% of bloodstream infections (BSIs) and usually resolves with prompt and appropriate antimicrobial therapy.^1,2 Current practice guidelines do not adequately address key aspects of the optimal management of gram-negative (GN)–BSI commonly encountered in hospital care.^3-7 Notably, antimicrobial duration, criteria to transition from intravenous (IV) to oral step-down therapy, choice of oral antimicrobials, and reassessment of follow-up blood cultures have not been addressed. In the absence of consensus guidelines, clinicians rely on “conventional wisdom” and clinical experience, which may not be supported by scientific rigor. A growing body of research now challenges some long-standing practices once thought to be standard of care.

In this narrative review, we aim to examine and synthesize emerging information to provide an evidence-based framework in the management of hospitalized patients with GN-BSI. We highlight the unintended consequences and potential harms of excessive antimicrobial exposure and focus on areas in the fundamental approach to duration of therapy, the role of oral antimicrobials, and usefulness of follow-up blood cultures. A comprehensive search of the published literature was performed in PubMed with an emphasis on articles published during 2015-2019 with use of search terms including gram-negative bacteremia, duration, antibiotics, adverse effects, intravascular catheter, and follow-up blood cultures.

Antimicrobial overuse is common and may be driven by concerns for undertreatment. Clinicians may believe that prolonged antimicrobial therapy maximizes cure rates, with treatment duration often defined arbitrarily by a fixed number of “Constantine-units” (dating back to the ancient Roman emperor’s decree of 7 days in a week).^8-10 Recent publications refute this notion and point out that the harms of overprescribing outweigh the perceived benefits of longer treatment duration.

Antimicrobials are lifesaving but not benign; adverse effects are common and costly to our patients and healthcare system. Among 1,488 hospitalized adults who received at least 24 hours of systemic antimicrobials, 20% had an antimicrobial-­associated adverse event, mostly gastrointestinal, renal, or hematologic in nature.¹¹ Prolonged duration of antimicrobials is further associated with adverse effects such as antimicrobial-associated diarrhea, increased rates of Clostridioides difficile infection (CDI), emergence of antimicrobial resistance, and longer hospital length of stay (LOS).^11-15 Vaughn and colleagues conducted the largest observational study to date, evaluating antimicrobial prescriptions for the treatment of nearly 6,500 adults with community-acquired pneumonia in a 43-hospital consortium in Michigan.¹⁴ More than two-thirds of patients received antimicrobial courses (median 8 days) that exceeded guideline-­recommended duration. Patients who received longer antimicrobial courses did not have reduced mortality, readmission, or emergency department visits. More importantly, each excess day of treatment was associated with a relative 5% increase in the odds of antimicrobial-associated adverse effects reported by patients. This is further supported by national and state hospital data that antimicrobial-associated adverse events are an independent predictor of longer LOS.¹²

CDI is commonly linked to destructive changes to the indigenous microbiota of the intestinal flora caused by antimicrobial administration. Stevens and colleagues identified 7,792 hospitalized patients who received at least 2 consecutive days of antimicrobial therapy¹³; comparing 241 cases of CDI with the control group, they observed a dose-dependent risk of CDI associated with increasing cumulative dose, number of antimicrobials, and days of antimicrobial exposure. Compared with patients who received fewer than 4 days of antimicrobials, the adjusted hazard ratios (aHR) for those who received 4-7 days or 8-18 days of therapy were 1.4 (95% CI, 0.8-2.4) and 3.0 (95% CI, 1.9-5.0), respectively. This correlates to a threefold increase in CDI risk for patients who received more than 7 days of antimicrobials. More specifically, the empiric use of antipseudomonal ß-lactams (APBL) for more than 48 hours was also found to be an independent risk factor for CDI among 808 patients with Enterobacteriaceae BSI.¹⁶ The risk of CDI within 90 days of BSI was higher among those who received >48 hours of APBL than it was among those who received ≤48 hours (HR, 3.6; 95% CI, 1.5-9.9).

While C difficile may be the most well-known pathogen implicated in antimicrobial usage, the incidence of multidrug-­resistant (MDR) organisms, either as infectious or colonizing pathogens, is also tied to antimicrobial exposure. Among patients receiving systemic antimicrobials, 6% developed an MDR infection within 90 days.¹¹ Over a 5-year period, Teshome and colleagues evaluated 7,118 critically ill patients and demonstrated that prolonged exposures to APBLs increased the risk of new antimicrobial resistance within 60 days.¹⁵ This resistance pattern was not an institutional or environmental finding but a patient-level finding. For each additional day of cefepime or piperacillin/tazobactam received, the risk of new antimicrobial resistance was increased by 8%. The authors concluded that defining a piperacillin/tazobactam course as 10 vs 7 days would result in a 24% higher relative risk of resistance per patient related to those 3 additional days of antimicrobial exposure.

Catheter complications including thrombophlebitis, infiltration, and infection are serious and frequent problems associated with IV medication administration.¹⁷ Even with short-term use, peripherally inserted central catheters (PICCs) carry a substantial risk of venous thrombosis (superficial and deep veins). The incidence of deep vein thrombosis (DVT) for PICCs is estimated between 5% and 15% for hospitalized patients and 2% and 5% for ambulatory patients.¹⁸ A recent randomized controlled trial (RCT) of oral vs IV antimicrobials for bone and joint infections reported that, compared with patients randomized to oral antimicrobials, those randomized to IV antimicrobials were more likely to have catheter complications (9.4% vs 1.0%; P < .001) and to discontinue therapy earlier (18.9% vs 12.8%; P = .006).¹⁹ Median hospital stay was also significantly longer in the IV group (14 days vs 11 days; P < .001).

Optimization of antimicrobial duration has long been recognized as one of the key strategies in reducing unnecessary antimicrobial exposure, yet high-quality evidence on comparative effectiveness of duration in the setting of bacteremia has been limited until recently.²⁰ The presence of bacteremia is often used as a justification for prolonged courses of antimicrobial regardless of infection source or clinical response. The Infectious Diseases Society of America guidelines suggest 7 to 14 days of treatment for intravascular catheter-associated gram-negative bacteremia, but the optimal duration for non–catheter-related gram-negative bacteremia is not addressed.²¹ This lack of clear guidance and the historical scarcity of robust data make it difficult to inform best practices, which leads to wide variability in clinical practice and 14 days being the most prescribed duration.^22,23

Pooled clinical trials’ data from subsets of patients with bacteremia and those from observational studies have been the best available evidence for the treatment duration of GN-BSI until recently (Table 1).^24-32 Two meta-analyses evaluating RCTs of adult and pediatric patients with pyelonephritis, UTI, peritonitis, and pneumonia found no differences in clinical failure, microbiologic cure, or survival between short and long courses of therapy in the subset of patient with associated bacteremia.^24,25 Six heterogeneous RCTs of short vs long courses of therapy for complicated UTI or pyelonephritis reported no differences in clinical cure rates in the subset of patients with associated GN-BSI.² The observational studies outlined in Table 1 are also consistent with RCT results supporting noninferiority in clinical cure and mortality outcomes between short and long courses of therapy.^26-32 These findings may also be extrapolated to immunocompromised hosts given a considerable representation of 10% to 47% of the study population with immunosuppressive conditions.

Nelson and colleagues conducted the only retrospective study to date reporting conflicting results of higher risk of treatment failure (defined as composite endpoint of mortality or recurrent infection within 90 days of index BSI) in patients receiving a short course of therapy.²⁷ However, the difference was driven by 90-day mortality (8.2% vs 3.3%; P = .04) not recurrent infection (6.7% vs 6.5%; P = 0.93). Giannella and colleagues also evaluated 90-day mortality as a primary endpoint in a much larger cohort of over 850 patients in Italy and found no difference in mortality rates between short and long courses of antimicrobials.³⁰

Yahav and colleagues conducted the first well-designed open-label RCT comparing short and long courses of antimicrobials in uncomplicated GN-BSI.³³ This noninferiority study randomized more than 600 hospitalized patients with adequate source control who were afebrile and hemodynamically stable for ≥48 hours to receive either 7 days or 14 days of therapy. The source of infections was predominantly urinary (68%), and the causative pathogens were 90% Enterobacteriacae, including 20% MDR strains. The primary outcome was a composite of 90-day all-cause mortality or clinical failure defined as either relapse of bacteremia, local or distant complications, readmission, or extended hospital stay >14 days. The authors reported no statistically significant differences in the primary outcome between short (45.8%) and long (48.3%) courses of treatment. In the prespecified post hoc analysis designed to evaluate infection-­related outcomes at an earlier time frame, there were no observed differences in complications, relapses, or mortality between study groups at 14 and 28 days. Further subgroup analysis demonstrated similar results among patients with MDR pathogens, primarily extended-spectrum ß-lactamases (ESBL). Interestingly, there was a more rapid return to baseline activity and functional capacity among patients randomized to a short course of therapy. The authors acknowledged that the patients’ perception of illness while taking antimicrobials may have influenced self-reported well-being and functional performance. In exploratory analysis, prolonged hospitalization and readmission were excluded from the primary study endpoint to mirror outcomes assessed by Nelson and colleagues. There were no statistically significant differences in death, relapses, or complications between groups randomized to short (18.6%) or long (15.1%) courses of therapy, with a risk difference of 3.5% (95% CI, –2.5% to 9.5%) in this study population.

Patients with Pseudomonas aeruginosa BSI often have more chronic medical comorbidities, immunocompromised conditions, higher severity of illness, and more indwelling catheters than do patients with Enterobacteriaceae BSI.³² It is uncertain whether shorter duration of therapy is generalizable to this population, given that Pseudomonas accounted for a relatively low number (8%) of infections in the published RCT.³³ Fabre and colleagues included high-risk patients with >65% of the cohort with severe immunocompromised conditions consisting of stem cell transplantation, recent chemotherapy, or neutropenia, and they reported no difference in 30-day mortality or recurrent infections among patients with pseudomonal BSI regardless of duration of therapy.³²

It is a well-accepted standard of practice that BSI are treated with upfront IV antimicrobials that can rapidly achieve therapeutic serum concentration. Whether IV administration is warranted for the entire duration of therapy, though, remains controversial. Even in an era of highly bioavailable oral antimicrobials, clinicians often assume that IV antimicrobials are more potent and efficacious than oral antimicrobials.^8,9 This belief has contributed to the dogma that IV therapy is necessary irrespective of the associated risks and costs. Oral antimicrobials are often overlooked as alternatives despite established benefits in avoiding complications associated with IV catheters, decreasing hospital LOS, and improving quality of life.³⁴ There are promising clinical data in support of the efficacy and safety of transitioning from sequential-IV to highly bioavailable oral agents for the treatment of uncomplicated bacteremia caused by both gram-positive and gram-negative pathogens.^2,35 Highly bioavailable oral antimicrobials are also increasingly integrated as sequential therapy for deep-seated infections in bone and joint infections, such as vertebral osteomyelitis.^19,36 These findings have been confirmed in a recent RCT demonstrating noninferiority of oral antimicrobial combinations after satisfactory clinical responses to at least 10 days of IV therapy, compared with continued IV regimens, in left-­sided infective endocarditis.³⁶ While not a prespecified endpoint, hospital LOS was shorter among patients randomized to oral antimicrobials.

Although there are no large-scale RCTs sufficiently powered to address the role of oral antimicrobials in the treatment of uncomplicated GN-BSI, some insights can be gleaned from the existing literature (Table 2). In the RCT establishing noninferiority of short vs long courses of antimicrobials for uncomplicated GN-BSI, the majority of patients randomized to 7 days vs 14 days of therapy, 64% and 81%, respectively, were de-escalated to oral antimicrobials, with fluoroquinolones (FQs) being the predominant (>70%) oral regimen, followed by trimethoprim/sulfamethoxazole (T/S) and oral ß-lactams.³³

Despite the Food and Drug Administration warnings of the potentially permanent adverse effects involving tendons, muscles, joints, nerves, and most recently, aortic aneurysms and ruptures,³⁷ FQs remain a unique class of drugs with favorable pharmacodynamic and pharmacokinetic properties that achieve approximately equivalent serum and tissue concentration when administered either intravenously or orally. This advantage was recognized early on as a potential IV-sparing therapeutic option. A prospective RCT that evaluated oral vs IV ciprofloxacin as initial empiric therapy among 141 patients with pyelonephritis or complicated UTI (38% with secondary BSI) reported no significant differences in microbiological failure or clinical response between the two treatment groups.³⁸ Two small RCTs have also demonstrated the safety and effectiveness of sequential-IV antimicrobial to oral FQs in the setting of GN-BSI secondary to urinary source and cholangitis.^39,40 Oral ß-lactams, however, achieve substantially lower serum concentration than do their IV counterparts and, accordingly, may be less reliably effective.²

Five retrospective cohort studies have more directly investigated the role of oral antimicrobials in the setting of GN-BSI secondary to common focal infections (Table 2 and Table 3).^41-45 Two observational studies reported no difference of treatment failure among patients who received IV-only therapy vs those who were switched to oral therapy in bacteremia secondary to UTIs.^41,42 Catheter-associated complications were higher in the IV cohort (6.1% vs 0.4%; P = .03).⁴² In the largest multicenter cohort study to date, which included 1,478 patients with Enterobacteriaceae bacteremia, there was no difference in 30-day mortality or recurrent bacteremia between patients converted to oral step-down therapy and patients who received the full course of IV antimicrobials.⁴³ Furthermore, the median hospital LOS was shorter (5 days vs 7 days; P < .001) among patients who were transitioned to oral therapy, a finding that is consistent with other studies.^39-42 In their analysis, the oral antimicrobials were categorized as low-bioavailability (ß-lactams) or high-bioavailability (FQ and T/S), and there was no difference in outcomes when results were stratified by bioavailability. Mercuro and colleagues reported similar clinical success among patients who received oral ß-lactams and those who received FQs as step-down therapy.⁴⁴ Notably, patients were more likely to tolerate ß-lactams without experiencing adverse effects than were those who received FQs (91.7% vs 82.1%; P = .049). In contrast, Kutob and colleagues compared step-down oral antimicrobials categorized as low bioavailability (ß-lactams), moderate bioavailability (ciprofloxacin and T/S), and high bioavailability (levofloxacin). They reported that treatment failures were significantly higher among patients who received low-bioavailability (14%) and moderate-­bioavailability (12%) antimicrobials, compared with those who received the high-bioavailability agent (2%; P = .02).⁴⁵ Interestingly, the bioavailability of ciprofloxacin reaches 85% and T/S approaches 90%, and they are often categorized as highly bioavailable agents in other studies.^43,46 If they were reclassified as highly bioavailable agents, the study conclusions might differ. Nevertheless, the reported success with oral step-down therapy exceeded 85% in all five studies.^41-45

It is important to acknowledge the possibility of unmeasured confounders in these retrospective, observational studies despite statistical adjustments and that they are likely underpowered to determine the clinical significance of oral bioavailability of antimicrobials. In a meta-analysis of published studies and abstracts that included 2,289 patients with Enterobacteriaceae bacteremia, all-cause mortality was similar between patients de-escalated to an oral FQ, T/S, or ß-lactam.⁴⁶ Overall recurrence of infection (bacteremia or primary site) occurred more frequently in patients transitioned to oral ß-lactams than FQs, but relapse of bacteremia was not statistically different between comparator groups. Bioavailability of the oral agents may not be the sole determinant of higher recurrence; adherence may be poor because of the more frequent dosing required for oral ß-lactams to achieve targeted pharmacokinetics. Additionally, suboptimal dosing of oral ß-lactams noted in the studies may have also contributed to the increased recurrences.

After source control has been achieved and bacterial inoculum burden is sufficiently reduced with appropriate upfront IV therapy, the bioavailability of oral antimicrobials may become less important. However, existing observational data indicate clinical experience is most established with highly bioavailable oral agents, particularly FQs, though the risks vs benefits require careful consideration. For now, the preferred oral agent remains uncertain and selections should be individualized based on susceptibility, patient factors, and other clinical considerations. More importantly, if there are no contraindications or concerns of malabsorption, oral step-down therapy should be initiated as soon as source control and good clinical responses have been achieved.

Routine follow-up blood cultures (FUBCs) are strongly recommended in Staphylococcus aureus bacteremia because of the propensity for endovascular and metastatic infection, which dictates clinical decision-making regarding duration of therapy. In contrast, GN-BSI secondary to focal infections is usually transient, and the need for confirmation of blood culture clearance is less clear. The low yield of FUBC in many clinical settings suggests that it may not be helpful.^47-50 Despite the questionable impact on the clinical management of GN-BSI, FUBCs are routinely ordered in the hospital.^1,47 Although there is no high-quality evidence addressing the utility of FUBC, several observational studies suggest clinicians should reconsider routinely ordering FUBC.

Canzoneri and colleagues retrospectively evaluated 383 episodes of bacteremia with at least one FUBC drawn after the initial blood culture.⁴⁸ On average, 2.32 FUBC were performed per patient for GN-BSI episode, and only 8 patients (5.7%) had persistent bacteremia. Specifically, only 3% had documented positive FUBC among patients with urinary tract source of infection. It was estimated that 17 FUBCs are needed to yield one positive result for GN-BSI. This finding is consistent with results from another study that examined 1,801 episodes of bacteremia, 901 of which were gram-negative organisms, predominantly (67%) Escherichia coli and Klebsiella spp.⁴⁹ Among GN-BSI episodes, FUBCs were performed in 247 cases, with 27 (10.9%) cases demonstrating persistent bacteremia. A nested case-­control analysis between patients with cleared or persistent bacteremia found a lower yield in FUBC with gram-negative organisms and a genitourinary source of infection. Moreover, persistent bacteremia did not influence a change in antimicrobial regimen. Kang and colleagues investigated 1,068 episodes of Klebsiella pneumoniae bacteremia, with FUBCs performed in 862 (80.7%) cases despite only a 7.2% incidence of persistent bacteremia.⁵⁰ The independent risk factors associated with persistent bacteremia were intra-abdominal infection, solid organ transplantation, high Charlson comorbidity index score, and unfavorable treatment responses, which suggests the need for FUBC may be individualized rather than routine.

In the setting of GN-BSI in which the probability of persistent bacteremia is relatively low, especially in genitourinary sources of infection, FUBCs are not warranted. It is uncomfortable for patients and exposes them to harms of false-positive results, leading to antimicrobial administration with possible adverse effects, which can be further compounded by unnecessary testing, potentially missed alternative diagnosis, and increasing hospital LOS.^1,51 Given the low yield of FUBC in GN-BSI, and the lack of association of persistent bacteremia with change in antimicrobial therapy or clinical outcomes, we recommend avoiding FUBC as a test of cure. Documentation of gram-negative blood culture clearance should be reserved for situations in which there is concern for deeper or otherwise uncontrolled source of infection.

The optimal management of gram-negative bacteremia in hospitalized patients is evolving. There is a growing body of evidence supporting shorter duration for a total of 7 days with oral step-down therapy as safe and effective for patients with uncomplicated Enterobacteriaceae bacteremia who have achieved adequate source control and demonstrated clinical stability and improvement. Although comparative data regarding the optimal duration of therapy in the setting of MDR strains such as ESBL Enterobacteriaceae and pseudomonal BSI are limited, available data appear promising in favor of shorter treatment duration with oral step-down therapy. Routine follow-up blood culture is not cost-effective and may result in unnecessary healthcare resource utilization and inappropriate use of antimicrobials. Table 4 provides a framework for the clinical management of GN-BSI in the hospital. Taken together, these steps will facilitate antimicrobial stewardship, limit unnecessary antimicrobial exposure, and improve quality of patient care.

The authors have no conflicts of interest to disclose.