MDedge Emergency Medicine

A new analysis from Michigan’s largest health system provides sobering verification of the risks for QT interval prolongation in COVID-19 patients treated with hydroxychloroquine and azithromycin (HCQ/AZM).

One in five patients (21%) had a corrected QT (QTc) interval of at least 500 msec, a value that increases the risk for torsade de pointes in the general population and at which cardiovascular leaders have suggested withholding HCQ/AZM in COVID-19 patients.

“One of the most striking findings was when we looked at the other drugs being administered to these patients; 61% were being administered drugs that had QT-prolonging effects concomitantly with the HCQ and AZM therapy. So they were inadvertently doubling down on the QT-prolonging effects of these drugs,” senior author David E. Haines, MD, director of the Heart Rhythm Center at William Beaumont Hospital, Royal Oak, Mich., said in an interview.

A total of 34 medications overlapped with HCQ/AZM therapy are known or suspected to increase the risk for torsade de pointes, a potentially life-threatening ventricular tachycardia. The most common of these were propofol coadministered in 123 patients, ondansetron in 114, dexmedetomidine in 54, haloperidol in 44, amiodarone in 43, and tramadol in 26.

“This speaks to the medical complexity of this patient population, but also suggests inadequate awareness of the QT-prolonging effects of many common medications,” the researchers say.

The study was published Aug. 5 in JACC Clinical Electrophysiology.

Both hydroxychloroquine and azithromycin increase the risk for QTc-interval prolongation by blocking the KCHN2-encoded hERG potassium channel. Several reports have linked the drugs to a triggering of QT prolongation in patients with COVID-19.

For the present study, Dr. Haines and colleagues examined data from 586 consecutive patients admitted with COVID-19 to the Beaumont Hospitals in Royal Oak and Troy, Mich., between March 13 and April 6. A baseline QTc interval was measured with 12-lead ECG prior to treatment initiation with hydroxychloroquine 400 mg twice daily for two doses, then 200 mg twice daily for 4 days, and azithromycin 500 mg once followed by 250 mg daily for 4 days.

Because of limited availability at the time, lead II ECG telemetry monitoring over the 5-day course of HCQ/AZM was recommended only in patients with baseline QTc intervals of at least 440 msec.

Patients without an interpretable baseline ECG or available telemetry/ECG monitoring for at least 1 day were also excluded, leaving 415 patients (mean age, 64 years; 45% female) in the study population. More than half (52%) were Black, 52% had hypertension, 30% had diabetes, and 14% had cancer.

As seen in previous studies, the QTc interval increased progressively and significantly after the administration of HCQ/AZM, from 443 msec to 473 msec.

The average time to maximum QTc was 2.9 days in a subset of 135 patients with QTc measurements prior to starting therapy and on days 1 through 5.

In multivariate analysis, independent predictors of a potentially hazardous QTc interval of at least 500 msec were:

• Age older than 65 years (odds ratio, 3.0; 95% confidence interval, 1.62-5.54).
• History of  (OR, 4.65; 95% CI, 2.01-10.74).
• Admission  of at least 1.5 mg/dL (OR, 2.22; 95% CI, 1.28-3.84).
• Peak troponin I level above 0.04 mg/mL (OR, 3.89; 95% CI, 2.22-6.83).
• Body mass index below 30 kg/m² (OR for a BMI of 30 kg/m² or higher, 0.45; 95% CI, 0.26-0.78).

Concomitant use of drugs with known risk for torsade de pointes was a significant risk factor in univariate analysis (OR, 1.73; P = .036), but fell out in the multivariate model.

No patients experienced high-grade arrhythmias during the study. In all, 112 of the 586 patients died during hospitalization, including 85 (21%) of the 415 study patients.

The change in QTc interval from baseline was greater in patients who died. Despite this, the only independent predictor of mortality was older age. One possible explanation is that the decision to monitor patients with baseline QTc intervals of at least 440 msec may have skewed the study population toward people with moderate or slightly long QTc intervals prior to the initiation of HCQ/AZM, Dr. Haines suggested. Monitoring and treatment duration were short, and clinicians also likely adjusted medications when excess QTc prolongation was observed.

Although it’s been months since data collection was completed in April, and the paper was written in record-breaking time, the study “is still very relevant because the drug is still out there,” observed Dr. Haines. “Even though it may not be used in as widespread a fashion as it had been when we first submitted the paper, it is still being used routinely by many hospitals and many practitioners.”

The use of hydroxychloroquine is “going through the roof” because of COVID-19, commented Dhanunjaya Lakkireddy, MD, medical director for the Kansas City Heart Rhythm Institute, HCA Midwest Health, Overland Park, Kan., who was not involved in the study.

“This study is very relevant, and I’m glad they shared their experience, and it’s pretty consistent with the data presented by other people. The question of whether hydroxychloroquine helps people with COVID is up for debate, but there is more evidence today that it is not as helpful as it was 3 months ago,” said Dr. Lakkireddy, who is also chair of the American College of Cardiology Electrophysiology Council.

He expressed concern for patients who may be taking HCQ with other medications that have QT-prolonging effects, and for the lack of long-term protocols in place for the drug.

In the coming weeks, however, the ACC and rheumatology leaders will be publishing an expert consensus statement that addresses key issues, such as how to best to use HCQ, maintenance HCQ, electrolyte monitoring, the optimal timing of electrocardiography and cardiac magnetic imaging, and symptoms to look for if cardiac involvement is suspected, Dr. Lakkireddy said.

Asked whether HCQ and AZM should be used in COVID-19 patients, Dr. Haines said in an interview that the “QT-prolonging effects are real, the arrhythmogenic potential is real, and the benefit to patients is nil or marginal. So I think that use of these drugs is appropriate and reasonable if it is done in a setting of a controlled trial, and I support that. But the routine use of these drugs probably is not warranted based on the data that we have available.”

Still, hydroxychloroquine continues to be dragged into the spotlight in recent days as an effective treatment for COVID-19, despite discredited research and the U.S. Food and Drug Administration’s June 15 revocation of its emergency-use authorization to allow use of HCQ and chloroquine to treat certain hospitalized COVID-19 patients.

“The unfortunate politicization of this issue has really muddied the waters because the general public doesn’t know what to believe or who to believe. The fact that treatment for a disease as serious as COVID should be modulated by political affiliation is just crazy to me,” said Dr. Haines. “We should be using the best science and taking careful observations, and whatever the recommendations derived from that should be uniformly adopted by everybody, irrespective of your political affiliation.”

Dr. Haines has received honoraria from Biosense Webster, Farapulse, and Sagentia, and is a consultant for Affera, Boston Scientific, Integer, Medtronic, Philips Healthcare, and Zoll. Dr. Lakkireddy has served as a consultant to Abbott, Biosense Webster, Biotronik, Boston Scientific, and Medtronic. 

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

A new analysis from Michigan’s largest health system provides sobering verification of the risks for QT interval prolongation in COVID-19 patients treated with hydroxychloroquine and azithromycin (HCQ/AZM).

One in five patients (21%) had a corrected QT (QTc) interval of at least 500 msec, a value that increases the risk for torsade de pointes in the general population and at which cardiovascular leaders have suggested withholding HCQ/AZM in COVID-19 patients.

“One of the most striking findings was when we looked at the other drugs being administered to these patients; 61% were being administered drugs that had QT-prolonging effects concomitantly with the HCQ and AZM therapy. So they were inadvertently doubling down on the QT-prolonging effects of these drugs,” senior author David E. Haines, MD, director of the Heart Rhythm Center at William Beaumont Hospital, Royal Oak, Mich., said in an interview.

A total of 34 medications overlapped with HCQ/AZM therapy are known or suspected to increase the risk for torsade de pointes, a potentially life-threatening ventricular tachycardia. The most common of these were propofol coadministered in 123 patients, ondansetron in 114, dexmedetomidine in 54, haloperidol in 44, amiodarone in 43, and tramadol in 26.

“This speaks to the medical complexity of this patient population, but also suggests inadequate awareness of the QT-prolonging effects of many common medications,” the researchers say.

The study was published Aug. 5 in JACC Clinical Electrophysiology.

Both hydroxychloroquine and azithromycin increase the risk for QTc-interval prolongation by blocking the KCHN2-encoded hERG potassium channel. Several reports have linked the drugs to a triggering of QT prolongation in patients with COVID-19.

For the present study, Dr. Haines and colleagues examined data from 586 consecutive patients admitted with COVID-19 to the Beaumont Hospitals in Royal Oak and Troy, Mich., between March 13 and April 6. A baseline QTc interval was measured with 12-lead ECG prior to treatment initiation with hydroxychloroquine 400 mg twice daily for two doses, then 200 mg twice daily for 4 days, and azithromycin 500 mg once followed by 250 mg daily for 4 days.

Because of limited availability at the time, lead II ECG telemetry monitoring over the 5-day course of HCQ/AZM was recommended only in patients with baseline QTc intervals of at least 440 msec.

Patients without an interpretable baseline ECG or available telemetry/ECG monitoring for at least 1 day were also excluded, leaving 415 patients (mean age, 64 years; 45% female) in the study population. More than half (52%) were Black, 52% had hypertension, 30% had diabetes, and 14% had cancer.

As seen in previous studies, the QTc interval increased progressively and significantly after the administration of HCQ/AZM, from 443 msec to 473 msec.

The average time to maximum QTc was 2.9 days in a subset of 135 patients with QTc measurements prior to starting therapy and on days 1 through 5.

In multivariate analysis, independent predictors of a potentially hazardous QTc interval of at least 500 msec were:

• Age older than 65 years (odds ratio, 3.0; 95% confidence interval, 1.62-5.54).
• History of  (OR, 4.65; 95% CI, 2.01-10.74).
• Admission  of at least 1.5 mg/dL (OR, 2.22; 95% CI, 1.28-3.84).
• Peak troponin I level above 0.04 mg/mL (OR, 3.89; 95% CI, 2.22-6.83).
• Body mass index below 30 kg/m² (OR for a BMI of 30 kg/m² or higher, 0.45; 95% CI, 0.26-0.78).

Concomitant use of drugs with known risk for torsade de pointes was a significant risk factor in univariate analysis (OR, 1.73; P = .036), but fell out in the multivariate model.

No patients experienced high-grade arrhythmias during the study. In all, 112 of the 586 patients died during hospitalization, including 85 (21%) of the 415 study patients.

The change in QTc interval from baseline was greater in patients who died. Despite this, the only independent predictor of mortality was older age. One possible explanation is that the decision to monitor patients with baseline QTc intervals of at least 440 msec may have skewed the study population toward people with moderate or slightly long QTc intervals prior to the initiation of HCQ/AZM, Dr. Haines suggested. Monitoring and treatment duration were short, and clinicians also likely adjusted medications when excess QTc prolongation was observed.

Although it’s been months since data collection was completed in April, and the paper was written in record-breaking time, the study “is still very relevant because the drug is still out there,” observed Dr. Haines. “Even though it may not be used in as widespread a fashion as it had been when we first submitted the paper, it is still being used routinely by many hospitals and many practitioners.”

The use of hydroxychloroquine is “going through the roof” because of COVID-19, commented Dhanunjaya Lakkireddy, MD, medical director for the Kansas City Heart Rhythm Institute, HCA Midwest Health, Overland Park, Kan., who was not involved in the study.

“This study is very relevant, and I’m glad they shared their experience, and it’s pretty consistent with the data presented by other people. The question of whether hydroxychloroquine helps people with COVID is up for debate, but there is more evidence today that it is not as helpful as it was 3 months ago,” said Dr. Lakkireddy, who is also chair of the American College of Cardiology Electrophysiology Council.

He expressed concern for patients who may be taking HCQ with other medications that have QT-prolonging effects, and for the lack of long-term protocols in place for the drug.

In the coming weeks, however, the ACC and rheumatology leaders will be publishing an expert consensus statement that addresses key issues, such as how to best to use HCQ, maintenance HCQ, electrolyte monitoring, the optimal timing of electrocardiography and cardiac magnetic imaging, and symptoms to look for if cardiac involvement is suspected, Dr. Lakkireddy said.

Asked whether HCQ and AZM should be used in COVID-19 patients, Dr. Haines said in an interview that the “QT-prolonging effects are real, the arrhythmogenic potential is real, and the benefit to patients is nil or marginal. So I think that use of these drugs is appropriate and reasonable if it is done in a setting of a controlled trial, and I support that. But the routine use of these drugs probably is not warranted based on the data that we have available.”

Still, hydroxychloroquine continues to be dragged into the spotlight in recent days as an effective treatment for COVID-19, despite discredited research and the U.S. Food and Drug Administration’s June 15 revocation of its emergency-use authorization to allow use of HCQ and chloroquine to treat certain hospitalized COVID-19 patients.

“The unfortunate politicization of this issue has really muddied the waters because the general public doesn’t know what to believe or who to believe. The fact that treatment for a disease as serious as COVID should be modulated by political affiliation is just crazy to me,” said Dr. Haines. “We should be using the best science and taking careful observations, and whatever the recommendations derived from that should be uniformly adopted by everybody, irrespective of your political affiliation.”

Dr. Haines has received honoraria from Biosense Webster, Farapulse, and Sagentia, and is a consultant for Affera, Boston Scientific, Integer, Medtronic, Philips Healthcare, and Zoll. Dr. Lakkireddy has served as a consultant to Abbott, Biosense Webster, Biotronik, Boston Scientific, and Medtronic. 

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

A new analysis from Michigan’s largest health system provides sobering verification of the risks for QT interval prolongation in COVID-19 patients treated with hydroxychloroquine and azithromycin (HCQ/AZM).

One in five patients (21%) had a corrected QT (QTc) interval of at least 500 msec, a value that increases the risk for torsade de pointes in the general population and at which cardiovascular leaders have suggested withholding HCQ/AZM in COVID-19 patients.

“One of the most striking findings was when we looked at the other drugs being administered to these patients; 61% were being administered drugs that had QT-prolonging effects concomitantly with the HCQ and AZM therapy. So they were inadvertently doubling down on the QT-prolonging effects of these drugs,” senior author David E. Haines, MD, director of the Heart Rhythm Center at William Beaumont Hospital, Royal Oak, Mich., said in an interview.

A total of 34 medications overlapped with HCQ/AZM therapy are known or suspected to increase the risk for torsade de pointes, a potentially life-threatening ventricular tachycardia. The most common of these were propofol coadministered in 123 patients, ondansetron in 114, dexmedetomidine in 54, haloperidol in 44, amiodarone in 43, and tramadol in 26.

“This speaks to the medical complexity of this patient population, but also suggests inadequate awareness of the QT-prolonging effects of many common medications,” the researchers say.

The study was published Aug. 5 in JACC Clinical Electrophysiology.

Both hydroxychloroquine and azithromycin increase the risk for QTc-interval prolongation by blocking the KCHN2-encoded hERG potassium channel. Several reports have linked the drugs to a triggering of QT prolongation in patients with COVID-19.

For the present study, Dr. Haines and colleagues examined data from 586 consecutive patients admitted with COVID-19 to the Beaumont Hospitals in Royal Oak and Troy, Mich., between March 13 and April 6. A baseline QTc interval was measured with 12-lead ECG prior to treatment initiation with hydroxychloroquine 400 mg twice daily for two doses, then 200 mg twice daily for 4 days, and azithromycin 500 mg once followed by 250 mg daily for 4 days.

Because of limited availability at the time, lead II ECG telemetry monitoring over the 5-day course of HCQ/AZM was recommended only in patients with baseline QTc intervals of at least 440 msec.

Patients without an interpretable baseline ECG or available telemetry/ECG monitoring for at least 1 day were also excluded, leaving 415 patients (mean age, 64 years; 45% female) in the study population. More than half (52%) were Black, 52% had hypertension, 30% had diabetes, and 14% had cancer.

As seen in previous studies, the QTc interval increased progressively and significantly after the administration of HCQ/AZM, from 443 msec to 473 msec.

The average time to maximum QTc was 2.9 days in a subset of 135 patients with QTc measurements prior to starting therapy and on days 1 through 5.

In multivariate analysis, independent predictors of a potentially hazardous QTc interval of at least 500 msec were:

• Age older than 65 years (odds ratio, 3.0; 95% confidence interval, 1.62-5.54).
• History of  (OR, 4.65; 95% CI, 2.01-10.74).
• Admission  of at least 1.5 mg/dL (OR, 2.22; 95% CI, 1.28-3.84).
• Peak troponin I level above 0.04 mg/mL (OR, 3.89; 95% CI, 2.22-6.83).
• Body mass index below 30 kg/m² (OR for a BMI of 30 kg/m² or higher, 0.45; 95% CI, 0.26-0.78).

Concomitant use of drugs with known risk for torsade de pointes was a significant risk factor in univariate analysis (OR, 1.73; P = .036), but fell out in the multivariate model.

No patients experienced high-grade arrhythmias during the study. In all, 112 of the 586 patients died during hospitalization, including 85 (21%) of the 415 study patients.

The change in QTc interval from baseline was greater in patients who died. Despite this, the only independent predictor of mortality was older age. One possible explanation is that the decision to monitor patients with baseline QTc intervals of at least 440 msec may have skewed the study population toward people with moderate or slightly long QTc intervals prior to the initiation of HCQ/AZM, Dr. Haines suggested. Monitoring and treatment duration were short, and clinicians also likely adjusted medications when excess QTc prolongation was observed.

Although it’s been months since data collection was completed in April, and the paper was written in record-breaking time, the study “is still very relevant because the drug is still out there,” observed Dr. Haines. “Even though it may not be used in as widespread a fashion as it had been when we first submitted the paper, it is still being used routinely by many hospitals and many practitioners.”

The use of hydroxychloroquine is “going through the roof” because of COVID-19, commented Dhanunjaya Lakkireddy, MD, medical director for the Kansas City Heart Rhythm Institute, HCA Midwest Health, Overland Park, Kan., who was not involved in the study.

“This study is very relevant, and I’m glad they shared their experience, and it’s pretty consistent with the data presented by other people. The question of whether hydroxychloroquine helps people with COVID is up for debate, but there is more evidence today that it is not as helpful as it was 3 months ago,” said Dr. Lakkireddy, who is also chair of the American College of Cardiology Electrophysiology Council.

He expressed concern for patients who may be taking HCQ with other medications that have QT-prolonging effects, and for the lack of long-term protocols in place for the drug.

In the coming weeks, however, the ACC and rheumatology leaders will be publishing an expert consensus statement that addresses key issues, such as how to best to use HCQ, maintenance HCQ, electrolyte monitoring, the optimal timing of electrocardiography and cardiac magnetic imaging, and symptoms to look for if cardiac involvement is suspected, Dr. Lakkireddy said.

Asked whether HCQ and AZM should be used in COVID-19 patients, Dr. Haines said in an interview that the “QT-prolonging effects are real, the arrhythmogenic potential is real, and the benefit to patients is nil or marginal. So I think that use of these drugs is appropriate and reasonable if it is done in a setting of a controlled trial, and I support that. But the routine use of these drugs probably is not warranted based on the data that we have available.”

Still, hydroxychloroquine continues to be dragged into the spotlight in recent days as an effective treatment for COVID-19, despite discredited research and the U.S. Food and Drug Administration’s June 15 revocation of its emergency-use authorization to allow use of HCQ and chloroquine to treat certain hospitalized COVID-19 patients.

“The unfortunate politicization of this issue has really muddied the waters because the general public doesn’t know what to believe or who to believe. The fact that treatment for a disease as serious as COVID should be modulated by political affiliation is just crazy to me,” said Dr. Haines. “We should be using the best science and taking careful observations, and whatever the recommendations derived from that should be uniformly adopted by everybody, irrespective of your political affiliation.”

Dr. Haines has received honoraria from Biosense Webster, Farapulse, and Sagentia, and is a consultant for Affera, Boston Scientific, Integer, Medtronic, Philips Healthcare, and Zoll. Dr. Lakkireddy has served as a consultant to Abbott, Biosense Webster, Biotronik, Boston Scientific, and Medtronic. 

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

Fractional flow reserve derived noninvasively from coronary CT angiography is a safe and accurate method for assessing the significance of coronary artery disease in patients with severe aortic stenosis who are headed for transcatheter aortic valve replacement (TAVR), according to results of the CAST-FFR prospective study.

Indeed, utilization of coronary CT angiography–derived fractional flow reserve (CT-FFR) for this purpose offers the advantage of using a single noninvasive imaging method to replace two invasive procedures: coronary angiography to assess the anatomy of coronary lesions, and conventional FFR using a pressure wire to determine the functional significance of a given coronary stenosis as a cause of ischemia, Michael Michail, MBBS, explained in reporting the results at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

“Because up to 50% of patients with severe aortic stenosis undergoing TAVR have coexisting coronary artery disease, it remains common practice to perform prior invasive coronary angiography. However, this is associated with inherent risks, particularly in an elderly cohort with comorbidities. Additionally, coronary angiography provides no information on the functional impact of coronary stenoses, which may be important in guiding revascularization decisions prior to TAVR,” noted Dr. Michail, a cardiologist at Monash University, Melbourne.
 

Simulating FFR: ‘A one-stop shop cardiac CT’

Dr. Michail presented the results of the prospective CAST-FFR study, the first evaluation of CT-FFR for assessment of coronary arteries in patients with severe symptomatic aortic stenosis. This method uses computational fluid dynamics to transform data obtained noninvasively from a standard coronary CT angiography acquisition into a simulated FFR. And it offers the potential to streamline patient care.

“In current practice we see elderly patients with a long pre-TAVR assessment period, with numerous appointments and invasive procedures. Our vision is a one-stop shop cardiac CT that will provide the cardiologist with a complete assessment of the annular measurements, peripheral vasculature, and the coronary arteries ahead of their procedure,” according to Dr. Michail.

“We believe the ability to perform the requisite coronary assessment using CT-FFR will translate to improved patient care in several ways,” he continued. “Firstly, this will shorten the number of tests and overall diagnostic journey for patients. It will reduce the risk from unnecessary invasive procedures, and this will also reduce discomfort for the patient. Based on emerging evidence on the adverse prognostic impact of functionally significant coronary disease in aortic stenosis, this data has the potential to improve procedural risk stratification. And finally, contingent on further data, this may improve lesion selection for upfront revascularization.”

The CAST-FFR study was a small, single-center, proof-of-concept study in which 42 patients with severe aortic stenosis underwent both coronary CT angiography and conventional FFR with a pressure wire. The CT data was sent to a core laboratory for conversion into CT-FFR by evaluators blinded to the conventional FFR values.

Of the 42 participants, 39 (93%) had usable CT-FFR data on 60 coronary vessels. Dr. Michail and coinvestigators found a strong correlation between the conventional pressure wire FFR and CT-FFR findings, with a receiver operating characteristic area under the curve of 0.83 per vessel. CT-FFR had a diagnostic sensitivity and specificity of 73.9% and 78.4%, respectively, with a positive predictive value of 68%, a negative predictive value of 82.9%, and a diagnostic accuracy of 76.7%.

He cited as study limitations the small size, the fact that patients with previous revascularization or significant left ventricular impairment were excluded, and the study cohort’s relative youth.

“With a mean age of 76.2 years, it’s unclear whether these results can be extrapolated to very elderly patients with more calcified arteries undergoing TAVR. Encouragingly, though, a subgroup analysis based on calcium score showed no effect on accuracy,” according to the cardiologist.

CT-FFR may ‘shorten the diagnostic journey’ for fragile patients

Discussant Daniele Andreini, MD, PhD, praised the investigators’ concept of integrating the functional assessment provided by CT-FFR into a one-stop shop examination by cardiac CT angiography for TAVR planning.

“I would like to underline one of Dr. Michail’s messages: It’s really important to shorten the diagnostic journey for these fragile, older patients with aortic stenosis in order to improve safety, use less contrast, and avoid complications,” said Dr. Andreini, a cardiologist at the University of Milan and director of the cardiovascular CT and radiology unit at Monzino Cardiology Center, also in Milan.

Both Dr. Michail and Dr. Andreini reported having no financial conflicts of interest.

[email protected]

Fractional flow reserve derived noninvasively from coronary CT angiography is a safe and accurate method for assessing the significance of coronary artery disease in patients with severe aortic stenosis who are headed for transcatheter aortic valve replacement (TAVR), according to results of the CAST-FFR prospective study.

Indeed, utilization of coronary CT angiography–derived fractional flow reserve (CT-FFR) for this purpose offers the advantage of using a single noninvasive imaging method to replace two invasive procedures: coronary angiography to assess the anatomy of coronary lesions, and conventional FFR using a pressure wire to determine the functional significance of a given coronary stenosis as a cause of ischemia, Michael Michail, MBBS, explained in reporting the results at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

“Because up to 50% of patients with severe aortic stenosis undergoing TAVR have coexisting coronary artery disease, it remains common practice to perform prior invasive coronary angiography. However, this is associated with inherent risks, particularly in an elderly cohort with comorbidities. Additionally, coronary angiography provides no information on the functional impact of coronary stenoses, which may be important in guiding revascularization decisions prior to TAVR,” noted Dr. Michail, a cardiologist at Monash University, Melbourne.
 

Simulating FFR: ‘A one-stop shop cardiac CT’

Dr. Michail presented the results of the prospective CAST-FFR study, the first evaluation of CT-FFR for assessment of coronary arteries in patients with severe symptomatic aortic stenosis. This method uses computational fluid dynamics to transform data obtained noninvasively from a standard coronary CT angiography acquisition into a simulated FFR. And it offers the potential to streamline patient care.

“In current practice we see elderly patients with a long pre-TAVR assessment period, with numerous appointments and invasive procedures. Our vision is a one-stop shop cardiac CT that will provide the cardiologist with a complete assessment of the annular measurements, peripheral vasculature, and the coronary arteries ahead of their procedure,” according to Dr. Michail.

“We believe the ability to perform the requisite coronary assessment using CT-FFR will translate to improved patient care in several ways,” he continued. “Firstly, this will shorten the number of tests and overall diagnostic journey for patients. It will reduce the risk from unnecessary invasive procedures, and this will also reduce discomfort for the patient. Based on emerging evidence on the adverse prognostic impact of functionally significant coronary disease in aortic stenosis, this data has the potential to improve procedural risk stratification. And finally, contingent on further data, this may improve lesion selection for upfront revascularization.”

The CAST-FFR study was a small, single-center, proof-of-concept study in which 42 patients with severe aortic stenosis underwent both coronary CT angiography and conventional FFR with a pressure wire. The CT data was sent to a core laboratory for conversion into CT-FFR by evaluators blinded to the conventional FFR values.

Of the 42 participants, 39 (93%) had usable CT-FFR data on 60 coronary vessels. Dr. Michail and coinvestigators found a strong correlation between the conventional pressure wire FFR and CT-FFR findings, with a receiver operating characteristic area under the curve of 0.83 per vessel. CT-FFR had a diagnostic sensitivity and specificity of 73.9% and 78.4%, respectively, with a positive predictive value of 68%, a negative predictive value of 82.9%, and a diagnostic accuracy of 76.7%.

He cited as study limitations the small size, the fact that patients with previous revascularization or significant left ventricular impairment were excluded, and the study cohort’s relative youth.

“With a mean age of 76.2 years, it’s unclear whether these results can be extrapolated to very elderly patients with more calcified arteries undergoing TAVR. Encouragingly, though, a subgroup analysis based on calcium score showed no effect on accuracy,” according to the cardiologist.

CT-FFR may ‘shorten the diagnostic journey’ for fragile patients

Discussant Daniele Andreini, MD, PhD, praised the investigators’ concept of integrating the functional assessment provided by CT-FFR into a one-stop shop examination by cardiac CT angiography for TAVR planning.

“I would like to underline one of Dr. Michail’s messages: It’s really important to shorten the diagnostic journey for these fragile, older patients with aortic stenosis in order to improve safety, use less contrast, and avoid complications,” said Dr. Andreini, a cardiologist at the University of Milan and director of the cardiovascular CT and radiology unit at Monzino Cardiology Center, also in Milan.

Both Dr. Michail and Dr. Andreini reported having no financial conflicts of interest.

[email protected]

Fractional flow reserve derived noninvasively from coronary CT angiography is a safe and accurate method for assessing the significance of coronary artery disease in patients with severe aortic stenosis who are headed for transcatheter aortic valve replacement (TAVR), according to results of the CAST-FFR prospective study.

Indeed, utilization of coronary CT angiography–derived fractional flow reserve (CT-FFR) for this purpose offers the advantage of using a single noninvasive imaging method to replace two invasive procedures: coronary angiography to assess the anatomy of coronary lesions, and conventional FFR using a pressure wire to determine the functional significance of a given coronary stenosis as a cause of ischemia, Michael Michail, MBBS, explained in reporting the results at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

“Because up to 50% of patients with severe aortic stenosis undergoing TAVR have coexisting coronary artery disease, it remains common practice to perform prior invasive coronary angiography. However, this is associated with inherent risks, particularly in an elderly cohort with comorbidities. Additionally, coronary angiography provides no information on the functional impact of coronary stenoses, which may be important in guiding revascularization decisions prior to TAVR,” noted Dr. Michail, a cardiologist at Monash University, Melbourne.
 

Simulating FFR: ‘A one-stop shop cardiac CT’

Dr. Michail presented the results of the prospective CAST-FFR study, the first evaluation of CT-FFR for assessment of coronary arteries in patients with severe symptomatic aortic stenosis. This method uses computational fluid dynamics to transform data obtained noninvasively from a standard coronary CT angiography acquisition into a simulated FFR. And it offers the potential to streamline patient care.

“In current practice we see elderly patients with a long pre-TAVR assessment period, with numerous appointments and invasive procedures. Our vision is a one-stop shop cardiac CT that will provide the cardiologist with a complete assessment of the annular measurements, peripheral vasculature, and the coronary arteries ahead of their procedure,” according to Dr. Michail.

“We believe the ability to perform the requisite coronary assessment using CT-FFR will translate to improved patient care in several ways,” he continued. “Firstly, this will shorten the number of tests and overall diagnostic journey for patients. It will reduce the risk from unnecessary invasive procedures, and this will also reduce discomfort for the patient. Based on emerging evidence on the adverse prognostic impact of functionally significant coronary disease in aortic stenosis, this data has the potential to improve procedural risk stratification. And finally, contingent on further data, this may improve lesion selection for upfront revascularization.”

The CAST-FFR study was a small, single-center, proof-of-concept study in which 42 patients with severe aortic stenosis underwent both coronary CT angiography and conventional FFR with a pressure wire. The CT data was sent to a core laboratory for conversion into CT-FFR by evaluators blinded to the conventional FFR values.

Of the 42 participants, 39 (93%) had usable CT-FFR data on 60 coronary vessels. Dr. Michail and coinvestigators found a strong correlation between the conventional pressure wire FFR and CT-FFR findings, with a receiver operating characteristic area under the curve of 0.83 per vessel. CT-FFR had a diagnostic sensitivity and specificity of 73.9% and 78.4%, respectively, with a positive predictive value of 68%, a negative predictive value of 82.9%, and a diagnostic accuracy of 76.7%.

He cited as study limitations the small size, the fact that patients with previous revascularization or significant left ventricular impairment were excluded, and the study cohort’s relative youth.

“With a mean age of 76.2 years, it’s unclear whether these results can be extrapolated to very elderly patients with more calcified arteries undergoing TAVR. Encouragingly, though, a subgroup analysis based on calcium score showed no effect on accuracy,” according to the cardiologist.

CT-FFR may ‘shorten the diagnostic journey’ for fragile patients

Discussant Daniele Andreini, MD, PhD, praised the investigators’ concept of integrating the functional assessment provided by CT-FFR into a one-stop shop examination by cardiac CT angiography for TAVR planning.

“I would like to underline one of Dr. Michail’s messages: It’s really important to shorten the diagnostic journey for these fragile, older patients with aortic stenosis in order to improve safety, use less contrast, and avoid complications,” said Dr. Andreini, a cardiologist at the University of Milan and director of the cardiovascular CT and radiology unit at Monzino Cardiology Center, also in Milan.

Both Dr. Michail and Dr. Andreini reported having no financial conflicts of interest.

[email protected]

Monogenic disorders with heart and vascular effects are each pretty rare in clinical practice but collectively can make up a fair proportion of the patients cardiologists see. Still, the diagnosis is missed more often than not, even when the clinical signs are there, suggests an observational study, supporting broader genetic testing in cardiovascular patients.

In a cohort of more than 8,000 patients referred for cardiac catheterization, diagnosis of such a monogenic cardiovascular disease (MCVD) was made in only 35% of those with one related gene variant and signs of phenotypic expression in the electronic health record.

The findings are novel for measuring the field’s “burden of missed diagnoses” in patients with MCVD, which “represent a missed opportunity that could be addressed by genetic screening,” contended the study report, published in the Aug. 18 issue of the Journal of the American College of Cardiology.

“The underrecognition of these diseases underscores the importance of including monogenic diseases in the treating physician’s differential diagnosis,” say the authors, led by Jawan W. Abdulrahim, MD, Duke University, Durham, N.C.

Diagnosis of MCVDs can be important, the group wrote, because many, including familial transthyretin amyloidosis (TTR) and other disorders that pose an increased risk for sudden death, have evidence-based treatment modalities available or are clinically actionable. “Identification of patients with MCVD variants” is also “important for cascade screening of family members who are at risk of inheriting the pathogenic mutations.”

“We tend to ignore these monogenic diseases because they are so rare individually but, in aggregate, monogenic diseases are actually quite common,” senior author Svati H. Shah, MD, MHS, also of Duke University, said in an interview.

The results “support that the cardiology community over time adopt a genotype-forward approach,” one in which every patient presenting to a cardiovascular clinic is genotyped, she said.

One implication of such an approach, Dr. Shah agreed, is that “we would be able to pick these people up earlier in their disease, especially in the context of therapies that could improve certainly their progression, but even their survival.”

For now, she said, the study suggests that “these disorders are more frequent than perhaps all cardiologists are aware of, and we just need to keep our eyes open and know when to refer patients to a cardiovascular genetics clinic, which maybe has more time and can deal with all the nuances that go along with genetic testing.”

In the total cohort, 4.5% were found to carry a gene variant known or believed to cause such diseases. The most frequently represented conditions were familial TTR, hereditary hemochromatosis, heterozygous familial hypercholesterolemia, and various cardiomyopathies.

Of those patients, 52 received a clinical diagnosis of the monogenic disorder after an EHR review. Of the 290 without such a diagnosis, two-thirds showed no evidence in their EHR of the variant’s phenotypic signs. But the records of the other third featured at least some signs that the disease had manifested clinically.

“These data serve as a reminder that monogenic Mendelian disease, including heart and vascular disease, varies in penetrance from individual to individual and may not always present with clinically detectable phenotypes,” noted an editorial accompanying the report.

They also “provide a compelling basis for expanding the role of targeted genetic testing in patients with more traditional forms of heart and vascular disease,” wrote Scott M. Damrauer, MD, University of Pennsylvania, Philadelphia, and William S. Weintraub, MD, Medstar Washington Hospital Center and Georgetown University, Washington.

“Based on the current report, the number needed to screen in a complex cardiovascular patient population to detect 1 case of undiagnosed monogenic cardiovascular disease is 85,” they wrote. “This places targeted genetic testing well within what is considered to be efficacious for most screening programs and in the range of that of other common cardiovascular diseases and cancers.”

Among the 342 patients with a variant predicting a single MCVD – in addition to the 52 who received a diagnosis – 193 had records with no indication of phenotypic expression and so did not receive a diagnosis.

But the 97 patients without a diagnosis who nevertheless had documented signs of some phenotypic expression were deemed, on the basis of extent of expression, to represent a possibly, probably, or definitely missed diagnosis.

Familial TTR made up about 45% of such potentially missed diagnoses, the report noted.

Broader screening of patients with cardiovascular disease, Dr. Shah speculated, “might actually be not only a clinically useful endeavor, but – when we think about the aggregate burden of these monogenic disorders – potentially even cost-effective.”

As the price of genetic sequencing drops, she said, “I think we’ll start to see even more health systems wanting to incorporate the genotype-forward approach.”

Dr. Shah reports serving as primary investigator for research sponsored by Verily Life Sciences and AstraZeneca. Dr. Abdulrahim reports no relevant relationships. Disclosures for the other authors are in the report. Dr. Damrauer discloses receiving research support from RenalytixAI and consulting fees from Calico Labs. Dr. Weintraub had no relevant disclosures.

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

Monogenic disorders with heart and vascular effects are each pretty rare in clinical practice but collectively can make up a fair proportion of the patients cardiologists see. Still, the diagnosis is missed more often than not, even when the clinical signs are there, suggests an observational study, supporting broader genetic testing in cardiovascular patients.

In a cohort of more than 8,000 patients referred for cardiac catheterization, diagnosis of such a monogenic cardiovascular disease (MCVD) was made in only 35% of those with one related gene variant and signs of phenotypic expression in the electronic health record.

The findings are novel for measuring the field’s “burden of missed diagnoses” in patients with MCVD, which “represent a missed opportunity that could be addressed by genetic screening,” contended the study report, published in the Aug. 18 issue of the Journal of the American College of Cardiology.

“The underrecognition of these diseases underscores the importance of including monogenic diseases in the treating physician’s differential diagnosis,” say the authors, led by Jawan W. Abdulrahim, MD, Duke University, Durham, N.C.

Diagnosis of MCVDs can be important, the group wrote, because many, including familial transthyretin amyloidosis (TTR) and other disorders that pose an increased risk for sudden death, have evidence-based treatment modalities available or are clinically actionable. “Identification of patients with MCVD variants” is also “important for cascade screening of family members who are at risk of inheriting the pathogenic mutations.”

“We tend to ignore these monogenic diseases because they are so rare individually but, in aggregate, monogenic diseases are actually quite common,” senior author Svati H. Shah, MD, MHS, also of Duke University, said in an interview.

The results “support that the cardiology community over time adopt a genotype-forward approach,” one in which every patient presenting to a cardiovascular clinic is genotyped, she said.

One implication of such an approach, Dr. Shah agreed, is that “we would be able to pick these people up earlier in their disease, especially in the context of therapies that could improve certainly their progression, but even their survival.”

For now, she said, the study suggests that “these disorders are more frequent than perhaps all cardiologists are aware of, and we just need to keep our eyes open and know when to refer patients to a cardiovascular genetics clinic, which maybe has more time and can deal with all the nuances that go along with genetic testing.”

In the total cohort, 4.5% were found to carry a gene variant known or believed to cause such diseases. The most frequently represented conditions were familial TTR, hereditary hemochromatosis, heterozygous familial hypercholesterolemia, and various cardiomyopathies.

Of those patients, 52 received a clinical diagnosis of the monogenic disorder after an EHR review. Of the 290 without such a diagnosis, two-thirds showed no evidence in their EHR of the variant’s phenotypic signs. But the records of the other third featured at least some signs that the disease had manifested clinically.

“These data serve as a reminder that monogenic Mendelian disease, including heart and vascular disease, varies in penetrance from individual to individual and may not always present with clinically detectable phenotypes,” noted an editorial accompanying the report.

They also “provide a compelling basis for expanding the role of targeted genetic testing in patients with more traditional forms of heart and vascular disease,” wrote Scott M. Damrauer, MD, University of Pennsylvania, Philadelphia, and William S. Weintraub, MD, Medstar Washington Hospital Center and Georgetown University, Washington.

“Based on the current report, the number needed to screen in a complex cardiovascular patient population to detect 1 case of undiagnosed monogenic cardiovascular disease is 85,” they wrote. “This places targeted genetic testing well within what is considered to be efficacious for most screening programs and in the range of that of other common cardiovascular diseases and cancers.”

Among the 342 patients with a variant predicting a single MCVD – in addition to the 52 who received a diagnosis – 193 had records with no indication of phenotypic expression and so did not receive a diagnosis.

But the 97 patients without a diagnosis who nevertheless had documented signs of some phenotypic expression were deemed, on the basis of extent of expression, to represent a possibly, probably, or definitely missed diagnosis.

Familial TTR made up about 45% of such potentially missed diagnoses, the report noted.

Broader screening of patients with cardiovascular disease, Dr. Shah speculated, “might actually be not only a clinically useful endeavor, but – when we think about the aggregate burden of these monogenic disorders – potentially even cost-effective.”

As the price of genetic sequencing drops, she said, “I think we’ll start to see even more health systems wanting to incorporate the genotype-forward approach.”

Dr. Shah reports serving as primary investigator for research sponsored by Verily Life Sciences and AstraZeneca. Dr. Abdulrahim reports no relevant relationships. Disclosures for the other authors are in the report. Dr. Damrauer discloses receiving research support from RenalytixAI and consulting fees from Calico Labs. Dr. Weintraub had no relevant disclosures.

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

Monogenic disorders with heart and vascular effects are each pretty rare in clinical practice but collectively can make up a fair proportion of the patients cardiologists see. Still, the diagnosis is missed more often than not, even when the clinical signs are there, suggests an observational study, supporting broader genetic testing in cardiovascular patients.

In a cohort of more than 8,000 patients referred for cardiac catheterization, diagnosis of such a monogenic cardiovascular disease (MCVD) was made in only 35% of those with one related gene variant and signs of phenotypic expression in the electronic health record.

The findings are novel for measuring the field’s “burden of missed diagnoses” in patients with MCVD, which “represent a missed opportunity that could be addressed by genetic screening,” contended the study report, published in the Aug. 18 issue of the Journal of the American College of Cardiology.

“The underrecognition of these diseases underscores the importance of including monogenic diseases in the treating physician’s differential diagnosis,” say the authors, led by Jawan W. Abdulrahim, MD, Duke University, Durham, N.C.

Diagnosis of MCVDs can be important, the group wrote, because many, including familial transthyretin amyloidosis (TTR) and other disorders that pose an increased risk for sudden death, have evidence-based treatment modalities available or are clinically actionable. “Identification of patients with MCVD variants” is also “important for cascade screening of family members who are at risk of inheriting the pathogenic mutations.”

“We tend to ignore these monogenic diseases because they are so rare individually but, in aggregate, monogenic diseases are actually quite common,” senior author Svati H. Shah, MD, MHS, also of Duke University, said in an interview.

The results “support that the cardiology community over time adopt a genotype-forward approach,” one in which every patient presenting to a cardiovascular clinic is genotyped, she said.

One implication of such an approach, Dr. Shah agreed, is that “we would be able to pick these people up earlier in their disease, especially in the context of therapies that could improve certainly their progression, but even their survival.”

For now, she said, the study suggests that “these disorders are more frequent than perhaps all cardiologists are aware of, and we just need to keep our eyes open and know when to refer patients to a cardiovascular genetics clinic, which maybe has more time and can deal with all the nuances that go along with genetic testing.”

In the total cohort, 4.5% were found to carry a gene variant known or believed to cause such diseases. The most frequently represented conditions were familial TTR, hereditary hemochromatosis, heterozygous familial hypercholesterolemia, and various cardiomyopathies.

Of those patients, 52 received a clinical diagnosis of the monogenic disorder after an EHR review. Of the 290 without such a diagnosis, two-thirds showed no evidence in their EHR of the variant’s phenotypic signs. But the records of the other third featured at least some signs that the disease had manifested clinically.

“These data serve as a reminder that monogenic Mendelian disease, including heart and vascular disease, varies in penetrance from individual to individual and may not always present with clinically detectable phenotypes,” noted an editorial accompanying the report.

They also “provide a compelling basis for expanding the role of targeted genetic testing in patients with more traditional forms of heart and vascular disease,” wrote Scott M. Damrauer, MD, University of Pennsylvania, Philadelphia, and William S. Weintraub, MD, Medstar Washington Hospital Center and Georgetown University, Washington.

“Based on the current report, the number needed to screen in a complex cardiovascular patient population to detect 1 case of undiagnosed monogenic cardiovascular disease is 85,” they wrote. “This places targeted genetic testing well within what is considered to be efficacious for most screening programs and in the range of that of other common cardiovascular diseases and cancers.”

Among the 342 patients with a variant predicting a single MCVD – in addition to the 52 who received a diagnosis – 193 had records with no indication of phenotypic expression and so did not receive a diagnosis.

But the 97 patients without a diagnosis who nevertheless had documented signs of some phenotypic expression were deemed, on the basis of extent of expression, to represent a possibly, probably, or definitely missed diagnosis.

Familial TTR made up about 45% of such potentially missed diagnoses, the report noted.

Broader screening of patients with cardiovascular disease, Dr. Shah speculated, “might actually be not only a clinically useful endeavor, but – when we think about the aggregate burden of these monogenic disorders – potentially even cost-effective.”

As the price of genetic sequencing drops, she said, “I think we’ll start to see even more health systems wanting to incorporate the genotype-forward approach.”

Dr. Shah reports serving as primary investigator for research sponsored by Verily Life Sciences and AstraZeneca. Dr. Abdulrahim reports no relevant relationships. Disclosures for the other authors are in the report. Dr. Damrauer discloses receiving research support from RenalytixAI and consulting fees from Calico Labs. Dr. Weintraub had no relevant disclosures.

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

A group of experts representing various international professional societies has drafted a consensus statement on the determination of brain death or death by neurologic criteria (BD/DNC). The document, a result of the World Brain Death Project, surveys the clinical aspects of this determination, such as clinical testing, apnea testing, and the number of examinations required, as well as its social and legal aspects, including documentation, qualifications for making the determination, and religious attitudes toward BD/DNC.

The recommendations are the minimum criteria for BD/DNC, and countries and professional societies may choose to adopt stricter criteria, the authors noted. Seventeen supplements to the consensus statement contain detailed reports on topics the statement examines, including focuses on both adults and children.

“Perhaps the most important points of this project are, first, to show the worldwide acceptance of the concept of BD/DNC and what the minimum requirements are for BD/DNC,” said corresponding author Gene Sung, MD, MPH, director of the neurocritical care and stroke division at the University of Southern California, Los Angeles. Second, “this standard is centered around a clinical determination without the need for other testing.”

The consensus document and supplements were published online Aug. 3 in JAMA.

Comprehensive review

A lack of rigor has led to many differences in the determination of BD/DNC, said Dr. Sung. “Some of the variance that is common are the numbers of exams and examiners that are required and whether ancillary tests are required for determination of BD/DNC. In addition, a lot of guidelines and protocols that are in use are not thorough in detailing how to do the examinations and what to do in different circumstances.”

Professional societies such as the World Federation of Intensive and Critical Care recruited experts in BD/DNC to develop recommendations, which were based on relevant articles that they identified during a literature search. “We wanted to develop a fairly comprehensive document that, along with the 17 supplements, builds a foundation to show how to determine BD/DNC – what the minimum clinical criteria needed are and what to do in special circumstances,” Dr. Sung said.

Major sections of the statement include recommendations for the minimum clinical standards for the determination of BD/DNC in adults and children.

Determination must begin by establishing that the patient has sustained an irreversible brain injury that resulted in the loss of all brain function, according to the authors. Confounders such as pharmacologic paralysis and the effect of CNS depressant medications should be ruled out.

In addition, clinical evaluation must include an assessment for coma and an evaluation for brain stem areflexia. Among other criteria, the pupils should be fixed and nonresponsive to light, the face should not move in response to noxious cranial stimulation, and the gag and cough reflexes should be absent. Apnea testing is recommended to evaluate the responsiveness of respiratory centers in the medulla.

Although the definition of BD/DNC is the same in children as in adults, less evidence is available for the determination of BD/DNC in the very young. The authors thus advised a cautious approach to the evaluation of infants and younger children.

Recommendations vary by age and often require serial examinations, including apnea testing, they noted.

Ancillary testing

The consensus statement also reviews ancillary testing, which the authors recommend be required when the minimum clinical examination, including the apnea test, cannot be completed and when it is in the presence of confounding conditions that cannot be resolved.

The authors recommended digital subtraction angiography, radionuclide studies, and transcranial Doppler ultrasonography as ancillary tests based on blood flow in the brain. However, CT angiography and magnetic resonance angiography not be used.

A lack of guidance makes performing an apnea test in patients receiving extracorporeal membrane oxygenation (ECMO) challenging, according to the authors. Nevertheless, they recommended that the same principles of BD/DNC be applied to adults and children receiving ECMO.

They further recommended a period of preoxygenation before the apnea test, and the document describes in detail the method for administering this test to people receiving ECMO.

Another potentially challenging situation pointed out in the consensus document is the determination of BD/DNC in patients who have been treated with targeted temperature management. Therapeutic hypothermia, particularly if it is preceded or accompanied by sedation, can temporarily impair brain stem reflexes, thus mimicking BD/DNC.

The new document includes a flowchart and step-by-step recommendations as well as suggestions for determining BD/DNC under these circumstances.

Among document limitations acknowledged by the authors is the lack of high-quality data from randomized, controlled trials on which to base their recommendations.

In addition, economic, technological, or personnel limitations may reduce the available options for ancillary testing, they added. Also, the recommendations do not incorporate contributions from patients or social or religious groups, although the authors were mindful of their concerns.

To promote the national and international harmonization of BD/DNC criteria, “medical societies and countries can evaluate their own policies in relation to this document and fix any deficiencies,” Dr. Sung said.

“Many countries do not have any BD/DNC policies and can use the documents from this project to create their own. There may need to be discussions with legal, governmental, religious, and societal leaders to help understand and accept BD/DNC and to help enact policies in different communities,” he added.

Divergent definitions

The determination of death is not simply a scientific question, but also a philosophical, religious, and cultural question, wrote Robert D. Truog, MD, director of the Harvard Center for Bioethics, Boston, and colleagues in an accompanying editorial. Future research should consider cultural differences over these questions.

“Most important is that there be a clear and logical consistency between the definition of death and the tests that are used to diagnose it,” Dr. Truog said.

The concept of whole brain death was advanced as an equivalent to biological death, “such that, when the brain dies, the body literally disintegrates, just as it does after cardiac arrest,” but evidence indicates that this claim is untrue, Dr. Truog said. Current tests also do not diagnose the death of the whole brain.

Another hypothesis is that brain stem death represents the irreversible loss of consciousness and the capacity for spontaneous respiration.

“Instead of focusing on biology, [this definition] focuses on values and is based on the claim that when a person is in a state of irreversible apneic unconsciousness, we may consider them to be dead,” said Dr. Truog. He and his coeditorialists argued that the concept of whole brain death should be replaced with that of brain stem death.

“This report should be a call for our profession, as well as for federal and state lawmakers, to reform our laws so that they are consistent with our diagnostic criteria,” Dr. Truog said.

“The most straightforward way of doing this would be to change U.S. law and adopt the British standard of brain stem death, and then refine our testing to make the diagnosis of irreversible apneic unconsciousness as reliable and safe as possible,” he concluded.

The drafting of the consensus statement was not supported by outside funding. Dr. Sung reported no relevant financial relationships. Dr. Truog reported receiving compensation from Sanofi and Covance for participating in data and safety monitoring boards unrelated to the consensus document.

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

A group of experts representing various international professional societies has drafted a consensus statement on the determination of brain death or death by neurologic criteria (BD/DNC). The document, a result of the World Brain Death Project, surveys the clinical aspects of this determination, such as clinical testing, apnea testing, and the number of examinations required, as well as its social and legal aspects, including documentation, qualifications for making the determination, and religious attitudes toward BD/DNC.

The recommendations are the minimum criteria for BD/DNC, and countries and professional societies may choose to adopt stricter criteria, the authors noted. Seventeen supplements to the consensus statement contain detailed reports on topics the statement examines, including focuses on both adults and children.

“Perhaps the most important points of this project are, first, to show the worldwide acceptance of the concept of BD/DNC and what the minimum requirements are for BD/DNC,” said corresponding author Gene Sung, MD, MPH, director of the neurocritical care and stroke division at the University of Southern California, Los Angeles. Second, “this standard is centered around a clinical determination without the need for other testing.”

The consensus document and supplements were published online Aug. 3 in JAMA.

Comprehensive review

A lack of rigor has led to many differences in the determination of BD/DNC, said Dr. Sung. “Some of the variance that is common are the numbers of exams and examiners that are required and whether ancillary tests are required for determination of BD/DNC. In addition, a lot of guidelines and protocols that are in use are not thorough in detailing how to do the examinations and what to do in different circumstances.”

Professional societies such as the World Federation of Intensive and Critical Care recruited experts in BD/DNC to develop recommendations, which were based on relevant articles that they identified during a literature search. “We wanted to develop a fairly comprehensive document that, along with the 17 supplements, builds a foundation to show how to determine BD/DNC – what the minimum clinical criteria needed are and what to do in special circumstances,” Dr. Sung said.

Major sections of the statement include recommendations for the minimum clinical standards for the determination of BD/DNC in adults and children.

Determination must begin by establishing that the patient has sustained an irreversible brain injury that resulted in the loss of all brain function, according to the authors. Confounders such as pharmacologic paralysis and the effect of CNS depressant medications should be ruled out.

In addition, clinical evaluation must include an assessment for coma and an evaluation for brain stem areflexia. Among other criteria, the pupils should be fixed and nonresponsive to light, the face should not move in response to noxious cranial stimulation, and the gag and cough reflexes should be absent. Apnea testing is recommended to evaluate the responsiveness of respiratory centers in the medulla.

Although the definition of BD/DNC is the same in children as in adults, less evidence is available for the determination of BD/DNC in the very young. The authors thus advised a cautious approach to the evaluation of infants and younger children.

Recommendations vary by age and often require serial examinations, including apnea testing, they noted.

Ancillary testing

The consensus statement also reviews ancillary testing, which the authors recommend be required when the minimum clinical examination, including the apnea test, cannot be completed and when it is in the presence of confounding conditions that cannot be resolved.

The authors recommended digital subtraction angiography, radionuclide studies, and transcranial Doppler ultrasonography as ancillary tests based on blood flow in the brain. However, CT angiography and magnetic resonance angiography not be used.

A lack of guidance makes performing an apnea test in patients receiving extracorporeal membrane oxygenation (ECMO) challenging, according to the authors. Nevertheless, they recommended that the same principles of BD/DNC be applied to adults and children receiving ECMO.

They further recommended a period of preoxygenation before the apnea test, and the document describes in detail the method for administering this test to people receiving ECMO.

Another potentially challenging situation pointed out in the consensus document is the determination of BD/DNC in patients who have been treated with targeted temperature management. Therapeutic hypothermia, particularly if it is preceded or accompanied by sedation, can temporarily impair brain stem reflexes, thus mimicking BD/DNC.

The new document includes a flowchart and step-by-step recommendations as well as suggestions for determining BD/DNC under these circumstances.

Among document limitations acknowledged by the authors is the lack of high-quality data from randomized, controlled trials on which to base their recommendations.

In addition, economic, technological, or personnel limitations may reduce the available options for ancillary testing, they added. Also, the recommendations do not incorporate contributions from patients or social or religious groups, although the authors were mindful of their concerns.

To promote the national and international harmonization of BD/DNC criteria, “medical societies and countries can evaluate their own policies in relation to this document and fix any deficiencies,” Dr. Sung said.

“Many countries do not have any BD/DNC policies and can use the documents from this project to create their own. There may need to be discussions with legal, governmental, religious, and societal leaders to help understand and accept BD/DNC and to help enact policies in different communities,” he added.

Divergent definitions

The determination of death is not simply a scientific question, but also a philosophical, religious, and cultural question, wrote Robert D. Truog, MD, director of the Harvard Center for Bioethics, Boston, and colleagues in an accompanying editorial. Future research should consider cultural differences over these questions.

“Most important is that there be a clear and logical consistency between the definition of death and the tests that are used to diagnose it,” Dr. Truog said.

The concept of whole brain death was advanced as an equivalent to biological death, “such that, when the brain dies, the body literally disintegrates, just as it does after cardiac arrest,” but evidence indicates that this claim is untrue, Dr. Truog said. Current tests also do not diagnose the death of the whole brain.

Another hypothesis is that brain stem death represents the irreversible loss of consciousness and the capacity for spontaneous respiration.

“Instead of focusing on biology, [this definition] focuses on values and is based on the claim that when a person is in a state of irreversible apneic unconsciousness, we may consider them to be dead,” said Dr. Truog. He and his coeditorialists argued that the concept of whole brain death should be replaced with that of brain stem death.

“This report should be a call for our profession, as well as for federal and state lawmakers, to reform our laws so that they are consistent with our diagnostic criteria,” Dr. Truog said.

“The most straightforward way of doing this would be to change U.S. law and adopt the British standard of brain stem death, and then refine our testing to make the diagnosis of irreversible apneic unconsciousness as reliable and safe as possible,” he concluded.

The drafting of the consensus statement was not supported by outside funding. Dr. Sung reported no relevant financial relationships. Dr. Truog reported receiving compensation from Sanofi and Covance for participating in data and safety monitoring boards unrelated to the consensus document.

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

A group of experts representing various international professional societies has drafted a consensus statement on the determination of brain death or death by neurologic criteria (BD/DNC). The document, a result of the World Brain Death Project, surveys the clinical aspects of this determination, such as clinical testing, apnea testing, and the number of examinations required, as well as its social and legal aspects, including documentation, qualifications for making the determination, and religious attitudes toward BD/DNC.

The recommendations are the minimum criteria for BD/DNC, and countries and professional societies may choose to adopt stricter criteria, the authors noted. Seventeen supplements to the consensus statement contain detailed reports on topics the statement examines, including focuses on both adults and children.

“Perhaps the most important points of this project are, first, to show the worldwide acceptance of the concept of BD/DNC and what the minimum requirements are for BD/DNC,” said corresponding author Gene Sung, MD, MPH, director of the neurocritical care and stroke division at the University of Southern California, Los Angeles. Second, “this standard is centered around a clinical determination without the need for other testing.”

The consensus document and supplements were published online Aug. 3 in JAMA.

Comprehensive review

A lack of rigor has led to many differences in the determination of BD/DNC, said Dr. Sung. “Some of the variance that is common are the numbers of exams and examiners that are required and whether ancillary tests are required for determination of BD/DNC. In addition, a lot of guidelines and protocols that are in use are not thorough in detailing how to do the examinations and what to do in different circumstances.”

Professional societies such as the World Federation of Intensive and Critical Care recruited experts in BD/DNC to develop recommendations, which were based on relevant articles that they identified during a literature search. “We wanted to develop a fairly comprehensive document that, along with the 17 supplements, builds a foundation to show how to determine BD/DNC – what the minimum clinical criteria needed are and what to do in special circumstances,” Dr. Sung said.

Major sections of the statement include recommendations for the minimum clinical standards for the determination of BD/DNC in adults and children.

Determination must begin by establishing that the patient has sustained an irreversible brain injury that resulted in the loss of all brain function, according to the authors. Confounders such as pharmacologic paralysis and the effect of CNS depressant medications should be ruled out.

In addition, clinical evaluation must include an assessment for coma and an evaluation for brain stem areflexia. Among other criteria, the pupils should be fixed and nonresponsive to light, the face should not move in response to noxious cranial stimulation, and the gag and cough reflexes should be absent. Apnea testing is recommended to evaluate the responsiveness of respiratory centers in the medulla.

Although the definition of BD/DNC is the same in children as in adults, less evidence is available for the determination of BD/DNC in the very young. The authors thus advised a cautious approach to the evaluation of infants and younger children.

Recommendations vary by age and often require serial examinations, including apnea testing, they noted.

Ancillary testing

The consensus statement also reviews ancillary testing, which the authors recommend be required when the minimum clinical examination, including the apnea test, cannot be completed and when it is in the presence of confounding conditions that cannot be resolved.

The authors recommended digital subtraction angiography, radionuclide studies, and transcranial Doppler ultrasonography as ancillary tests based on blood flow in the brain. However, CT angiography and magnetic resonance angiography not be used.

A lack of guidance makes performing an apnea test in patients receiving extracorporeal membrane oxygenation (ECMO) challenging, according to the authors. Nevertheless, they recommended that the same principles of BD/DNC be applied to adults and children receiving ECMO.

They further recommended a period of preoxygenation before the apnea test, and the document describes in detail the method for administering this test to people receiving ECMO.

Another potentially challenging situation pointed out in the consensus document is the determination of BD/DNC in patients who have been treated with targeted temperature management. Therapeutic hypothermia, particularly if it is preceded or accompanied by sedation, can temporarily impair brain stem reflexes, thus mimicking BD/DNC.

The new document includes a flowchart and step-by-step recommendations as well as suggestions for determining BD/DNC under these circumstances.

Among document limitations acknowledged by the authors is the lack of high-quality data from randomized, controlled trials on which to base their recommendations.

In addition, economic, technological, or personnel limitations may reduce the available options for ancillary testing, they added. Also, the recommendations do not incorporate contributions from patients or social or religious groups, although the authors were mindful of their concerns.

To promote the national and international harmonization of BD/DNC criteria, “medical societies and countries can evaluate their own policies in relation to this document and fix any deficiencies,” Dr. Sung said.

“Many countries do not have any BD/DNC policies and can use the documents from this project to create their own. There may need to be discussions with legal, governmental, religious, and societal leaders to help understand and accept BD/DNC and to help enact policies in different communities,” he added.

Divergent definitions

The determination of death is not simply a scientific question, but also a philosophical, religious, and cultural question, wrote Robert D. Truog, MD, director of the Harvard Center for Bioethics, Boston, and colleagues in an accompanying editorial. Future research should consider cultural differences over these questions.

“Most important is that there be a clear and logical consistency between the definition of death and the tests that are used to diagnose it,” Dr. Truog said.

The concept of whole brain death was advanced as an equivalent to biological death, “such that, when the brain dies, the body literally disintegrates, just as it does after cardiac arrest,” but evidence indicates that this claim is untrue, Dr. Truog said. Current tests also do not diagnose the death of the whole brain.

Another hypothesis is that brain stem death represents the irreversible loss of consciousness and the capacity for spontaneous respiration.

“Instead of focusing on biology, [this definition] focuses on values and is based on the claim that when a person is in a state of irreversible apneic unconsciousness, we may consider them to be dead,” said Dr. Truog. He and his coeditorialists argued that the concept of whole brain death should be replaced with that of brain stem death.

“This report should be a call for our profession, as well as for federal and state lawmakers, to reform our laws so that they are consistent with our diagnostic criteria,” Dr. Truog said.

“The most straightforward way of doing this would be to change U.S. law and adopt the British standard of brain stem death, and then refine our testing to make the diagnosis of irreversible apneic unconsciousness as reliable and safe as possible,” he concluded.

The drafting of the consensus statement was not supported by outside funding. Dr. Sung reported no relevant financial relationships. Dr. Truog reported receiving compensation from Sanofi and Covance for participating in data and safety monitoring boards unrelated to the consensus document.

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

Chloroquine may be associated with serious psychiatric side effects, even in patients with no family or personal history of psychiatric disorders, a new review suggests.

In a letter to the editor published online July 28 in The Journal of Clinical Psychiatry, the authors summarize data from several studies published as far back as 1993 and as recently as May 2020.

“In addition to previously reported side effects, chloroquine could also induce psychiatric side effects which are polymorphic and can persist even after stopping the drug,” lead author Florence Gressier, MD, PhD, CESP, Inserm, department of psychiatry, Le Kremlin Bicêtre, France, said in an interview.

“In COVID-19 patients who may still be [undergoing treatment] with chloroquine, close psychiatric assessment and monitoring should be performed,” she said.
 

Heated controversy

Chloroquine and hydroxychloroquine have been at the center of heated controversy for their potential role in preventing or treating COVID-19.

Following findings of a small French study that suggested efficacy in lowering the viral load in patients with COVID-19, President Donald Trump expressed optimism regarding the role of hydroxychloroquine in treating COVID-19, calling it a “game changer”.

Other studies, however, have called into question both the efficacy and the safety of hydroxychloroquine in treating COVID-19. On June 15, the Food and Drug Administration revoked the emergency use authorization it had given in March to chloroquine and hydroxychloroquine for the treatment of COVID-19.

Nevertheless, hydroxychloroquine continues to be prescribed for COVID-19. For example, an article that appeared in Click2Houston on June 15 quoted the chief medical officer of Houston’s United Memorial Center as saying he plans to continue prescribing hydroxychloroquine for patients with COVID-19 until he finds a better alternative.

As discussed in a Medscape expert commentary, a group of physicians who held a “white coat summit” in front of the U.S. Supreme Court building promoted the use of hydroxychloroquine for the treatment of COVID-19. The video of their summit was retweeted by President Trump and garnered millions of views before it was taken down by Twitter, Facebook, and YouTube.
 

Sudden onset

For the new review, “we wanted to alert the public and practitioners on the potentially psychiatric risks induced by chloroquine, as it could be taken as self-medication or potentially still prescribed,” Dr. Gressier said.

“We think the format of the letter to the editor allows information to be provided in a concise and clear manner,” she added.

According to the FDA’s Adverse Event Reporting System database, 12% of reported adverse events (520 of 4,336) following the use of chloroquine that occurred between the fourth quarter of 2012 and the fourth quarter of 2019 were neuropsychiatric. These events included amnesia, delirium, hallucinations, depression, and loss of consciousness, the authors write.

The researchers acknowledged that the incidence of psychiatric adverse effects associated with the use of chloroquine is “unclear in the absence of high-quality, randomized placebo-controlled trials of its safety.” Nevertheless, they pointed out that there have been reports of insomnia and depression when the drug was used as prophylaxis against malaria .

Moreover, some case series or case reports describe symptoms such as depression, anxiety, agitation, violent outburst, suicidal ideation, and psychosis in patients who have been treated with chloroquine for malaria, lupus erythematosus, and rheumatoid arthritis .

“In contrast to many other psychoses, chloroquine psychosis may be more affective and include prominent visual hallucinations, symptoms of derealization, and disorders of thought, with preserved insight,” the authors wrote.

They noted that the frequency of symptoms does not appear to be connected to the cumulative dose or the duration of treatment, and the onset of psychosis or other adverse effects is usually “sudden.”

In addition, they warn that the drug’s psychiatric effects may go unnoticed, especially because COVID-19 itself has been associated with neuropsychiatric symptoms, making it hard to distinguish between symptoms caused by the illness and those caused by the drug.

Although the psychiatric symptoms typically occur early after treatment initiation, some “subtle” symptoms might persist after stopping the drug, possibly owing to its “extremely long” half-life, the authors stated.

Dr. Gressier noted that practicing clinicians should look up reports about self-medication with chloroquine “and warn their patients about the risk induced by chloroquine.”
 

Safe but ‘not benign’

Nilanjana Bose, MD, MBA, a rheumatologist at the Rheumatology Center of Houston, said she uses hydroxychloroquine “all the time” in clinical practice to treat patients with rheumatic conditions.

“I cannot comment on whether it [hydroxychloroquine or chloroquine] is a potential prophylactic or treatment for COVID-19, but I can say that, from a safety point of view, as a rheumatologist who uses hydroxychloroquine at a dose of 400 mg/day, I do not think we need to worry about serious [psychiatric] side effects,” Dr. Bose said in an interview.

Because clinicians are trying all types of possible treatments for COVID-19, “if this medication has possible efficacy, it is a great medicine from a rheumatologic perspective and is safe,” she added.

Nevertheless, the drug is “not benign, and regular side effects will be there, and of course, higher doses will cause more side effects,” said Dr. Bose, who was not involved in authoring the letter.

She counsels patients about potential psychiatric side effects of hydroxychloroquine because some of her patients have complained about irritability, worsening anxiety and depression, and difficulty sleeping.
 

Be wary

James “Jimmy” Potash, MD, MPH, Henry Phipps Professor of Psychiatry and Behavioral Sciences, Johns Hopkins Medicine, Baltimore, said in an interview that the “take-home message of this letter is that serious psychiatric effects, psychotic illness in particular,” can occur in individuals who take chloroquine and hydroxychloroquine.

In addition, “these are potentially very concerning side effects that psychiatrists should be aware of,” noted Dr. Potash, department director and psychiatrist-in-chief at Johns Hopkins.

He said that one of his patients who had been “completely psychiatrically healthy” took chloroquine prophylactically prior to traveling overseas. After she began taking the drug, she had an episode of mania that resolved once she discontinued the medication and received treatment for the mania.

“If you add potential psychiatric side effects to the other side effects that can result from these medications, that adds up to a pretty important reason to be wary of taking them, particularly for the indication of COVID-19, where the level of evidence that it helps in any way is still quite weak,” Dr. Potash said.

In an interview, Remington Nevin, MD, MPH, DrPH, executive director at the Quinism Foundation, White River Junction, Vt., a nonprofit organization that supports and promotes education and research on disorders caused by poisoning by quinoline drugs; and faculty associate in the department of mental health at Johns Hopkins Bloomberg School of Public Health, said that the authors of the letter “are to be commended for their efforts in raising awareness of the potentially lasting and disabling psychiatric effects of chloroquine and hydroxychloroquine, which, as with similar effects from other synthetic quinoline antimalarials, have occasionally been overlooked or misattributed to other conditions.”

He added: “I have proposed that the chronic neuropsychiatric effects of this class of drug are best considered not as side effects but as signs and symptoms of a disorder known as chronic quinoline encephalopathy caused by poisoning of the central nervous system.”

Dr. Gressier and the other letter authors, Dr. Bose, and Dr. Potash have reported no relevant financial relationships. Dr. Nevin has been retained as a consultant and expert witness in legal cases involving claims of adverse effects from quinoline antimalarial drugs.

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

Chloroquine may be associated with serious psychiatric side effects, even in patients with no family or personal history of psychiatric disorders, a new review suggests.

In a letter to the editor published online July 28 in The Journal of Clinical Psychiatry, the authors summarize data from several studies published as far back as 1993 and as recently as May 2020.

“In addition to previously reported side effects, chloroquine could also induce psychiatric side effects which are polymorphic and can persist even after stopping the drug,” lead author Florence Gressier, MD, PhD, CESP, Inserm, department of psychiatry, Le Kremlin Bicêtre, France, said in an interview.

“In COVID-19 patients who may still be [undergoing treatment] with chloroquine, close psychiatric assessment and monitoring should be performed,” she said.
 

Heated controversy

Chloroquine and hydroxychloroquine have been at the center of heated controversy for their potential role in preventing or treating COVID-19.

Following findings of a small French study that suggested efficacy in lowering the viral load in patients with COVID-19, President Donald Trump expressed optimism regarding the role of hydroxychloroquine in treating COVID-19, calling it a “game changer”.

Other studies, however, have called into question both the efficacy and the safety of hydroxychloroquine in treating COVID-19. On June 15, the Food and Drug Administration revoked the emergency use authorization it had given in March to chloroquine and hydroxychloroquine for the treatment of COVID-19.

Nevertheless, hydroxychloroquine continues to be prescribed for COVID-19. For example, an article that appeared in Click2Houston on June 15 quoted the chief medical officer of Houston’s United Memorial Center as saying he plans to continue prescribing hydroxychloroquine for patients with COVID-19 until he finds a better alternative.

As discussed in a Medscape expert commentary, a group of physicians who held a “white coat summit” in front of the U.S. Supreme Court building promoted the use of hydroxychloroquine for the treatment of COVID-19. The video of their summit was retweeted by President Trump and garnered millions of views before it was taken down by Twitter, Facebook, and YouTube.
 

Sudden onset

For the new review, “we wanted to alert the public and practitioners on the potentially psychiatric risks induced by chloroquine, as it could be taken as self-medication or potentially still prescribed,” Dr. Gressier said.

“We think the format of the letter to the editor allows information to be provided in a concise and clear manner,” she added.

According to the FDA’s Adverse Event Reporting System database, 12% of reported adverse events (520 of 4,336) following the use of chloroquine that occurred between the fourth quarter of 2012 and the fourth quarter of 2019 were neuropsychiatric. These events included amnesia, delirium, hallucinations, depression, and loss of consciousness, the authors write.

The researchers acknowledged that the incidence of psychiatric adverse effects associated with the use of chloroquine is “unclear in the absence of high-quality, randomized placebo-controlled trials of its safety.” Nevertheless, they pointed out that there have been reports of insomnia and depression when the drug was used as prophylaxis against malaria .

Moreover, some case series or case reports describe symptoms such as depression, anxiety, agitation, violent outburst, suicidal ideation, and psychosis in patients who have been treated with chloroquine for malaria, lupus erythematosus, and rheumatoid arthritis .

“In contrast to many other psychoses, chloroquine psychosis may be more affective and include prominent visual hallucinations, symptoms of derealization, and disorders of thought, with preserved insight,” the authors wrote.

They noted that the frequency of symptoms does not appear to be connected to the cumulative dose or the duration of treatment, and the onset of psychosis or other adverse effects is usually “sudden.”

In addition, they warn that the drug’s psychiatric effects may go unnoticed, especially because COVID-19 itself has been associated with neuropsychiatric symptoms, making it hard to distinguish between symptoms caused by the illness and those caused by the drug.

Although the psychiatric symptoms typically occur early after treatment initiation, some “subtle” symptoms might persist after stopping the drug, possibly owing to its “extremely long” half-life, the authors stated.

Dr. Gressier noted that practicing clinicians should look up reports about self-medication with chloroquine “and warn their patients about the risk induced by chloroquine.”
 

Safe but ‘not benign’

Nilanjana Bose, MD, MBA, a rheumatologist at the Rheumatology Center of Houston, said she uses hydroxychloroquine “all the time” in clinical practice to treat patients with rheumatic conditions.

“I cannot comment on whether it [hydroxychloroquine or chloroquine] is a potential prophylactic or treatment for COVID-19, but I can say that, from a safety point of view, as a rheumatologist who uses hydroxychloroquine at a dose of 400 mg/day, I do not think we need to worry about serious [psychiatric] side effects,” Dr. Bose said in an interview.

Because clinicians are trying all types of possible treatments for COVID-19, “if this medication has possible efficacy, it is a great medicine from a rheumatologic perspective and is safe,” she added.

Nevertheless, the drug is “not benign, and regular side effects will be there, and of course, higher doses will cause more side effects,” said Dr. Bose, who was not involved in authoring the letter.

She counsels patients about potential psychiatric side effects of hydroxychloroquine because some of her patients have complained about irritability, worsening anxiety and depression, and difficulty sleeping.
 

Be wary

James “Jimmy” Potash, MD, MPH, Henry Phipps Professor of Psychiatry and Behavioral Sciences, Johns Hopkins Medicine, Baltimore, said in an interview that the “take-home message of this letter is that serious psychiatric effects, psychotic illness in particular,” can occur in individuals who take chloroquine and hydroxychloroquine.

In addition, “these are potentially very concerning side effects that psychiatrists should be aware of,” noted Dr. Potash, department director and psychiatrist-in-chief at Johns Hopkins.

He said that one of his patients who had been “completely psychiatrically healthy” took chloroquine prophylactically prior to traveling overseas. After she began taking the drug, she had an episode of mania that resolved once she discontinued the medication and received treatment for the mania.

“If you add potential psychiatric side effects to the other side effects that can result from these medications, that adds up to a pretty important reason to be wary of taking them, particularly for the indication of COVID-19, where the level of evidence that it helps in any way is still quite weak,” Dr. Potash said.

In an interview, Remington Nevin, MD, MPH, DrPH, executive director at the Quinism Foundation, White River Junction, Vt., a nonprofit organization that supports and promotes education and research on disorders caused by poisoning by quinoline drugs; and faculty associate in the department of mental health at Johns Hopkins Bloomberg School of Public Health, said that the authors of the letter “are to be commended for their efforts in raising awareness of the potentially lasting and disabling psychiatric effects of chloroquine and hydroxychloroquine, which, as with similar effects from other synthetic quinoline antimalarials, have occasionally been overlooked or misattributed to other conditions.”

He added: “I have proposed that the chronic neuropsychiatric effects of this class of drug are best considered not as side effects but as signs and symptoms of a disorder known as chronic quinoline encephalopathy caused by poisoning of the central nervous system.”

Dr. Gressier and the other letter authors, Dr. Bose, and Dr. Potash have reported no relevant financial relationships. Dr. Nevin has been retained as a consultant and expert witness in legal cases involving claims of adverse effects from quinoline antimalarial drugs.

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

Chloroquine may be associated with serious psychiatric side effects, even in patients with no family or personal history of psychiatric disorders, a new review suggests.

In a letter to the editor published online July 28 in The Journal of Clinical Psychiatry, the authors summarize data from several studies published as far back as 1993 and as recently as May 2020.

“In addition to previously reported side effects, chloroquine could also induce psychiatric side effects which are polymorphic and can persist even after stopping the drug,” lead author Florence Gressier, MD, PhD, CESP, Inserm, department of psychiatry, Le Kremlin Bicêtre, France, said in an interview.

“In COVID-19 patients who may still be [undergoing treatment] with chloroquine, close psychiatric assessment and monitoring should be performed,” she said.
 

Heated controversy

Chloroquine and hydroxychloroquine have been at the center of heated controversy for their potential role in preventing or treating COVID-19.

Following findings of a small French study that suggested efficacy in lowering the viral load in patients with COVID-19, President Donald Trump expressed optimism regarding the role of hydroxychloroquine in treating COVID-19, calling it a “game changer”.

Other studies, however, have called into question both the efficacy and the safety of hydroxychloroquine in treating COVID-19. On June 15, the Food and Drug Administration revoked the emergency use authorization it had given in March to chloroquine and hydroxychloroquine for the treatment of COVID-19.

Nevertheless, hydroxychloroquine continues to be prescribed for COVID-19. For example, an article that appeared in Click2Houston on June 15 quoted the chief medical officer of Houston’s United Memorial Center as saying he plans to continue prescribing hydroxychloroquine for patients with COVID-19 until he finds a better alternative.

As discussed in a Medscape expert commentary, a group of physicians who held a “white coat summit” in front of the U.S. Supreme Court building promoted the use of hydroxychloroquine for the treatment of COVID-19. The video of their summit was retweeted by President Trump and garnered millions of views before it was taken down by Twitter, Facebook, and YouTube.
 

Sudden onset

For the new review, “we wanted to alert the public and practitioners on the potentially psychiatric risks induced by chloroquine, as it could be taken as self-medication or potentially still prescribed,” Dr. Gressier said.

“We think the format of the letter to the editor allows information to be provided in a concise and clear manner,” she added.

According to the FDA’s Adverse Event Reporting System database, 12% of reported adverse events (520 of 4,336) following the use of chloroquine that occurred between the fourth quarter of 2012 and the fourth quarter of 2019 were neuropsychiatric. These events included amnesia, delirium, hallucinations, depression, and loss of consciousness, the authors write.

The researchers acknowledged that the incidence of psychiatric adverse effects associated with the use of chloroquine is “unclear in the absence of high-quality, randomized placebo-controlled trials of its safety.” Nevertheless, they pointed out that there have been reports of insomnia and depression when the drug was used as prophylaxis against malaria .

Moreover, some case series or case reports describe symptoms such as depression, anxiety, agitation, violent outburst, suicidal ideation, and psychosis in patients who have been treated with chloroquine for malaria, lupus erythematosus, and rheumatoid arthritis .

“In contrast to many other psychoses, chloroquine psychosis may be more affective and include prominent visual hallucinations, symptoms of derealization, and disorders of thought, with preserved insight,” the authors wrote.

They noted that the frequency of symptoms does not appear to be connected to the cumulative dose or the duration of treatment, and the onset of psychosis or other adverse effects is usually “sudden.”

In addition, they warn that the drug’s psychiatric effects may go unnoticed, especially because COVID-19 itself has been associated with neuropsychiatric symptoms, making it hard to distinguish between symptoms caused by the illness and those caused by the drug.

Although the psychiatric symptoms typically occur early after treatment initiation, some “subtle” symptoms might persist after stopping the drug, possibly owing to its “extremely long” half-life, the authors stated.

Dr. Gressier noted that practicing clinicians should look up reports about self-medication with chloroquine “and warn their patients about the risk induced by chloroquine.”
 

Safe but ‘not benign’

Nilanjana Bose, MD, MBA, a rheumatologist at the Rheumatology Center of Houston, said she uses hydroxychloroquine “all the time” in clinical practice to treat patients with rheumatic conditions.

“I cannot comment on whether it [hydroxychloroquine or chloroquine] is a potential prophylactic or treatment for COVID-19, but I can say that, from a safety point of view, as a rheumatologist who uses hydroxychloroquine at a dose of 400 mg/day, I do not think we need to worry about serious [psychiatric] side effects,” Dr. Bose said in an interview.

Because clinicians are trying all types of possible treatments for COVID-19, “if this medication has possible efficacy, it is a great medicine from a rheumatologic perspective and is safe,” she added.

Nevertheless, the drug is “not benign, and regular side effects will be there, and of course, higher doses will cause more side effects,” said Dr. Bose, who was not involved in authoring the letter.

She counsels patients about potential psychiatric side effects of hydroxychloroquine because some of her patients have complained about irritability, worsening anxiety and depression, and difficulty sleeping.
 

Be wary

James “Jimmy” Potash, MD, MPH, Henry Phipps Professor of Psychiatry and Behavioral Sciences, Johns Hopkins Medicine, Baltimore, said in an interview that the “take-home message of this letter is that serious psychiatric effects, psychotic illness in particular,” can occur in individuals who take chloroquine and hydroxychloroquine.

In addition, “these are potentially very concerning side effects that psychiatrists should be aware of,” noted Dr. Potash, department director and psychiatrist-in-chief at Johns Hopkins.

He said that one of his patients who had been “completely psychiatrically healthy” took chloroquine prophylactically prior to traveling overseas. After she began taking the drug, she had an episode of mania that resolved once she discontinued the medication and received treatment for the mania.

“If you add potential psychiatric side effects to the other side effects that can result from these medications, that adds up to a pretty important reason to be wary of taking them, particularly for the indication of COVID-19, where the level of evidence that it helps in any way is still quite weak,” Dr. Potash said.

In an interview, Remington Nevin, MD, MPH, DrPH, executive director at the Quinism Foundation, White River Junction, Vt., a nonprofit organization that supports and promotes education and research on disorders caused by poisoning by quinoline drugs; and faculty associate in the department of mental health at Johns Hopkins Bloomberg School of Public Health, said that the authors of the letter “are to be commended for their efforts in raising awareness of the potentially lasting and disabling psychiatric effects of chloroquine and hydroxychloroquine, which, as with similar effects from other synthetic quinoline antimalarials, have occasionally been overlooked or misattributed to other conditions.”

He added: “I have proposed that the chronic neuropsychiatric effects of this class of drug are best considered not as side effects but as signs and symptoms of a disorder known as chronic quinoline encephalopathy caused by poisoning of the central nervous system.”

Dr. Gressier and the other letter authors, Dr. Bose, and Dr. Potash have reported no relevant financial relationships. Dr. Nevin has been retained as a consultant and expert witness in legal cases involving claims of adverse effects from quinoline antimalarial drugs.

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

A new study of hypertension treatment trends found that uncontrolled high blood pressure along with considerable undertreatment of the condition were prevalent in individuals with a history of both hypertension and stroke. “To our knowledge, the present study is the first to analyze and report national antihypertensive medication trends exclusively among individuals with a history of stroke in the United States,” wrote Daniel Santos, MD, and Mandip S. Dhamoon, MD, DrPH, of the Icahn School of Medicine at Mount Sinai, New York. Their study was published in JAMA Neurology.

To examine blood pressure control and treatment trends among stroke survivors, the researchers examined more than a decade of data from the National Health and Nutrition Examination Survey (NHANES). The cross-sectional survey is conducted in 2-year cycles; the authors analyzed the results from 2005 to 2016 and uncovered a total of 4,971,136 eligible individuals with a history of both stroke and hypertension.

The mean age of the study population was 67.1 (95% confidence interval, 66.1-68.1), and 2,790,518 (56.1%) were women. Their mean blood pressure was 134/68 mm Hg (95% CI, 133/67–136/69), and the average number of antihypertensive medications they were taking was 1.8 (95% CI, 1.7-1.9). Of the 4,971,136 analyzed individuals, 4,721,409 (95%) were aware of their hypertension diagnosis yet more than 10% of that group had not previously been prescribed an antihypertensive medication.

More than 37% (n = 1,846,470) of the participants had uncontrolled high blood pressure upon examination (95% CI, 33.5%-40.8%), and 15.3% (95% CI, 12.5%-18.0%) were not taking any medication for it at all. The most commonly used antihypertensive medications included ACE inhibitors or angiotensin receptor blockers (59.2%; 95% CI, 54.9%-63.4%), beta-blockers (43.8%; 95% CI, 40.3%-47.3%), diuretics (41.6%; 95% CI, 37.3%-45.9%) and calcium-channel blockers (31.5%; 95% CI, 28.2%-34.8%).* Roughly 57% of the sample was taking more than one antihypertensive medication (95% CI, 52.8%-60.6%) while 28% (95% CI, 24.6%-31.5%) were taking only one.
 

Continued surveillance is key

“All the studies that have ever been done show that hypertension is inadequately treated,” Louis Caplan, MD, of Harvard Medical School and Beth Israel Deaconess Medical Center, both in Boston, said in an interview. “One of the reasons is that it can be hard to get some of the patients to seek treatment, particularly Black Americans. Also, a lot of the medicines to treat high blood pressure have side effects, so many patients don’t want to take the pills.

“Treating hypertension really requires continued surveillance,” he added. “It’s not one visit where the doctor gives you a pill. It’s taking the pill, following your blood pressure, and seeing if it works. If it doesn’t, then maybe you change the dose, get another pill, and are followed once again. That doesn’t happen as often as it should.”

In regard to next steps, Dr. Caplan urged that hypertension “be evaluated more seriously. Even as home blood pressure kits and monitoring become increasingly available, many doctors are still going by a casual blood pressure test in the office, which doesn’t tell you how serious the problem is. There needs to be more use of technology and more conditioning of patients to monitor their own blood pressure as a guide, and then we go from there.”

The authors acknowledged their study’s limitations, including the NHANES’s reliance on self-reporting a history of stroke and the inability to distinguish between subtypes of stroke. In addition, they noted that many antihypertensive medications have uses beyond treating hypertension, which introduces “another confounding factor to medication trends.”

The authors and Dr. Caplan reported no conflicts of interest.

SOURCE: Santos D et al. JAMA Neurol. 2020 Jul 27. doi: 10.1001/jamaneurol.2020.2499.

Correction, 8/20/20: An earlier version of this article misstated the confidence interval for diuretics.

A new study of hypertension treatment trends found that uncontrolled high blood pressure along with considerable undertreatment of the condition were prevalent in individuals with a history of both hypertension and stroke. “To our knowledge, the present study is the first to analyze and report national antihypertensive medication trends exclusively among individuals with a history of stroke in the United States,” wrote Daniel Santos, MD, and Mandip S. Dhamoon, MD, DrPH, of the Icahn School of Medicine at Mount Sinai, New York. Their study was published in JAMA Neurology.

To examine blood pressure control and treatment trends among stroke survivors, the researchers examined more than a decade of data from the National Health and Nutrition Examination Survey (NHANES). The cross-sectional survey is conducted in 2-year cycles; the authors analyzed the results from 2005 to 2016 and uncovered a total of 4,971,136 eligible individuals with a history of both stroke and hypertension.

The mean age of the study population was 67.1 (95% confidence interval, 66.1-68.1), and 2,790,518 (56.1%) were women. Their mean blood pressure was 134/68 mm Hg (95% CI, 133/67–136/69), and the average number of antihypertensive medications they were taking was 1.8 (95% CI, 1.7-1.9). Of the 4,971,136 analyzed individuals, 4,721,409 (95%) were aware of their hypertension diagnosis yet more than 10% of that group had not previously been prescribed an antihypertensive medication.

More than 37% (n = 1,846,470) of the participants had uncontrolled high blood pressure upon examination (95% CI, 33.5%-40.8%), and 15.3% (95% CI, 12.5%-18.0%) were not taking any medication for it at all. The most commonly used antihypertensive medications included ACE inhibitors or angiotensin receptor blockers (59.2%; 95% CI, 54.9%-63.4%), beta-blockers (43.8%; 95% CI, 40.3%-47.3%), diuretics (41.6%; 95% CI, 37.3%-45.9%) and calcium-channel blockers (31.5%; 95% CI, 28.2%-34.8%).* Roughly 57% of the sample was taking more than one antihypertensive medication (95% CI, 52.8%-60.6%) while 28% (95% CI, 24.6%-31.5%) were taking only one.
 

Continued surveillance is key

“All the studies that have ever been done show that hypertension is inadequately treated,” Louis Caplan, MD, of Harvard Medical School and Beth Israel Deaconess Medical Center, both in Boston, said in an interview. “One of the reasons is that it can be hard to get some of the patients to seek treatment, particularly Black Americans. Also, a lot of the medicines to treat high blood pressure have side effects, so many patients don’t want to take the pills.

“Treating hypertension really requires continued surveillance,” he added. “It’s not one visit where the doctor gives you a pill. It’s taking the pill, following your blood pressure, and seeing if it works. If it doesn’t, then maybe you change the dose, get another pill, and are followed once again. That doesn’t happen as often as it should.”

In regard to next steps, Dr. Caplan urged that hypertension “be evaluated more seriously. Even as home blood pressure kits and monitoring become increasingly available, many doctors are still going by a casual blood pressure test in the office, which doesn’t tell you how serious the problem is. There needs to be more use of technology and more conditioning of patients to monitor their own blood pressure as a guide, and then we go from there.”

The authors acknowledged their study’s limitations, including the NHANES’s reliance on self-reporting a history of stroke and the inability to distinguish between subtypes of stroke. In addition, they noted that many antihypertensive medications have uses beyond treating hypertension, which introduces “another confounding factor to medication trends.”

The authors and Dr. Caplan reported no conflicts of interest.

SOURCE: Santos D et al. JAMA Neurol. 2020 Jul 27. doi: 10.1001/jamaneurol.2020.2499.

Correction, 8/20/20: An earlier version of this article misstated the confidence interval for diuretics.

A new study of hypertension treatment trends found that uncontrolled high blood pressure along with considerable undertreatment of the condition were prevalent in individuals with a history of both hypertension and stroke. “To our knowledge, the present study is the first to analyze and report national antihypertensive medication trends exclusively among individuals with a history of stroke in the United States,” wrote Daniel Santos, MD, and Mandip S. Dhamoon, MD, DrPH, of the Icahn School of Medicine at Mount Sinai, New York. Their study was published in JAMA Neurology.

To examine blood pressure control and treatment trends among stroke survivors, the researchers examined more than a decade of data from the National Health and Nutrition Examination Survey (NHANES). The cross-sectional survey is conducted in 2-year cycles; the authors analyzed the results from 2005 to 2016 and uncovered a total of 4,971,136 eligible individuals with a history of both stroke and hypertension.

The mean age of the study population was 67.1 (95% confidence interval, 66.1-68.1), and 2,790,518 (56.1%) were women. Their mean blood pressure was 134/68 mm Hg (95% CI, 133/67–136/69), and the average number of antihypertensive medications they were taking was 1.8 (95% CI, 1.7-1.9). Of the 4,971,136 analyzed individuals, 4,721,409 (95%) were aware of their hypertension diagnosis yet more than 10% of that group had not previously been prescribed an antihypertensive medication.

More than 37% (n = 1,846,470) of the participants had uncontrolled high blood pressure upon examination (95% CI, 33.5%-40.8%), and 15.3% (95% CI, 12.5%-18.0%) were not taking any medication for it at all. The most commonly used antihypertensive medications included ACE inhibitors or angiotensin receptor blockers (59.2%; 95% CI, 54.9%-63.4%), beta-blockers (43.8%; 95% CI, 40.3%-47.3%), diuretics (41.6%; 95% CI, 37.3%-45.9%) and calcium-channel blockers (31.5%; 95% CI, 28.2%-34.8%).* Roughly 57% of the sample was taking more than one antihypertensive medication (95% CI, 52.8%-60.6%) while 28% (95% CI, 24.6%-31.5%) were taking only one.
 

Continued surveillance is key

“All the studies that have ever been done show that hypertension is inadequately treated,” Louis Caplan, MD, of Harvard Medical School and Beth Israel Deaconess Medical Center, both in Boston, said in an interview. “One of the reasons is that it can be hard to get some of the patients to seek treatment, particularly Black Americans. Also, a lot of the medicines to treat high blood pressure have side effects, so many patients don’t want to take the pills.

“Treating hypertension really requires continued surveillance,” he added. “It’s not one visit where the doctor gives you a pill. It’s taking the pill, following your blood pressure, and seeing if it works. If it doesn’t, then maybe you change the dose, get another pill, and are followed once again. That doesn’t happen as often as it should.”

In regard to next steps, Dr. Caplan urged that hypertension “be evaluated more seriously. Even as home blood pressure kits and monitoring become increasingly available, many doctors are still going by a casual blood pressure test in the office, which doesn’t tell you how serious the problem is. There needs to be more use of technology and more conditioning of patients to monitor their own blood pressure as a guide, and then we go from there.”

The authors acknowledged their study’s limitations, including the NHANES’s reliance on self-reporting a history of stroke and the inability to distinguish between subtypes of stroke. In addition, they noted that many antihypertensive medications have uses beyond treating hypertension, which introduces “another confounding factor to medication trends.”

The authors and Dr. Caplan reported no conflicts of interest.

SOURCE: Santos D et al. JAMA Neurol. 2020 Jul 27. doi: 10.1001/jamaneurol.2020.2499.

Correction, 8/20/20: An earlier version of this article misstated the confidence interval for diuretics.

Most primary care physicians agree that antibiotic resistance and inappropriate prescribing are problems in the United States, but they are much less inclined to recognize these issues in their own practices, according to the results of a nationwide survey.

“This lack of recognition of physicians’ own contributions to inappropriate prescribing presents a barrier to encouraging widespread stewardship uptake,” Rachel M. Zetts, MPH, of the Pew Charitable Trusts, Washington, D.C., and associates wrote in Open Forum Infectious Diseases.

Almost all (94%) of the 1,550 internists, family physicians, and pediatricians who responded to the survey said that antibiotic resistance is a national problem, and nearly that many (91%) agreed that “inappropriate antibiotic prescribing is a problem in outpatient health care settings,” the investigators acknowledged.

Narrowing the focus to their own practices, however, changed some opinions. At that level, only 55% of the respondents said that resistance was a problem for their practices, and just 37% said that there any sort of inappropriate prescribing going on, based on data from the survey, which was conducted from August to October 2018 by Pew and the American Medical Association.

Antibiotic stewardship, defined as activities meant to ensure appropriate prescribing of antibiotics, should include “staff and patient education, clinician-level antibiotic prescribing feedback, and communications training on how to discuss antibiotic prescribing with patients,” Ms. Zetts and associates explained.

The need for such stewardship in health care settings was acknowledged by 72% of respondents, but 53% of those surveyed also said that all they need to do to support such efforts “is to talk with their patients about the value of an antibiotic for their symptoms,” they noted.

The bacteria, it seems, are not the only ones with some resistance. Half of the primary care physicians believe that it would be difficult to fairly and accurately track the appropriate use of antibiotics, and 52% agreed with the statement that “practice-based reporting requirements for antibiotic use would be too onerous,” the researchers pointed out.

“Antibiotic resistance is an impending public health crisis. We are seeing today, as we respond to the COVID-19 pandemic, what our health system looks like with no or limited treatments available to tackle an outbreak. … We must all remain vigilant in combating the spread of antibiotic resistant bacteria and be prudent when prescribing antibiotics,” AMA President Susan R. Bailey, MD, said in a written statement.

[email protected]

SOURCE: Zetts RM et al. Open Forum Infect Dis. 2020 July;7(7). doi: 10.1093/ofid/ofaa244.

Most primary care physicians agree that antibiotic resistance and inappropriate prescribing are problems in the United States, but they are much less inclined to recognize these issues in their own practices, according to the results of a nationwide survey.

“This lack of recognition of physicians’ own contributions to inappropriate prescribing presents a barrier to encouraging widespread stewardship uptake,” Rachel M. Zetts, MPH, of the Pew Charitable Trusts, Washington, D.C., and associates wrote in Open Forum Infectious Diseases.

Almost all (94%) of the 1,550 internists, family physicians, and pediatricians who responded to the survey said that antibiotic resistance is a national problem, and nearly that many (91%) agreed that “inappropriate antibiotic prescribing is a problem in outpatient health care settings,” the investigators acknowledged.

Narrowing the focus to their own practices, however, changed some opinions. At that level, only 55% of the respondents said that resistance was a problem for their practices, and just 37% said that there any sort of inappropriate prescribing going on, based on data from the survey, which was conducted from August to October 2018 by Pew and the American Medical Association.

Antibiotic stewardship, defined as activities meant to ensure appropriate prescribing of antibiotics, should include “staff and patient education, clinician-level antibiotic prescribing feedback, and communications training on how to discuss antibiotic prescribing with patients,” Ms. Zetts and associates explained.

The need for such stewardship in health care settings was acknowledged by 72% of respondents, but 53% of those surveyed also said that all they need to do to support such efforts “is to talk with their patients about the value of an antibiotic for their symptoms,” they noted.

The bacteria, it seems, are not the only ones with some resistance. Half of the primary care physicians believe that it would be difficult to fairly and accurately track the appropriate use of antibiotics, and 52% agreed with the statement that “practice-based reporting requirements for antibiotic use would be too onerous,” the researchers pointed out.

“Antibiotic resistance is an impending public health crisis. We are seeing today, as we respond to the COVID-19 pandemic, what our health system looks like with no or limited treatments available to tackle an outbreak. … We must all remain vigilant in combating the spread of antibiotic resistant bacteria and be prudent when prescribing antibiotics,” AMA President Susan R. Bailey, MD, said in a written statement.

[email protected]

SOURCE: Zetts RM et al. Open Forum Infect Dis. 2020 July;7(7). doi: 10.1093/ofid/ofaa244.

Most primary care physicians agree that antibiotic resistance and inappropriate prescribing are problems in the United States, but they are much less inclined to recognize these issues in their own practices, according to the results of a nationwide survey.

“This lack of recognition of physicians’ own contributions to inappropriate prescribing presents a barrier to encouraging widespread stewardship uptake,” Rachel M. Zetts, MPH, of the Pew Charitable Trusts, Washington, D.C., and associates wrote in Open Forum Infectious Diseases.

Almost all (94%) of the 1,550 internists, family physicians, and pediatricians who responded to the survey said that antibiotic resistance is a national problem, and nearly that many (91%) agreed that “inappropriate antibiotic prescribing is a problem in outpatient health care settings,” the investigators acknowledged.

Narrowing the focus to their own practices, however, changed some opinions. At that level, only 55% of the respondents said that resistance was a problem for their practices, and just 37% said that there any sort of inappropriate prescribing going on, based on data from the survey, which was conducted from August to October 2018 by Pew and the American Medical Association.

Antibiotic stewardship, defined as activities meant to ensure appropriate prescribing of antibiotics, should include “staff and patient education, clinician-level antibiotic prescribing feedback, and communications training on how to discuss antibiotic prescribing with patients,” Ms. Zetts and associates explained.

The need for such stewardship in health care settings was acknowledged by 72% of respondents, but 53% of those surveyed also said that all they need to do to support such efforts “is to talk with their patients about the value of an antibiotic for their symptoms,” they noted.

The bacteria, it seems, are not the only ones with some resistance. Half of the primary care physicians believe that it would be difficult to fairly and accurately track the appropriate use of antibiotics, and 52% agreed with the statement that “practice-based reporting requirements for antibiotic use would be too onerous,” the researchers pointed out.

“Antibiotic resistance is an impending public health crisis. We are seeing today, as we respond to the COVID-19 pandemic, what our health system looks like with no or limited treatments available to tackle an outbreak. … We must all remain vigilant in combating the spread of antibiotic resistant bacteria and be prudent when prescribing antibiotics,” AMA President Susan R. Bailey, MD, said in a written statement.

[email protected]

SOURCE: Zetts RM et al. Open Forum Infect Dis. 2020 July;7(7). doi: 10.1093/ofid/ofaa244.

Dr. Ira Weintraub, a recently retired orthopedic surgeon who now works at a medical billing consultancy, saw a hip replacement bill for over $400,000 earlier this year.

“The patient stayed in the hospital 17 days, which is only 17 times normal. The bill got paid,” mused Weintraub, chief medical officer of Portland, Oregon-based WellRithms, which helps self-funded employers and workers’ compensation insurers make sense of large, complex medical bills and ensure they pay the fair amount.

Charges like that go a long way toward explaining why hospitals are eager to restore joint replacements to pre-COVID levels as quickly as possible – an eagerness tempered only by safety concerns amid a resurgence of the coronavirus in some regions of the country. Revenue losses at hospitals and outpatient surgery centers may have exceeded $5 billion from canceled knee and hip replacements alone during a roughly two-month hiatus on elective procedures earlier this year.

The cost of joint replacement surgery varies widely – though, on average, it is in the tens, not hundreds, of thousands of dollars. Still, given the high and rapidly growing volume, it’s easy to see why joint replacement operations have become a vital chunk of revenue at most U.S. hospitals.

The rate of knee and hip replacements more than doubled from 2000 to 2015, according to inpatient discharge data from the Agency for Healthcare Research and Quality. And that growth is likely to continue: Knee replacements are expected to triple between now and 2040, with hip replacements not far behind, according to projections published last year in the Journal of Rheumatology.

Joint procedures are usually not emergencies, and they were among the first to be scrubbed or delayed when hospitals froze elective surgeries in March – and again in July in some areas plagued by renewed COVID outbreaks. Loss of the revenue has hit hospitals hard, and regaining it will be crucial to their financial convalescence.

“Without orthopedic volumes returning to something near their pre-pandemic levels, it will make it difficult for health systems to get back to anywhere near break-even from a bottom-line perspective,” said Stephen Thome, a principal in health care consulting at Grant Thornton, an advisory, audit and tax firm.

It’s impossible to know exactly how much knee and hip replacements are worth to hospitals, because no definitive data on total volume or price exists.

But using published estimates of volume, extrapolating average commercial payments from published Medicare rates based on a study, and making an educated guess of patient coinsurance, Thome helped KHN arrive at an annual market value for American hospitals and surgery centers of between $15.5 billion and $21.5 billion for knee replacements alone.

That suggests a revenue loss of $1.3 billion to $1.8 billion per month for the period the surgeries were shut down. These figures include ambulatory surgery centers not owned by hospitals, which also suspended most operations in late March, all of April and into May.

If you add hip replacements, which account for about half the volume of knees and are paid at similar rates, the total annual value rises to a range of $23 billion to $32 billion, with monthly revenue losses from $1.9 billion to $2.7 billion.

The American Hospital Association projects total revenue lost at U.S. hospitals will reach $323 billion by year’s end, not counting additional losses from surgeries canceled during the current coronavirus spike. That amount is partially offset by $69 billion in federal relief dollars hospitals have received so far, according to the association. The California Hospital Association puts the net revenue loss for hospitals in that state at about $10.5 billion, said spokesperson Jan Emerson-Shea.

Hospitals resumed joint replacement surgeries in early to mid-May, with the timing and ramp-up speed varying by region and hospital. Some hospitals restored volume quickly; others took a more cautious route and continue to lose revenue. Still others have had to shut down again.

At the NYU Langone Orthopedic Hospital in New York City, “people are starting to come in and you see the operating rooms full again,” said Dr. Claudette Lajam, chief orthopedic safety officer.

At St. Jude Medical Center in Fullerton, California, where the coronavirus is raging, inpatient joint replacements resumed in the second or third week of May – cautiously at first, but volume is “very close to pre-pandemic levels at this point,” said Dr. Kevin Khajavi, chairman of the hospital’s orthopedic surgery department. However, “we are constantly monitoring the situation to determine if we have to scale back once again,” he said.

In large swaths of Texas, elective surgeries were once again suspended in July because of the COVID-19 resurgence. The same is true at many hospitals in Florida, Alabama, South Carolina and Nevada.

The Mayo Clinic in Phoenix suspended nonemergency joint replacement surgeries in early July. It resumed outpatient replacement procedures the week of July 27, but still has not resumed nonemergency inpatient procedures, said Dr. Mark Spangehl, an orthopedic surgeon there. In terms of medical urgency, joint replacements are “at the bottom of the totem pole,” Spangehl said.

In terms of cash flow, however, joint replacements are decidedly not at the bottom of the totem pole. They have become a cash cow as the number of patients undergoing them has skyrocketed in recent decades.

The volume is being driven by an aging population, an epidemic of obesity and a significant rise in the number of younger people replacing joints worn out by years of sports and exercise.

It’s also being driven by the cash. Once only done in hospitals, the operations are now increasingly performed at ambulatory surgery centers – especially on younger, healthier patients who don’t require hospitalization.

The surgery centers are often physician-owned, but private equity groups such as Bain Capital and KKR & Co. have taken an interest in them, drawn by their high growth potential, robust financial returns and ability to offer competitive prices.

“[G]enerally the savings should be very good – but I do see a lot of outlier surgery centers where they are charging exorbitant amounts of money – $100,000 wouldn’t be too much,” said WellRithm’s Weintraub, who co-owned such a surgery center in Portland.

Fear of catching the coronavirus in a hospital is reinforcing the outpatient trend. Matthew Davis, a 58-year-old resident of Washington, was scheduled for a hip replacement on March 30 but got cold feet because of COVID-19, and canceled just before all elective surgeries were halted. When it came time to reschedule in June, he overcame his reservations in large part because the surgeon planned to perform the procedure at a free-standing surgery center.

“That was key to me – avoiding an overnight hospital stay to minimize my exposure,” Davis said. “These joint replacements are almost industrial-scale. They are cranking out joint replacements 9 to 5. I went in at 6:30 a.m. and I was walking out the door at 11:30.”

Acutely aware of the financial benefits, hospitals and surgery clinics have been marketing joint replacements for years, competing for coveted rankings and running ads that show healthy aging people, all smiles, engaged in vigorous activity.

However, a 2014 study concluded that one-third of knee replacements were not warranted, mainly because the symptoms of the patients were not severe enough to justify the procedures.

“The whole marketing of health care is so manipulative to the consuming public,” said Lisa McGiffert, a longtime consumer advocate and co-founder of the Patient Safety Action Network. “People might be encouraged to get a knee replacement, when in reality something less invasive could have improved their condition.”

McGiffert recounted a conversation with an orthopedic surgeon in Washington state who told her about a patient who requested a knee replacement, even though he had not tried any lower-impact treatments to fix the problem. “I asked the surgeon, ‘You didn’t do it, did you?’ And he said, ‘Of course I did. He would just have gone to somebody else.’ ”

This Kaiser Health News story first published on California Healthline, a service of the California Health Care Foundation.

Dr. Ira Weintraub, a recently retired orthopedic surgeon who now works at a medical billing consultancy, saw a hip replacement bill for over $400,000 earlier this year.

“The patient stayed in the hospital 17 days, which is only 17 times normal. The bill got paid,” mused Weintraub, chief medical officer of Portland, Oregon-based WellRithms, which helps self-funded employers and workers’ compensation insurers make sense of large, complex medical bills and ensure they pay the fair amount.

Charges like that go a long way toward explaining why hospitals are eager to restore joint replacements to pre-COVID levels as quickly as possible – an eagerness tempered only by safety concerns amid a resurgence of the coronavirus in some regions of the country. Revenue losses at hospitals and outpatient surgery centers may have exceeded $5 billion from canceled knee and hip replacements alone during a roughly two-month hiatus on elective procedures earlier this year.

The cost of joint replacement surgery varies widely – though, on average, it is in the tens, not hundreds, of thousands of dollars. Still, given the high and rapidly growing volume, it’s easy to see why joint replacement operations have become a vital chunk of revenue at most U.S. hospitals.

The rate of knee and hip replacements more than doubled from 2000 to 2015, according to inpatient discharge data from the Agency for Healthcare Research and Quality. And that growth is likely to continue: Knee replacements are expected to triple between now and 2040, with hip replacements not far behind, according to projections published last year in the Journal of Rheumatology.

Joint procedures are usually not emergencies, and they were among the first to be scrubbed or delayed when hospitals froze elective surgeries in March – and again in July in some areas plagued by renewed COVID outbreaks. Loss of the revenue has hit hospitals hard, and regaining it will be crucial to their financial convalescence.

“Without orthopedic volumes returning to something near their pre-pandemic levels, it will make it difficult for health systems to get back to anywhere near break-even from a bottom-line perspective,” said Stephen Thome, a principal in health care consulting at Grant Thornton, an advisory, audit and tax firm.

It’s impossible to know exactly how much knee and hip replacements are worth to hospitals, because no definitive data on total volume or price exists.

But using published estimates of volume, extrapolating average commercial payments from published Medicare rates based on a study, and making an educated guess of patient coinsurance, Thome helped KHN arrive at an annual market value for American hospitals and surgery centers of between $15.5 billion and $21.5 billion for knee replacements alone.

That suggests a revenue loss of $1.3 billion to $1.8 billion per month for the period the surgeries were shut down. These figures include ambulatory surgery centers not owned by hospitals, which also suspended most operations in late March, all of April and into May.

If you add hip replacements, which account for about half the volume of knees and are paid at similar rates, the total annual value rises to a range of $23 billion to $32 billion, with monthly revenue losses from $1.9 billion to $2.7 billion.

The American Hospital Association projects total revenue lost at U.S. hospitals will reach $323 billion by year’s end, not counting additional losses from surgeries canceled during the current coronavirus spike. That amount is partially offset by $69 billion in federal relief dollars hospitals have received so far, according to the association. The California Hospital Association puts the net revenue loss for hospitals in that state at about $10.5 billion, said spokesperson Jan Emerson-Shea.

Hospitals resumed joint replacement surgeries in early to mid-May, with the timing and ramp-up speed varying by region and hospital. Some hospitals restored volume quickly; others took a more cautious route and continue to lose revenue. Still others have had to shut down again.

At the NYU Langone Orthopedic Hospital in New York City, “people are starting to come in and you see the operating rooms full again,” said Dr. Claudette Lajam, chief orthopedic safety officer.

At St. Jude Medical Center in Fullerton, California, where the coronavirus is raging, inpatient joint replacements resumed in the second or third week of May – cautiously at first, but volume is “very close to pre-pandemic levels at this point,” said Dr. Kevin Khajavi, chairman of the hospital’s orthopedic surgery department. However, “we are constantly monitoring the situation to determine if we have to scale back once again,” he said.

In large swaths of Texas, elective surgeries were once again suspended in July because of the COVID-19 resurgence. The same is true at many hospitals in Florida, Alabama, South Carolina and Nevada.

The Mayo Clinic in Phoenix suspended nonemergency joint replacement surgeries in early July. It resumed outpatient replacement procedures the week of July 27, but still has not resumed nonemergency inpatient procedures, said Dr. Mark Spangehl, an orthopedic surgeon there. In terms of medical urgency, joint replacements are “at the bottom of the totem pole,” Spangehl said.

In terms of cash flow, however, joint replacements are decidedly not at the bottom of the totem pole. They have become a cash cow as the number of patients undergoing them has skyrocketed in recent decades.

The volume is being driven by an aging population, an epidemic of obesity and a significant rise in the number of younger people replacing joints worn out by years of sports and exercise.

It’s also being driven by the cash. Once only done in hospitals, the operations are now increasingly performed at ambulatory surgery centers – especially on younger, healthier patients who don’t require hospitalization.

The surgery centers are often physician-owned, but private equity groups such as Bain Capital and KKR & Co. have taken an interest in them, drawn by their high growth potential, robust financial returns and ability to offer competitive prices.

“[G]enerally the savings should be very good – but I do see a lot of outlier surgery centers where they are charging exorbitant amounts of money – $100,000 wouldn’t be too much,” said WellRithm’s Weintraub, who co-owned such a surgery center in Portland.

Fear of catching the coronavirus in a hospital is reinforcing the outpatient trend. Matthew Davis, a 58-year-old resident of Washington, was scheduled for a hip replacement on March 30 but got cold feet because of COVID-19, and canceled just before all elective surgeries were halted. When it came time to reschedule in June, he overcame his reservations in large part because the surgeon planned to perform the procedure at a free-standing surgery center.

“That was key to me – avoiding an overnight hospital stay to minimize my exposure,” Davis said. “These joint replacements are almost industrial-scale. They are cranking out joint replacements 9 to 5. I went in at 6:30 a.m. and I was walking out the door at 11:30.”

Acutely aware of the financial benefits, hospitals and surgery clinics have been marketing joint replacements for years, competing for coveted rankings and running ads that show healthy aging people, all smiles, engaged in vigorous activity.

However, a 2014 study concluded that one-third of knee replacements were not warranted, mainly because the symptoms of the patients were not severe enough to justify the procedures.

“The whole marketing of health care is so manipulative to the consuming public,” said Lisa McGiffert, a longtime consumer advocate and co-founder of the Patient Safety Action Network. “People might be encouraged to get a knee replacement, when in reality something less invasive could have improved their condition.”

McGiffert recounted a conversation with an orthopedic surgeon in Washington state who told her about a patient who requested a knee replacement, even though he had not tried any lower-impact treatments to fix the problem. “I asked the surgeon, ‘You didn’t do it, did you?’ And he said, ‘Of course I did. He would just have gone to somebody else.’ ”

This Kaiser Health News story first published on California Healthline, a service of the California Health Care Foundation.

Dr. Ira Weintraub, a recently retired orthopedic surgeon who now works at a medical billing consultancy, saw a hip replacement bill for over $400,000 earlier this year.

“The patient stayed in the hospital 17 days, which is only 17 times normal. The bill got paid,” mused Weintraub, chief medical officer of Portland, Oregon-based WellRithms, which helps self-funded employers and workers’ compensation insurers make sense of large, complex medical bills and ensure they pay the fair amount.

Charges like that go a long way toward explaining why hospitals are eager to restore joint replacements to pre-COVID levels as quickly as possible – an eagerness tempered only by safety concerns amid a resurgence of the coronavirus in some regions of the country. Revenue losses at hospitals and outpatient surgery centers may have exceeded $5 billion from canceled knee and hip replacements alone during a roughly two-month hiatus on elective procedures earlier this year.

The cost of joint replacement surgery varies widely – though, on average, it is in the tens, not hundreds, of thousands of dollars. Still, given the high and rapidly growing volume, it’s easy to see why joint replacement operations have become a vital chunk of revenue at most U.S. hospitals.

The rate of knee and hip replacements more than doubled from 2000 to 2015, according to inpatient discharge data from the Agency for Healthcare Research and Quality. And that growth is likely to continue: Knee replacements are expected to triple between now and 2040, with hip replacements not far behind, according to projections published last year in the Journal of Rheumatology.

Joint procedures are usually not emergencies, and they were among the first to be scrubbed or delayed when hospitals froze elective surgeries in March – and again in July in some areas plagued by renewed COVID outbreaks. Loss of the revenue has hit hospitals hard, and regaining it will be crucial to their financial convalescence.

“Without orthopedic volumes returning to something near their pre-pandemic levels, it will make it difficult for health systems to get back to anywhere near break-even from a bottom-line perspective,” said Stephen Thome, a principal in health care consulting at Grant Thornton, an advisory, audit and tax firm.

It’s impossible to know exactly how much knee and hip replacements are worth to hospitals, because no definitive data on total volume or price exists.

But using published estimates of volume, extrapolating average commercial payments from published Medicare rates based on a study, and making an educated guess of patient coinsurance, Thome helped KHN arrive at an annual market value for American hospitals and surgery centers of between $15.5 billion and $21.5 billion for knee replacements alone.

That suggests a revenue loss of $1.3 billion to $1.8 billion per month for the period the surgeries were shut down. These figures include ambulatory surgery centers not owned by hospitals, which also suspended most operations in late March, all of April and into May.

If you add hip replacements, which account for about half the volume of knees and are paid at similar rates, the total annual value rises to a range of $23 billion to $32 billion, with monthly revenue losses from $1.9 billion to $2.7 billion.

The American Hospital Association projects total revenue lost at U.S. hospitals will reach $323 billion by year’s end, not counting additional losses from surgeries canceled during the current coronavirus spike. That amount is partially offset by $69 billion in federal relief dollars hospitals have received so far, according to the association. The California Hospital Association puts the net revenue loss for hospitals in that state at about $10.5 billion, said spokesperson Jan Emerson-Shea.

Hospitals resumed joint replacement surgeries in early to mid-May, with the timing and ramp-up speed varying by region and hospital. Some hospitals restored volume quickly; others took a more cautious route and continue to lose revenue. Still others have had to shut down again.

At the NYU Langone Orthopedic Hospital in New York City, “people are starting to come in and you see the operating rooms full again,” said Dr. Claudette Lajam, chief orthopedic safety officer.

At St. Jude Medical Center in Fullerton, California, where the coronavirus is raging, inpatient joint replacements resumed in the second or third week of May – cautiously at first, but volume is “very close to pre-pandemic levels at this point,” said Dr. Kevin Khajavi, chairman of the hospital’s orthopedic surgery department. However, “we are constantly monitoring the situation to determine if we have to scale back once again,” he said.

In large swaths of Texas, elective surgeries were once again suspended in July because of the COVID-19 resurgence. The same is true at many hospitals in Florida, Alabama, South Carolina and Nevada.

The Mayo Clinic in Phoenix suspended nonemergency joint replacement surgeries in early July. It resumed outpatient replacement procedures the week of July 27, but still has not resumed nonemergency inpatient procedures, said Dr. Mark Spangehl, an orthopedic surgeon there. In terms of medical urgency, joint replacements are “at the bottom of the totem pole,” Spangehl said.

In terms of cash flow, however, joint replacements are decidedly not at the bottom of the totem pole. They have become a cash cow as the number of patients undergoing them has skyrocketed in recent decades.

The volume is being driven by an aging population, an epidemic of obesity and a significant rise in the number of younger people replacing joints worn out by years of sports and exercise.

It’s also being driven by the cash. Once only done in hospitals, the operations are now increasingly performed at ambulatory surgery centers – especially on younger, healthier patients who don’t require hospitalization.

The surgery centers are often physician-owned, but private equity groups such as Bain Capital and KKR & Co. have taken an interest in them, drawn by their high growth potential, robust financial returns and ability to offer competitive prices.

“[G]enerally the savings should be very good – but I do see a lot of outlier surgery centers where they are charging exorbitant amounts of money – $100,000 wouldn’t be too much,” said WellRithm’s Weintraub, who co-owned such a surgery center in Portland.

Fear of catching the coronavirus in a hospital is reinforcing the outpatient trend. Matthew Davis, a 58-year-old resident of Washington, was scheduled for a hip replacement on March 30 but got cold feet because of COVID-19, and canceled just before all elective surgeries were halted. When it came time to reschedule in June, he overcame his reservations in large part because the surgeon planned to perform the procedure at a free-standing surgery center.

“That was key to me – avoiding an overnight hospital stay to minimize my exposure,” Davis said. “These joint replacements are almost industrial-scale. They are cranking out joint replacements 9 to 5. I went in at 6:30 a.m. and I was walking out the door at 11:30.”

Acutely aware of the financial benefits, hospitals and surgery clinics have been marketing joint replacements for years, competing for coveted rankings and running ads that show healthy aging people, all smiles, engaged in vigorous activity.

However, a 2014 study concluded that one-third of knee replacements were not warranted, mainly because the symptoms of the patients were not severe enough to justify the procedures.

“The whole marketing of health care is so manipulative to the consuming public,” said Lisa McGiffert, a longtime consumer advocate and co-founder of the Patient Safety Action Network. “People might be encouraged to get a knee replacement, when in reality something less invasive could have improved their condition.”

McGiffert recounted a conversation with an orthopedic surgeon in Washington state who told her about a patient who requested a knee replacement, even though he had not tried any lower-impact treatments to fix the problem. “I asked the surgeon, ‘You didn’t do it, did you?’ And he said, ‘Of course I did. He would just have gone to somebody else.’ ”

This Kaiser Health News story first published on California Healthline, a service of the California Health Care Foundation.

When officials closed U.S. schools in March to limit the spread of COVID-19, they may have prevented more than 1 million cases over a 26-day period, a new estimate published online July 29 in JAMA suggests.

But school closures also left blind spots in understanding how children and schools affect disease transmission.

“School closures early in pandemic responses thwarted larger-scale investigations of schools as a source of community transmission,” researchers noted in a separate study, published online July 30 in JAMA Pediatrics, that examined levels of viral RNA in children and adults with COVID-19.

“Our analyses suggest children younger than 5 years with mild to moderate COVID-19 have high amounts of SARS-CoV-2 viral RNA in their nasopharynx, compared with older children and adults,” reported Taylor Heald-Sargent, MD, PhD, and colleagues. “Thus, young children can potentially be important drivers of SARS-CoV-2 spread in the general population, as has been demonstrated with respiratory syncytial virus, where children with high viral loads are more likely to transmit.”

Although the study “was not designed to prove that younger children spread COVID-19 as much as adults,” it is a possibility, Dr. Heald-Sargent, a pediatric infectious diseases specialist at Ann and Robert H. Lurie Children’s Hospital and assistant professor of pediatrics at Northwestern University, Chicago, said in a related news release. “We need to take that into account in efforts to reduce transmission as we continue to learn more about this virus.”.

The study included 145 patients with mild or moderate illness who were within 1 week of symptom onset. The researchers used reverse transcriptase–polymerase chain reaction (rt-PCR) on nasopharyngeal swabs collected at inpatient, outpatient, emergency department, or drive-through testing sites to measure SARS-CoV-2 levels. The investigators compared PCR amplification cycle threshold (CT) values for children younger than 5 years (n = 46), children aged 5-17 years (n = 51), and adults aged 18-65 years (n = 48); lower CT values indicate higher amounts of viral nucleic acid.

Median CT values for older children and adults were similar (about 11), whereas the median CT value for young children was significantly lower (6.5). The differences between young children and adults “approximate a 10-fold to 100-fold greater amount of SARS-CoV-2 in the upper respiratory tract of young children,” the researchers wrote.

“Behavioral habits of young children and close quarters in school and day care settings raise concern for SARS-CoV-2 amplification in this population as public health restrictions are eased,” they write.
 

Modeling the impact of school closures

In the JAMA study, Katherine A. Auger, MD, of Cincinnati Children’s Hospital Medical Center, and colleagues examined at the U.S. population level whether closing schools, as all 50 states did in March, was associated with relative decreases in COVID-19 incidence and mortality.

To isolate the effect of school closures, the researchers used an interrupted time series analysis and included other state-level nonpharmaceutical interventions and variables in their regression models.

“Per week, the incidence was estimated to have been 39% of what it would have been had schools remained open,” Dr. Auger and colleagues wrote. “Extrapolating the absolute differences of 423.9 cases and 12.6 deaths per 100,000 to 322.2 million residents nationally suggests that school closure may have been associated with approximately 1.37 million fewer cases of COVID-19 over a 26-day period and 40,600 fewer deaths over a 16-day period; however, these figures do not account for uncertainty in the model assumptions and the resulting estimates.”

Relative reductions in incidence and mortality were largest in states that closed schools when the incidence of COVID-19 was low, the authors found.
 

Decisions with high stakes

In an accompanying editorial, Julie M. Donohue, PhD, and Elizabeth Miller, MD, PhD, both affiliated with the University of Pittsburgh, emphasized that the results are estimates. “School closures were enacted in close proximity ... to other physical distancing measures, such as nonessential business closures and stay-at-home orders, making it difficult to disentangle the potential effect of each intervention.”

Although the findings “suggest a role for school closures in virus mitigation, school and health officials must balance this with academic, health, and economic consequences,” Dr. Donohue and Dr. Miller added. “Given the strong connection between education, income, and life expectancy, school closures could have long-term deleterious consequences for child health, likely reaching into adulthood.” Schools provide “meals and nutrition, health care including behavioral health supports, physical activity, social interaction, supports for students with special education needs and disabilities, and other vital resources for healthy development.”

In a viewpoint article also published in JAMA, authors involved in the creation of a National Academies of Sciences, Engineering, and Medicine reported on the reopening of schools recommend that districts “make every effort to prioritize reopening with an emphasis on providing in-person instruction for students in kindergarten through grade 5 as well as those students with special needs who might be best served by in-person instruction.

“To reopen safely, school districts are encouraged to ensure ventilation and air filtration, clean surfaces frequently, provide facilities for regular handwashing, and provide space for physical distancing,” write Kenne A. Dibner, PhD, of the NASEM in Washington, D.C., and coauthors.

Furthermore, districts “need to consider transparent communication of the reality that while measures can be implemented to lower the risk of transmitting COVID-19 when schools reopen, there is no way to eliminate that risk entirely. It is critical to share both the risks and benefits of different scenarios,” they wrote.

The JAMA modeling study received funding from the Agency for Healthcare Research and Quality and the National Institutes of Health. The NASEM report was funded by the Brady Education Foundation and the Spencer Foundation. The authors disclosed no relevant financial relationships.

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

When officials closed U.S. schools in March to limit the spread of COVID-19, they may have prevented more than 1 million cases over a 26-day period, a new estimate published online July 29 in JAMA suggests.

But school closures also left blind spots in understanding how children and schools affect disease transmission.

“School closures early in pandemic responses thwarted larger-scale investigations of schools as a source of community transmission,” researchers noted in a separate study, published online July 30 in JAMA Pediatrics, that examined levels of viral RNA in children and adults with COVID-19.

“Our analyses suggest children younger than 5 years with mild to moderate COVID-19 have high amounts of SARS-CoV-2 viral RNA in their nasopharynx, compared with older children and adults,” reported Taylor Heald-Sargent, MD, PhD, and colleagues. “Thus, young children can potentially be important drivers of SARS-CoV-2 spread in the general population, as has been demonstrated with respiratory syncytial virus, where children with high viral loads are more likely to transmit.”

Although the study “was not designed to prove that younger children spread COVID-19 as much as adults,” it is a possibility, Dr. Heald-Sargent, a pediatric infectious diseases specialist at Ann and Robert H. Lurie Children’s Hospital and assistant professor of pediatrics at Northwestern University, Chicago, said in a related news release. “We need to take that into account in efforts to reduce transmission as we continue to learn more about this virus.”.

The study included 145 patients with mild or moderate illness who were within 1 week of symptom onset. The researchers used reverse transcriptase–polymerase chain reaction (rt-PCR) on nasopharyngeal swabs collected at inpatient, outpatient, emergency department, or drive-through testing sites to measure SARS-CoV-2 levels. The investigators compared PCR amplification cycle threshold (CT) values for children younger than 5 years (n = 46), children aged 5-17 years (n = 51), and adults aged 18-65 years (n = 48); lower CT values indicate higher amounts of viral nucleic acid.

Median CT values for older children and adults were similar (about 11), whereas the median CT value for young children was significantly lower (6.5). The differences between young children and adults “approximate a 10-fold to 100-fold greater amount of SARS-CoV-2 in the upper respiratory tract of young children,” the researchers wrote.

“Behavioral habits of young children and close quarters in school and day care settings raise concern for SARS-CoV-2 amplification in this population as public health restrictions are eased,” they write.
 

Modeling the impact of school closures

In the JAMA study, Katherine A. Auger, MD, of Cincinnati Children’s Hospital Medical Center, and colleagues examined at the U.S. population level whether closing schools, as all 50 states did in March, was associated with relative decreases in COVID-19 incidence and mortality.

To isolate the effect of school closures, the researchers used an interrupted time series analysis and included other state-level nonpharmaceutical interventions and variables in their regression models.

“Per week, the incidence was estimated to have been 39% of what it would have been had schools remained open,” Dr. Auger and colleagues wrote. “Extrapolating the absolute differences of 423.9 cases and 12.6 deaths per 100,000 to 322.2 million residents nationally suggests that school closure may have been associated with approximately 1.37 million fewer cases of COVID-19 over a 26-day period and 40,600 fewer deaths over a 16-day period; however, these figures do not account for uncertainty in the model assumptions and the resulting estimates.”

Relative reductions in incidence and mortality were largest in states that closed schools when the incidence of COVID-19 was low, the authors found.
 

Decisions with high stakes

In an accompanying editorial, Julie M. Donohue, PhD, and Elizabeth Miller, MD, PhD, both affiliated with the University of Pittsburgh, emphasized that the results are estimates. “School closures were enacted in close proximity ... to other physical distancing measures, such as nonessential business closures and stay-at-home orders, making it difficult to disentangle the potential effect of each intervention.”

Although the findings “suggest a role for school closures in virus mitigation, school and health officials must balance this with academic, health, and economic consequences,” Dr. Donohue and Dr. Miller added. “Given the strong connection between education, income, and life expectancy, school closures could have long-term deleterious consequences for child health, likely reaching into adulthood.” Schools provide “meals and nutrition, health care including behavioral health supports, physical activity, social interaction, supports for students with special education needs and disabilities, and other vital resources for healthy development.”

In a viewpoint article also published in JAMA, authors involved in the creation of a National Academies of Sciences, Engineering, and Medicine reported on the reopening of schools recommend that districts “make every effort to prioritize reopening with an emphasis on providing in-person instruction for students in kindergarten through grade 5 as well as those students with special needs who might be best served by in-person instruction.

“To reopen safely, school districts are encouraged to ensure ventilation and air filtration, clean surfaces frequently, provide facilities for regular handwashing, and provide space for physical distancing,” write Kenne A. Dibner, PhD, of the NASEM in Washington, D.C., and coauthors.

Furthermore, districts “need to consider transparent communication of the reality that while measures can be implemented to lower the risk of transmitting COVID-19 when schools reopen, there is no way to eliminate that risk entirely. It is critical to share both the risks and benefits of different scenarios,” they wrote.

The JAMA modeling study received funding from the Agency for Healthcare Research and Quality and the National Institutes of Health. The NASEM report was funded by the Brady Education Foundation and the Spencer Foundation. The authors disclosed no relevant financial relationships.

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

When officials closed U.S. schools in March to limit the spread of COVID-19, they may have prevented more than 1 million cases over a 26-day period, a new estimate published online July 29 in JAMA suggests.

But school closures also left blind spots in understanding how children and schools affect disease transmission.

“School closures early in pandemic responses thwarted larger-scale investigations of schools as a source of community transmission,” researchers noted in a separate study, published online July 30 in JAMA Pediatrics, that examined levels of viral RNA in children and adults with COVID-19.

“Our analyses suggest children younger than 5 years with mild to moderate COVID-19 have high amounts of SARS-CoV-2 viral RNA in their nasopharynx, compared with older children and adults,” reported Taylor Heald-Sargent, MD, PhD, and colleagues. “Thus, young children can potentially be important drivers of SARS-CoV-2 spread in the general population, as has been demonstrated with respiratory syncytial virus, where children with high viral loads are more likely to transmit.”

Although the study “was not designed to prove that younger children spread COVID-19 as much as adults,” it is a possibility, Dr. Heald-Sargent, a pediatric infectious diseases specialist at Ann and Robert H. Lurie Children’s Hospital and assistant professor of pediatrics at Northwestern University, Chicago, said in a related news release. “We need to take that into account in efforts to reduce transmission as we continue to learn more about this virus.”.

The study included 145 patients with mild or moderate illness who were within 1 week of symptom onset. The researchers used reverse transcriptase–polymerase chain reaction (rt-PCR) on nasopharyngeal swabs collected at inpatient, outpatient, emergency department, or drive-through testing sites to measure SARS-CoV-2 levels. The investigators compared PCR amplification cycle threshold (CT) values for children younger than 5 years (n = 46), children aged 5-17 years (n = 51), and adults aged 18-65 years (n = 48); lower CT values indicate higher amounts of viral nucleic acid.

Median CT values for older children and adults were similar (about 11), whereas the median CT value for young children was significantly lower (6.5). The differences between young children and adults “approximate a 10-fold to 100-fold greater amount of SARS-CoV-2 in the upper respiratory tract of young children,” the researchers wrote.

“Behavioral habits of young children and close quarters in school and day care settings raise concern for SARS-CoV-2 amplification in this population as public health restrictions are eased,” they write.
 

Modeling the impact of school closures

In the JAMA study, Katherine A. Auger, MD, of Cincinnati Children’s Hospital Medical Center, and colleagues examined at the U.S. population level whether closing schools, as all 50 states did in March, was associated with relative decreases in COVID-19 incidence and mortality.

To isolate the effect of school closures, the researchers used an interrupted time series analysis and included other state-level nonpharmaceutical interventions and variables in their regression models.

“Per week, the incidence was estimated to have been 39% of what it would have been had schools remained open,” Dr. Auger and colleagues wrote. “Extrapolating the absolute differences of 423.9 cases and 12.6 deaths per 100,000 to 322.2 million residents nationally suggests that school closure may have been associated with approximately 1.37 million fewer cases of COVID-19 over a 26-day period and 40,600 fewer deaths over a 16-day period; however, these figures do not account for uncertainty in the model assumptions and the resulting estimates.”

Relative reductions in incidence and mortality were largest in states that closed schools when the incidence of COVID-19 was low, the authors found.
 

Decisions with high stakes

In an accompanying editorial, Julie M. Donohue, PhD, and Elizabeth Miller, MD, PhD, both affiliated with the University of Pittsburgh, emphasized that the results are estimates. “School closures were enacted in close proximity ... to other physical distancing measures, such as nonessential business closures and stay-at-home orders, making it difficult to disentangle the potential effect of each intervention.”

Although the findings “suggest a role for school closures in virus mitigation, school and health officials must balance this with academic, health, and economic consequences,” Dr. Donohue and Dr. Miller added. “Given the strong connection between education, income, and life expectancy, school closures could have long-term deleterious consequences for child health, likely reaching into adulthood.” Schools provide “meals and nutrition, health care including behavioral health supports, physical activity, social interaction, supports for students with special education needs and disabilities, and other vital resources for healthy development.”

In a viewpoint article also published in JAMA, authors involved in the creation of a National Academies of Sciences, Engineering, and Medicine reported on the reopening of schools recommend that districts “make every effort to prioritize reopening with an emphasis on providing in-person instruction for students in kindergarten through grade 5 as well as those students with special needs who might be best served by in-person instruction.

“To reopen safely, school districts are encouraged to ensure ventilation and air filtration, clean surfaces frequently, provide facilities for regular handwashing, and provide space for physical distancing,” write Kenne A. Dibner, PhD, of the NASEM in Washington, D.C., and coauthors.

Furthermore, districts “need to consider transparent communication of the reality that while measures can be implemented to lower the risk of transmitting COVID-19 when schools reopen, there is no way to eliminate that risk entirely. It is critical to share both the risks and benefits of different scenarios,” they wrote.

The JAMA modeling study received funding from the Agency for Healthcare Research and Quality and the National Institutes of Health. The NASEM report was funded by the Brady Education Foundation and the Spencer Foundation. The authors disclosed no relevant financial relationships.

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

New guidance from the U.K. National Diabetes COVID-19 Response Group addresses glucose management in patients with COVID-19 who are receiving dexamethasone therapy.

Although there are already guidelines that address inpatient management of steroid-induced hyperglycemia, the authors of the new document wrote that this new expert opinion paper was needed “given the ‘triple insult’ of dexamethasone-induced–impaired glucose metabolism, COVID-19–induced insulin resistance, and COVID-19–impaired insulin production.”

RECOVERY trial spurs response

The document, which is the latest in a series from the Association of British Clinical Diabetologists, was published online Aug. 2 in Diabetic Medicine. The group is chaired by Gerry Rayman, MD, consultant physician at the diabetes centre and diabetes research unit, East Suffolk (England) and North East NHS Foundation Trust.

The guidance was developed in response to the recent “breakthrough” Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, which showed that dexamethasone reduced deaths in patients with COVID-19 on ventilators or receiving oxygen therapy. The advice is not intended for critical care units but can be adapted for that use.

The dose used in RECOVERY – 6 mg daily for 10 days – is 400%-500% greater than the therapeutic glucocorticoid replacement dose. High glucocorticoid doses can exacerbate hyperglycemia in people with established diabetes, unmask undiagnosed diabetes, precipitate hyperglycemia or new-onset diabetes, and can also cause hyperglycemic hyperosmolar state (HHS), the authors explained.

They recommended a target glucose of 6.0-10.0 mmol/L (108-180 mg/dL), although they say up to 12 mmol/L (216 mg/dL) is “acceptable.” They then gave advice on frequency of monitoring for people with and without known diabetes, exclusion of diabetic ketoacidosis and HHS, correction of initial hyperglycemia and maintenance of glycemic control using subcutaneous insulin, and prevention of hypoglycemia at the end of dexamethasone therapy (day 10) with insulin down-titration, discharge, and follow-up.

The detailed insulin guidance covers dose escalation for both insulin-treated and insulin-naive patients. A table suggests increasing correction doses of rapid-acting insulin based on prior total daily dose or weight.

Use of once- or twice-daily NPH insulin is recommended for patients whose glucose has risen above 12 mmol/L, in some cases with the addition of a long-acting analog. A second chart gives dose adjustments for those insulins. Additional guidance addresses patients on insulin pumps.

Guidance useful for U.S. physicians

Francisco Pasquel, MD, assistant professor of medicine in the division of endocrinology at Emory University, Atlanta, said in an interview that he believes the guidance is “acceptable” for worldwide use, and that “it’s coherent and consistent with what we typically do.”

However, Dr. Pasquel, who founded COVID-in-Diabetes, an online repository of published guidance and shared experience – to which this new document has now been added – did take issue with one piece of advice. The guidance says that patients already taking premixed insulin formulations can continue using them while increasing the dose by 20%-40%. Given the risk of hypoglycemia associated with those formulations, Dr. Pasquel said he would switch those patients to NPH during the time that they’re on dexamethasone.

He also noted that the rapid-acting insulin dose range of 2-10 units provided in the first table, for correction of initial hyperglycemia, are more conservative than those used at his hospital, where correction doses of up to 14-16 units are sometimes necessary.

But Dr. Pasquel praised the group’s overall efforts since the pandemic began, noting that “they’re very organized and constantly updating their recommendations. They have a unified system in the [National Health Service], so it’s easier to standardize. They have a unique [electronic health record] which is far superior to what we do from a public health perspective.”

Dr. Rayman reported no relevant financial relationships. Dr. Pasquel reported receiving research funding from Dexcom, Merck, and the National Institutes of Health, and consulting for AstraZeneca, Eli Lilly, Merck, and Boehringer Ingelheim.

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

New guidance from the U.K. National Diabetes COVID-19 Response Group addresses glucose management in patients with COVID-19 who are receiving dexamethasone therapy.

Although there are already guidelines that address inpatient management of steroid-induced hyperglycemia, the authors of the new document wrote that this new expert opinion paper was needed “given the ‘triple insult’ of dexamethasone-induced–impaired glucose metabolism, COVID-19–induced insulin resistance, and COVID-19–impaired insulin production.”

RECOVERY trial spurs response

The document, which is the latest in a series from the Association of British Clinical Diabetologists, was published online Aug. 2 in Diabetic Medicine. The group is chaired by Gerry Rayman, MD, consultant physician at the diabetes centre and diabetes research unit, East Suffolk (England) and North East NHS Foundation Trust.

The guidance was developed in response to the recent “breakthrough” Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, which showed that dexamethasone reduced deaths in patients with COVID-19 on ventilators or receiving oxygen therapy. The advice is not intended for critical care units but can be adapted for that use.

The dose used in RECOVERY – 6 mg daily for 10 days – is 400%-500% greater than the therapeutic glucocorticoid replacement dose. High glucocorticoid doses can exacerbate hyperglycemia in people with established diabetes, unmask undiagnosed diabetes, precipitate hyperglycemia or new-onset diabetes, and can also cause hyperglycemic hyperosmolar state (HHS), the authors explained.

They recommended a target glucose of 6.0-10.0 mmol/L (108-180 mg/dL), although they say up to 12 mmol/L (216 mg/dL) is “acceptable.” They then gave advice on frequency of monitoring for people with and without known diabetes, exclusion of diabetic ketoacidosis and HHS, correction of initial hyperglycemia and maintenance of glycemic control using subcutaneous insulin, and prevention of hypoglycemia at the end of dexamethasone therapy (day 10) with insulin down-titration, discharge, and follow-up.

The detailed insulin guidance covers dose escalation for both insulin-treated and insulin-naive patients. A table suggests increasing correction doses of rapid-acting insulin based on prior total daily dose or weight.

Use of once- or twice-daily NPH insulin is recommended for patients whose glucose has risen above 12 mmol/L, in some cases with the addition of a long-acting analog. A second chart gives dose adjustments for those insulins. Additional guidance addresses patients on insulin pumps.

Guidance useful for U.S. physicians

Francisco Pasquel, MD, assistant professor of medicine in the division of endocrinology at Emory University, Atlanta, said in an interview that he believes the guidance is “acceptable” for worldwide use, and that “it’s coherent and consistent with what we typically do.”

However, Dr. Pasquel, who founded COVID-in-Diabetes, an online repository of published guidance and shared experience – to which this new document has now been added – did take issue with one piece of advice. The guidance says that patients already taking premixed insulin formulations can continue using them while increasing the dose by 20%-40%. Given the risk of hypoglycemia associated with those formulations, Dr. Pasquel said he would switch those patients to NPH during the time that they’re on dexamethasone.

He also noted that the rapid-acting insulin dose range of 2-10 units provided in the first table, for correction of initial hyperglycemia, are more conservative than those used at his hospital, where correction doses of up to 14-16 units are sometimes necessary.

But Dr. Pasquel praised the group’s overall efforts since the pandemic began, noting that “they’re very organized and constantly updating their recommendations. They have a unified system in the [National Health Service], so it’s easier to standardize. They have a unique [electronic health record] which is far superior to what we do from a public health perspective.”

Dr. Rayman reported no relevant financial relationships. Dr. Pasquel reported receiving research funding from Dexcom, Merck, and the National Institutes of Health, and consulting for AstraZeneca, Eli Lilly, Merck, and Boehringer Ingelheim.

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

New guidance from the U.K. National Diabetes COVID-19 Response Group addresses glucose management in patients with COVID-19 who are receiving dexamethasone therapy.

Although there are already guidelines that address inpatient management of steroid-induced hyperglycemia, the authors of the new document wrote that this new expert opinion paper was needed “given the ‘triple insult’ of dexamethasone-induced–impaired glucose metabolism, COVID-19–induced insulin resistance, and COVID-19–impaired insulin production.”

RECOVERY trial spurs response

The document, which is the latest in a series from the Association of British Clinical Diabetologists, was published online Aug. 2 in Diabetic Medicine. The group is chaired by Gerry Rayman, MD, consultant physician at the diabetes centre and diabetes research unit, East Suffolk (England) and North East NHS Foundation Trust.

The guidance was developed in response to the recent “breakthrough” Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, which showed that dexamethasone reduced deaths in patients with COVID-19 on ventilators or receiving oxygen therapy. The advice is not intended for critical care units but can be adapted for that use.

The dose used in RECOVERY – 6 mg daily for 10 days – is 400%-500% greater than the therapeutic glucocorticoid replacement dose. High glucocorticoid doses can exacerbate hyperglycemia in people with established diabetes, unmask undiagnosed diabetes, precipitate hyperglycemia or new-onset diabetes, and can also cause hyperglycemic hyperosmolar state (HHS), the authors explained.

They recommended a target glucose of 6.0-10.0 mmol/L (108-180 mg/dL), although they say up to 12 mmol/L (216 mg/dL) is “acceptable.” They then gave advice on frequency of monitoring for people with and without known diabetes, exclusion of diabetic ketoacidosis and HHS, correction of initial hyperglycemia and maintenance of glycemic control using subcutaneous insulin, and prevention of hypoglycemia at the end of dexamethasone therapy (day 10) with insulin down-titration, discharge, and follow-up.

The detailed insulin guidance covers dose escalation for both insulin-treated and insulin-naive patients. A table suggests increasing correction doses of rapid-acting insulin based on prior total daily dose or weight.

Use of once- or twice-daily NPH insulin is recommended for patients whose glucose has risen above 12 mmol/L, in some cases with the addition of a long-acting analog. A second chart gives dose adjustments for those insulins. Additional guidance addresses patients on insulin pumps.

Guidance useful for U.S. physicians

Francisco Pasquel, MD, assistant professor of medicine in the division of endocrinology at Emory University, Atlanta, said in an interview that he believes the guidance is “acceptable” for worldwide use, and that “it’s coherent and consistent with what we typically do.”

However, Dr. Pasquel, who founded COVID-in-Diabetes, an online repository of published guidance and shared experience – to which this new document has now been added – did take issue with one piece of advice. The guidance says that patients already taking premixed insulin formulations can continue using them while increasing the dose by 20%-40%. Given the risk of hypoglycemia associated with those formulations, Dr. Pasquel said he would switch those patients to NPH during the time that they’re on dexamethasone.

He also noted that the rapid-acting insulin dose range of 2-10 units provided in the first table, for correction of initial hyperglycemia, are more conservative than those used at his hospital, where correction doses of up to 14-16 units are sometimes necessary.

But Dr. Pasquel praised the group’s overall efforts since the pandemic began, noting that “they’re very organized and constantly updating their recommendations. They have a unified system in the [National Health Service], so it’s easier to standardize. They have a unique [electronic health record] which is far superior to what we do from a public health perspective.”

Dr. Rayman reported no relevant financial relationships. Dr. Pasquel reported receiving research funding from Dexcom, Merck, and the National Institutes of Health, and consulting for AstraZeneca, Eli Lilly, Merck, and Boehringer Ingelheim.

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