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Safety, efficacy of analgesics for low back pain ‘uncertain’
Higher-quality randomized controlled trials of head-to-head comparisons are needed, study investigator Michael A. Wewege, PhD candidate, research fellow, University of New South Wales and Neuroscience Research Australia, Sydney, said in an interview.
“Until then, doctors should use caution when prescribing analgesic medicines for adults with nonspecific acute low back pain. They should use this new evidence in line with their own expertise and the patient sitting in front of them when making any decision about a medication,” he added.
The findings were published online in the BMJ.
Poor quality evidence
Analgesics such as ibuprofen, acetaminophen, and codeine are widely used to treat nonspecific low-back pain, which is defined as pain lasting less than 6 weeks, but evidence for the comparative efficacy of these agents is limited.
To fill this knowledge gap, the researchers conducted a systematic review and analysis of controlled trials comparing analgesics with another analgesic, placebo, or no treatment in patients with acute, nonspecific low back pain.
The review involved 98 randomized controlled trials that included 15,134 adults (49% women) aged 30-60 years with pain duration ranging from 24 hours to 21 days. The median baseline pain intensity was 65 on a pain scale of 0-100.
Of the included trials, 39% were placebo controlled, 67% masked both participants and clinicians, and 41% reported industry sponsorship.
The studies compared an analgesic medicine with another analgesic, placebo, or no treatment comprised of usual care or being placed on a wait list.
Study medications, which had to be approved in the United States, Europe, or Australia, included nonsteroidal anti-inflammatory drugs, paracetamol, opioids, anticonvulsants, antidepressants, muscle relaxants, and corticosteroids.
These drugs were administered systemically as a single drug or in combination formulations, at any dose.
Researchers used a network meta-analysis, which combines direct and indirect information across a network of randomized clinical trials to estimate the comparative effectiveness of multiple treatments.
The primary outcomes were reductions in low back pain intensity (measured with a visual analogue scale), numerical rating scale or another ordinal scale, and safety as indicated by the number of participants who had any adverse event.
Investigators found several medications were associated with large reductions in pain intensity, compared with placebo, though with low or very low confidence.
Low or very low confidence was found for reduced pain intensity after treatment with tolperisone (mean difference, −26.1; 95% confidence interval, −34.0 to −18.2), aceclofenac plus tizanidine (mean difference, −26.1; 95% CI, −38.5 to −13.6), pregabalin (mean difference, −24.7; 95% CI, −34.6 to −14.7), and 14 other medicines, compared with placebo, the researchers report.
In addition, they found low or very low confidence for no difference between the effects of several of these medications.
Increased adverse events had moderate to very low confidence with tramadol (risk ratio, 2.6; 95% CI, 1.5-4.5), paracetamol plus sustained release tramadol (RR, 2.4; 95% CI, 1.5-3.8), baclofen (RR, 2.3; 95% CI, 1.5-3.4), and paracetamol plus tramadol (RR, 2.1; 95% CI, 1.3-3.4), compared with placebo, the investigators add.
“These medicines could increase the risk of adverse events, compared with other medicines with moderate to low confidence. Moderate to low confidence was also noted for secondary outcomes and secondary analysis of medicine classes,” the researchers note.
The review suggested 14 additional comparisons favored the treatment over placebo, all with very low confidence except for one with low confidence.
In the 68 trials that included the number of participants reporting an adverse event, there was moderate confidence for increased adverse events with the opioid tramadol (RR, 2.6; 95% CI, 1.5-4.5), paracetamol plus sustained release tramadol (RR, 2.4; 95% CI, 1.5-3.8), paracetamol plus tramadol (RR, 2.1; 95% CI, 1.3-3.4), and low confidence for baclofen (RR, 2.3; 1.5-3.4), compared with placebo.
The review also uncovered moderate to low confidence for secondary outcomes, which included low back-specific function, serious adverse events, and acceptability (number of participants who dropped out).
Unexpected findings
The new results were somewhat unexpected, said Mr. Wewege.
“When we set out to do this review, we envisioned the evidence would be a lot more comprehensive. We didn’t think it would be so disconnected and there would be so few trials looking at the different comparisons that would lead us to have low confidence in most of the findings.”
Various factors contributed to this low confidence, he said. One was the risk of bias – about 90% of trials had some concerns or high risk of bias. Another factor was the heterogeneity in effect estimates.
Most of the evidence is based on studies comparing different analgesics to placebo, Mr. Wewege noted. The lack of head-to-head drug comparisons is because “the easiest way to get a drug approved is just to demonstrate it’s better than placebo,” he said.
In addition to these new findings, clinicians should consider a medication’s availability, their own expertise, and patient preferences when selecting an analgesic, said Mr. Wewege. He noted most patients with acute low back pain get better within a few weeks without any intervention.
“Patients should be reassured that things will heal naturally and that they are not going to be in pain forever,” he said.
Determining optimal treatment is key
Chris Gilligan, MD, associate chief medical officer, Brigham and Women’s Hospital, and associate professor of anesthesia, Harvard Medical School, both in Boston, said determining which medications are optimal is “key,” as acute low back pain is very common and analgesics are used frequently.
The new review does provide information on which medications have the strongest evidence for pain reduction, said Dr. Gilligan. “On the one hand, it directionally points you towards certain medications, and even certain classes of medication, for comparative effectiveness.”
However, he said, the confidence for this effectiveness is low or very low, “so I wouldn’t overweight it.”
The data on adverse effects, where the confidence is mostly moderate to low, might have more of an influence on prescribing, he said.
“For example, there’s some indication tramadol may be more closely associated with adverse events in patients with acute low back pain and that would add to our caution about using tramadol; it’s not that we would never use it, but [we]would take that into account.”
Dr. Gilligan agrees clinicians should be cautious about prescribing analgesics for low back pain. One reason for being conservative in terms of treatments, he noted, is that “acute low back pain has a very favorable natural history.”
While clinical practice guidelines recommend nonpharmacologic therapies as first- and second-line treatment for acute, nonspecific low back pain, Dr. Gilligan noted that as with drugs, evidence for nondrug therapies also has low or very low confidence.
The study received funding from a 2020 Exercise Physiology Research (Consumables) Grant from the University of New South Wales, which was used to obtain translations of studies published in languages other than English.
Mr. Wewege was supported by a Postgraduate Scholarship from the National Health and Medical Research Council of Australia, a School of Medical Sciences Top-Up Scholarship from the University of New South Wales, and a PhD Supplementary Scholarship from Neuroscience Research Australia. Dr. Gilligan reports that he conducts clinical trials with companies and groups, including the National Institutes of Health related to medications, devices, and procedures for pain.
A version of this article first appeared on Medscape.com.
Higher-quality randomized controlled trials of head-to-head comparisons are needed, study investigator Michael A. Wewege, PhD candidate, research fellow, University of New South Wales and Neuroscience Research Australia, Sydney, said in an interview.
“Until then, doctors should use caution when prescribing analgesic medicines for adults with nonspecific acute low back pain. They should use this new evidence in line with their own expertise and the patient sitting in front of them when making any decision about a medication,” he added.
The findings were published online in the BMJ.
Poor quality evidence
Analgesics such as ibuprofen, acetaminophen, and codeine are widely used to treat nonspecific low-back pain, which is defined as pain lasting less than 6 weeks, but evidence for the comparative efficacy of these agents is limited.
To fill this knowledge gap, the researchers conducted a systematic review and analysis of controlled trials comparing analgesics with another analgesic, placebo, or no treatment in patients with acute, nonspecific low back pain.
The review involved 98 randomized controlled trials that included 15,134 adults (49% women) aged 30-60 years with pain duration ranging from 24 hours to 21 days. The median baseline pain intensity was 65 on a pain scale of 0-100.
Of the included trials, 39% were placebo controlled, 67% masked both participants and clinicians, and 41% reported industry sponsorship.
The studies compared an analgesic medicine with another analgesic, placebo, or no treatment comprised of usual care or being placed on a wait list.
Study medications, which had to be approved in the United States, Europe, or Australia, included nonsteroidal anti-inflammatory drugs, paracetamol, opioids, anticonvulsants, antidepressants, muscle relaxants, and corticosteroids.
These drugs were administered systemically as a single drug or in combination formulations, at any dose.
Researchers used a network meta-analysis, which combines direct and indirect information across a network of randomized clinical trials to estimate the comparative effectiveness of multiple treatments.
The primary outcomes were reductions in low back pain intensity (measured with a visual analogue scale), numerical rating scale or another ordinal scale, and safety as indicated by the number of participants who had any adverse event.
Investigators found several medications were associated with large reductions in pain intensity, compared with placebo, though with low or very low confidence.
Low or very low confidence was found for reduced pain intensity after treatment with tolperisone (mean difference, −26.1; 95% confidence interval, −34.0 to −18.2), aceclofenac plus tizanidine (mean difference, −26.1; 95% CI, −38.5 to −13.6), pregabalin (mean difference, −24.7; 95% CI, −34.6 to −14.7), and 14 other medicines, compared with placebo, the researchers report.
In addition, they found low or very low confidence for no difference between the effects of several of these medications.
Increased adverse events had moderate to very low confidence with tramadol (risk ratio, 2.6; 95% CI, 1.5-4.5), paracetamol plus sustained release tramadol (RR, 2.4; 95% CI, 1.5-3.8), baclofen (RR, 2.3; 95% CI, 1.5-3.4), and paracetamol plus tramadol (RR, 2.1; 95% CI, 1.3-3.4), compared with placebo, the investigators add.
“These medicines could increase the risk of adverse events, compared with other medicines with moderate to low confidence. Moderate to low confidence was also noted for secondary outcomes and secondary analysis of medicine classes,” the researchers note.
The review suggested 14 additional comparisons favored the treatment over placebo, all with very low confidence except for one with low confidence.
In the 68 trials that included the number of participants reporting an adverse event, there was moderate confidence for increased adverse events with the opioid tramadol (RR, 2.6; 95% CI, 1.5-4.5), paracetamol plus sustained release tramadol (RR, 2.4; 95% CI, 1.5-3.8), paracetamol plus tramadol (RR, 2.1; 95% CI, 1.3-3.4), and low confidence for baclofen (RR, 2.3; 1.5-3.4), compared with placebo.
The review also uncovered moderate to low confidence for secondary outcomes, which included low back-specific function, serious adverse events, and acceptability (number of participants who dropped out).
Unexpected findings
The new results were somewhat unexpected, said Mr. Wewege.
“When we set out to do this review, we envisioned the evidence would be a lot more comprehensive. We didn’t think it would be so disconnected and there would be so few trials looking at the different comparisons that would lead us to have low confidence in most of the findings.”
Various factors contributed to this low confidence, he said. One was the risk of bias – about 90% of trials had some concerns or high risk of bias. Another factor was the heterogeneity in effect estimates.
Most of the evidence is based on studies comparing different analgesics to placebo, Mr. Wewege noted. The lack of head-to-head drug comparisons is because “the easiest way to get a drug approved is just to demonstrate it’s better than placebo,” he said.
In addition to these new findings, clinicians should consider a medication’s availability, their own expertise, and patient preferences when selecting an analgesic, said Mr. Wewege. He noted most patients with acute low back pain get better within a few weeks without any intervention.
“Patients should be reassured that things will heal naturally and that they are not going to be in pain forever,” he said.
Determining optimal treatment is key
Chris Gilligan, MD, associate chief medical officer, Brigham and Women’s Hospital, and associate professor of anesthesia, Harvard Medical School, both in Boston, said determining which medications are optimal is “key,” as acute low back pain is very common and analgesics are used frequently.
The new review does provide information on which medications have the strongest evidence for pain reduction, said Dr. Gilligan. “On the one hand, it directionally points you towards certain medications, and even certain classes of medication, for comparative effectiveness.”
However, he said, the confidence for this effectiveness is low or very low, “so I wouldn’t overweight it.”
The data on adverse effects, where the confidence is mostly moderate to low, might have more of an influence on prescribing, he said.
“For example, there’s some indication tramadol may be more closely associated with adverse events in patients with acute low back pain and that would add to our caution about using tramadol; it’s not that we would never use it, but [we]would take that into account.”
Dr. Gilligan agrees clinicians should be cautious about prescribing analgesics for low back pain. One reason for being conservative in terms of treatments, he noted, is that “acute low back pain has a very favorable natural history.”
While clinical practice guidelines recommend nonpharmacologic therapies as first- and second-line treatment for acute, nonspecific low back pain, Dr. Gilligan noted that as with drugs, evidence for nondrug therapies also has low or very low confidence.
The study received funding from a 2020 Exercise Physiology Research (Consumables) Grant from the University of New South Wales, which was used to obtain translations of studies published in languages other than English.
Mr. Wewege was supported by a Postgraduate Scholarship from the National Health and Medical Research Council of Australia, a School of Medical Sciences Top-Up Scholarship from the University of New South Wales, and a PhD Supplementary Scholarship from Neuroscience Research Australia. Dr. Gilligan reports that he conducts clinical trials with companies and groups, including the National Institutes of Health related to medications, devices, and procedures for pain.
A version of this article first appeared on Medscape.com.
Higher-quality randomized controlled trials of head-to-head comparisons are needed, study investigator Michael A. Wewege, PhD candidate, research fellow, University of New South Wales and Neuroscience Research Australia, Sydney, said in an interview.
“Until then, doctors should use caution when prescribing analgesic medicines for adults with nonspecific acute low back pain. They should use this new evidence in line with their own expertise and the patient sitting in front of them when making any decision about a medication,” he added.
The findings were published online in the BMJ.
Poor quality evidence
Analgesics such as ibuprofen, acetaminophen, and codeine are widely used to treat nonspecific low-back pain, which is defined as pain lasting less than 6 weeks, but evidence for the comparative efficacy of these agents is limited.
To fill this knowledge gap, the researchers conducted a systematic review and analysis of controlled trials comparing analgesics with another analgesic, placebo, or no treatment in patients with acute, nonspecific low back pain.
The review involved 98 randomized controlled trials that included 15,134 adults (49% women) aged 30-60 years with pain duration ranging from 24 hours to 21 days. The median baseline pain intensity was 65 on a pain scale of 0-100.
Of the included trials, 39% were placebo controlled, 67% masked both participants and clinicians, and 41% reported industry sponsorship.
The studies compared an analgesic medicine with another analgesic, placebo, or no treatment comprised of usual care or being placed on a wait list.
Study medications, which had to be approved in the United States, Europe, or Australia, included nonsteroidal anti-inflammatory drugs, paracetamol, opioids, anticonvulsants, antidepressants, muscle relaxants, and corticosteroids.
These drugs were administered systemically as a single drug or in combination formulations, at any dose.
Researchers used a network meta-analysis, which combines direct and indirect information across a network of randomized clinical trials to estimate the comparative effectiveness of multiple treatments.
The primary outcomes were reductions in low back pain intensity (measured with a visual analogue scale), numerical rating scale or another ordinal scale, and safety as indicated by the number of participants who had any adverse event.
Investigators found several medications were associated with large reductions in pain intensity, compared with placebo, though with low or very low confidence.
Low or very low confidence was found for reduced pain intensity after treatment with tolperisone (mean difference, −26.1; 95% confidence interval, −34.0 to −18.2), aceclofenac plus tizanidine (mean difference, −26.1; 95% CI, −38.5 to −13.6), pregabalin (mean difference, −24.7; 95% CI, −34.6 to −14.7), and 14 other medicines, compared with placebo, the researchers report.
In addition, they found low or very low confidence for no difference between the effects of several of these medications.
Increased adverse events had moderate to very low confidence with tramadol (risk ratio, 2.6; 95% CI, 1.5-4.5), paracetamol plus sustained release tramadol (RR, 2.4; 95% CI, 1.5-3.8), baclofen (RR, 2.3; 95% CI, 1.5-3.4), and paracetamol plus tramadol (RR, 2.1; 95% CI, 1.3-3.4), compared with placebo, the investigators add.
“These medicines could increase the risk of adverse events, compared with other medicines with moderate to low confidence. Moderate to low confidence was also noted for secondary outcomes and secondary analysis of medicine classes,” the researchers note.
The review suggested 14 additional comparisons favored the treatment over placebo, all with very low confidence except for one with low confidence.
In the 68 trials that included the number of participants reporting an adverse event, there was moderate confidence for increased adverse events with the opioid tramadol (RR, 2.6; 95% CI, 1.5-4.5), paracetamol plus sustained release tramadol (RR, 2.4; 95% CI, 1.5-3.8), paracetamol plus tramadol (RR, 2.1; 95% CI, 1.3-3.4), and low confidence for baclofen (RR, 2.3; 1.5-3.4), compared with placebo.
The review also uncovered moderate to low confidence for secondary outcomes, which included low back-specific function, serious adverse events, and acceptability (number of participants who dropped out).
Unexpected findings
The new results were somewhat unexpected, said Mr. Wewege.
“When we set out to do this review, we envisioned the evidence would be a lot more comprehensive. We didn’t think it would be so disconnected and there would be so few trials looking at the different comparisons that would lead us to have low confidence in most of the findings.”
Various factors contributed to this low confidence, he said. One was the risk of bias – about 90% of trials had some concerns or high risk of bias. Another factor was the heterogeneity in effect estimates.
Most of the evidence is based on studies comparing different analgesics to placebo, Mr. Wewege noted. The lack of head-to-head drug comparisons is because “the easiest way to get a drug approved is just to demonstrate it’s better than placebo,” he said.
In addition to these new findings, clinicians should consider a medication’s availability, their own expertise, and patient preferences when selecting an analgesic, said Mr. Wewege. He noted most patients with acute low back pain get better within a few weeks without any intervention.
“Patients should be reassured that things will heal naturally and that they are not going to be in pain forever,” he said.
Determining optimal treatment is key
Chris Gilligan, MD, associate chief medical officer, Brigham and Women’s Hospital, and associate professor of anesthesia, Harvard Medical School, both in Boston, said determining which medications are optimal is “key,” as acute low back pain is very common and analgesics are used frequently.
The new review does provide information on which medications have the strongest evidence for pain reduction, said Dr. Gilligan. “On the one hand, it directionally points you towards certain medications, and even certain classes of medication, for comparative effectiveness.”
However, he said, the confidence for this effectiveness is low or very low, “so I wouldn’t overweight it.”
The data on adverse effects, where the confidence is mostly moderate to low, might have more of an influence on prescribing, he said.
“For example, there’s some indication tramadol may be more closely associated with adverse events in patients with acute low back pain and that would add to our caution about using tramadol; it’s not that we would never use it, but [we]would take that into account.”
Dr. Gilligan agrees clinicians should be cautious about prescribing analgesics for low back pain. One reason for being conservative in terms of treatments, he noted, is that “acute low back pain has a very favorable natural history.”
While clinical practice guidelines recommend nonpharmacologic therapies as first- and second-line treatment for acute, nonspecific low back pain, Dr. Gilligan noted that as with drugs, evidence for nondrug therapies also has low or very low confidence.
The study received funding from a 2020 Exercise Physiology Research (Consumables) Grant from the University of New South Wales, which was used to obtain translations of studies published in languages other than English.
Mr. Wewege was supported by a Postgraduate Scholarship from the National Health and Medical Research Council of Australia, a School of Medical Sciences Top-Up Scholarship from the University of New South Wales, and a PhD Supplementary Scholarship from Neuroscience Research Australia. Dr. Gilligan reports that he conducts clinical trials with companies and groups, including the National Institutes of Health related to medications, devices, and procedures for pain.
A version of this article first appeared on Medscape.com.
FROM BMJ
Autism rates trending upwards, CDC reports
Childhood autism rates have ticked up once again, according to the latest data from Centers for Disease Control and Prevention.
According to the CDC, 1 in 36 (2.8%) 8-year-old children have been identified with autism spectrum disorder (ASD) – up from the previous 2018 estimate of 1 in 44 (2.3%).
The updated data come from 11 communities in the Autism and Developmental Disabilities Monitoring (ADDM) network and were published online in Morbidity and Mortality Weekly Report.
A separate report in the MMWR on 4-year-old children in the same 11 communities highlights the impact of COVID-19, showing disruptions in progress in early autism detection.
In the early months of the pandemic, 4-year-old children were less likely to have an evaluation or be identified with ASD than 8-year-old children when they were the same age. This coincides with interruptions in childcare and health care services during the COVID-19 pandemic.
“Disruptions due to the pandemic in the timely evaluation of children and delays in connecting children to the services and support they need could have long-lasting effects,” Karen Remley, MD, director of CDC’s National Center on Birth Defects and Developmental Disabilities, said in a statement.
“The data in this report can help communities better understand how the pandemic impacted early identification of autism in young children and anticipate future needs as these children get older,” Dr. Remley noted.
Shifting demographics
The latest data also show that ASD prevalence among Asian, Black, and Hispanic children was at least 30% higher in 2020 than in 2018, and ASD prevalence among White children was 14.6% higher than in 2018.
For the first time, according to the CDC, the percentage of 8-year-old Asian/Pacific Islander (3.3%), Hispanic (3.2%) and Black (2.9%) children identified with autism was higher than the percentage of 8-year-old White children (2.4%).
This is the opposite of racial and ethnic differences seen in previous ADDM reports for 8-year-olds. These shifts may reflect improved screening, awareness, and access to services among historically underserved groups, the CDC said.
Disparities for co-occurring intellectual disability have also persisted, with a higher percentage of Black children with autism identified with intellectual disability compared with White, Hispanic, or Asian/Pacific Islander children with autism. These differences could relate in part to access to services that diagnose and support children with autism, the CDC noted.
Overall, autism prevalence within the 11 ADDM communities was nearly four times higher for boys than girls. However, it’s the first time that the prevalence of autism among 8-year-old girls has topped 1%.
Community differences
Autism prevalence in the 11 ADDM communities ranged from 1 in 43 (2.3%) children in Maryland to 1 in 22 (4.5%) in California – variations that could be due to how communities identify children with autism.
This variability affords an opportunity to compare local policies and models for delivering diagnostic and interventional services that could enhance autism identification and provide more comprehensive support to people with autism, the CDC said.
A version of this article first appeared on Medscape.com.
Childhood autism rates have ticked up once again, according to the latest data from Centers for Disease Control and Prevention.
According to the CDC, 1 in 36 (2.8%) 8-year-old children have been identified with autism spectrum disorder (ASD) – up from the previous 2018 estimate of 1 in 44 (2.3%).
The updated data come from 11 communities in the Autism and Developmental Disabilities Monitoring (ADDM) network and were published online in Morbidity and Mortality Weekly Report.
A separate report in the MMWR on 4-year-old children in the same 11 communities highlights the impact of COVID-19, showing disruptions in progress in early autism detection.
In the early months of the pandemic, 4-year-old children were less likely to have an evaluation or be identified with ASD than 8-year-old children when they were the same age. This coincides with interruptions in childcare and health care services during the COVID-19 pandemic.
“Disruptions due to the pandemic in the timely evaluation of children and delays in connecting children to the services and support they need could have long-lasting effects,” Karen Remley, MD, director of CDC’s National Center on Birth Defects and Developmental Disabilities, said in a statement.
“The data in this report can help communities better understand how the pandemic impacted early identification of autism in young children and anticipate future needs as these children get older,” Dr. Remley noted.
Shifting demographics
The latest data also show that ASD prevalence among Asian, Black, and Hispanic children was at least 30% higher in 2020 than in 2018, and ASD prevalence among White children was 14.6% higher than in 2018.
For the first time, according to the CDC, the percentage of 8-year-old Asian/Pacific Islander (3.3%), Hispanic (3.2%) and Black (2.9%) children identified with autism was higher than the percentage of 8-year-old White children (2.4%).
This is the opposite of racial and ethnic differences seen in previous ADDM reports for 8-year-olds. These shifts may reflect improved screening, awareness, and access to services among historically underserved groups, the CDC said.
Disparities for co-occurring intellectual disability have also persisted, with a higher percentage of Black children with autism identified with intellectual disability compared with White, Hispanic, or Asian/Pacific Islander children with autism. These differences could relate in part to access to services that diagnose and support children with autism, the CDC noted.
Overall, autism prevalence within the 11 ADDM communities was nearly four times higher for boys than girls. However, it’s the first time that the prevalence of autism among 8-year-old girls has topped 1%.
Community differences
Autism prevalence in the 11 ADDM communities ranged from 1 in 43 (2.3%) children in Maryland to 1 in 22 (4.5%) in California – variations that could be due to how communities identify children with autism.
This variability affords an opportunity to compare local policies and models for delivering diagnostic and interventional services that could enhance autism identification and provide more comprehensive support to people with autism, the CDC said.
A version of this article first appeared on Medscape.com.
Childhood autism rates have ticked up once again, according to the latest data from Centers for Disease Control and Prevention.
According to the CDC, 1 in 36 (2.8%) 8-year-old children have been identified with autism spectrum disorder (ASD) – up from the previous 2018 estimate of 1 in 44 (2.3%).
The updated data come from 11 communities in the Autism and Developmental Disabilities Monitoring (ADDM) network and were published online in Morbidity and Mortality Weekly Report.
A separate report in the MMWR on 4-year-old children in the same 11 communities highlights the impact of COVID-19, showing disruptions in progress in early autism detection.
In the early months of the pandemic, 4-year-old children were less likely to have an evaluation or be identified with ASD than 8-year-old children when they were the same age. This coincides with interruptions in childcare and health care services during the COVID-19 pandemic.
“Disruptions due to the pandemic in the timely evaluation of children and delays in connecting children to the services and support they need could have long-lasting effects,” Karen Remley, MD, director of CDC’s National Center on Birth Defects and Developmental Disabilities, said in a statement.
“The data in this report can help communities better understand how the pandemic impacted early identification of autism in young children and anticipate future needs as these children get older,” Dr. Remley noted.
Shifting demographics
The latest data also show that ASD prevalence among Asian, Black, and Hispanic children was at least 30% higher in 2020 than in 2018, and ASD prevalence among White children was 14.6% higher than in 2018.
For the first time, according to the CDC, the percentage of 8-year-old Asian/Pacific Islander (3.3%), Hispanic (3.2%) and Black (2.9%) children identified with autism was higher than the percentage of 8-year-old White children (2.4%).
This is the opposite of racial and ethnic differences seen in previous ADDM reports for 8-year-olds. These shifts may reflect improved screening, awareness, and access to services among historically underserved groups, the CDC said.
Disparities for co-occurring intellectual disability have also persisted, with a higher percentage of Black children with autism identified with intellectual disability compared with White, Hispanic, or Asian/Pacific Islander children with autism. These differences could relate in part to access to services that diagnose and support children with autism, the CDC noted.
Overall, autism prevalence within the 11 ADDM communities was nearly four times higher for boys than girls. However, it’s the first time that the prevalence of autism among 8-year-old girls has topped 1%.
Community differences
Autism prevalence in the 11 ADDM communities ranged from 1 in 43 (2.3%) children in Maryland to 1 in 22 (4.5%) in California – variations that could be due to how communities identify children with autism.
This variability affords an opportunity to compare local policies and models for delivering diagnostic and interventional services that could enhance autism identification and provide more comprehensive support to people with autism, the CDC said.
A version of this article first appeared on Medscape.com.
ED doc and group owe $13.5M after patient’s serious brain injury
according to a report in the Idaho Capital Sun.
The suit, which took nearly 5 years after filing to wend its way through the courts, stems from an incident that took place in the early morning of March 29, 2016. An Ada County resident peered into the family bathroom and discovered that her husband, Carl B. Stiefel, lay on the floor confused and vomiting and complaining of a severe headache. Recently, the man had experienced several of these same symptoms, plus sinus congestion, dizziness, and tinnitus.
As Mr. Stiefel’s confusion worsened, his wife called for an ambulance, which arrived at the local hospital emergency department (ED) at 4:12 AM. Within approximately 11 minutes, the patient was examined by a doctor and later underwent a cranial CT scan, which a second doctor said showed “no intracranial process.”
Mr. Stiefel’s condition improved somewhat, although his dizziness persisted, leaving him still unable to walk. At this point, his primary ED doctor admitted him to the hospital for “benign positional vertigo.” The doctor also joined colleagues in suggesting that the patient might well be a candidate for an MRI, just in case his condition failed to improve over the next few hours.
But the transfer from the ED to the main hospital reportedly took at least 3 hours, during which time Mr. Stiefel’s condition deteriorated. Once admitted, he was observed by a healthcare provider — the news report doesn’t indicate precisely who — to be “delirious without meaningful interaction.” At least 4 hours would pass before the patient was seen by still another doctor, as the plaintiffs later claimed.
The patient remained disoriented and restless as the day unfolded. The MRI contemplated earlier was finally ordered, but the scan wasn’t available for several hours, according to nursing notes cited by the plaintiffs in their lawsuit.
Finally, the scan was administered at about 5:50 PM, almost 12 hours since Mr. Stiefel had first arrived at the ED. It showed that he had a torn artery in his neck and was experiencing a stroke. This was, clearly, a very different diagnosis from the one that his admitting doctor had entered into his notes.
A surgeon operated to repair the arterial tear, but the patient’s condition continued to worsen. Over the next 3 weeks, Mr. Stiefel went from the hospital to a local rehab facility, and back to the hospital with bacterial meningitis. Ultimately, he was diagnosed with “an irreparable brain injury,” which ultimately left him disabled and unable to work.
At this point, he and his wife sued a broad range of defendants — a radiology group, individual healthcare providers employed by the hospital, the primary ED physician, and that doctor’s emergency medicine group. In the nearly 5 intervening years, each of the named defendants settled, except the ED doctor and the emergency medicine group.
The two remaining defendants vigorously contested the claims against them, denying “any and all allegations of responsibility and liability” and contending that the patient’s injuries resulted from unforeseen complications rather than the care that had been administered.
The Ada County jury disagreed, however. It found that the primary ED doctor — and by extension the group to which the doctor belonged — did in fact negligently and recklessly fail to meet the proper standard of care, leading directly to the patient’s life-altering injuries.
For this failure, the jury awarded the plaintiffs $13.5 million, well over the state’s current inflation-adjusted cap of $400,000. (To date, Idaho’s largest med-mal award is nearly $30 million, handed down more than 20 years ago.)
At press time, there was no word of an appeal.
Man sues dentist, ends up changing state medical malpractice law
In a surprise move, the Connecticut Supreme Court in mid-February reversed its own precedent regarding a 2005 law requiring certain pre-litigation steps be taken before state residents are permitted to file a medical malpractice claim, as a story in the Claims Journal reports.
In its 2011 review of that earlier law — passed to ensure that complainants had a reasonable basis for their claims — the high court went the legislature one better. It held that state courts had no “personal jurisdiction” in adjudicating malpractice claims in the absence of required supporting documents — specifically, a proper certificate and opinion letter from “a similar healthcare provider.”
For the past 12 years, this meant that any suit lacking the proper documents could not only be halted but dismissed with prejudice, meaning that such a case couldn’t be refiled.
That interpretation of the law was eventually challenged, however, by a Connecticut man who sued his dentist. Filed in 2018, the suit alleged that, during a root canal, the dentist had failed to properly diagnose and treat his patient’s dental abscess, which ultimately required surgery.
Complying with what he regarded as state law, the man attached a letter of opinion to his complaint, which testified to the merits of his claim. But, in a twist with significant consequences, the letter was written by an endodontist, not a general dentist. In response, the dentist’s attorneys submitted a motion to dismiss to the trial court, arguing that the plaintiff had breached the “similar provider” provision and that therefore the opinion letter was defective and the entire suit should be dismissed.
The trial court agreed — and the Connecticut Appellate Court went on to affirm the lower-court ruling. The case might have ended there, but the plaintiff appealed to the Connecticut Supreme Court, which agreed to review the appellate court finding.
In a 6-0 decision, the high court looked back on its 2011 interpretation of the med-mal statute, which in the intervening years had given rise to “a body of case law.” The problem with that body of law, the justices argued, was that it had “imposed substantially greater burdens on plaintiffs than the legislature intended” — and it did so “by allowing potentially curable, technical, pre-litigation defects to defeat otherwise meritorious malpractice actions, sometimes after several years of litigation.”
In short, said the justices, there was nothing in the original statute that required a court to dismiss a suit once it found a letter of opinion to be deficient. This was a “curable” defect, one that shouldn’t be allowed to derail an otherwise meritorious claim.
As for the case that prompted the high court’s latest review — that is, the Connecticut man’s suit against his dentist — the justices found that the appellate court had also erred when it tossed out the endodontist’s opinion letter. Technically, the dentist might not have been an endodontist, said the justices, but he had in fact practiced in the field during the course of a long career, so close enough.
The justices kicked the case back to the trial court, with instructions that it deny the defendant’s motion to dismiss.
Stakeholders divided over new awards cap
Last month, Iowa Gov. Kim Reynolds signed a bill into law that limits the amount of noneconomic damages a successful med-mal plaintiff can collect, explains a story posted on Radio Iowa, among other news sites.
Under the new law, the limit for suits involving hospitals is capped at $2 million — while those involving all other healthcare providers are capped at $1 million. Beginning in 2028, those caps will be adjusted annually for inflation by 2.1%.
“When mistakes happen, Iowans deserve compensation, but arbitrary multimillion-dollar awards do more than that,” said Gov. Reynolds. “They act as a tax on all Iowans by raising the cost of care. They drive medical clinics out of business and medical students out of state.”
The CEO of Knoxville Hospital and Clinics — a well-known regional provider — agreed, saying that the new law helped to make Iowa “a more attractive place to practice medicine.”
But most Democrats in the GOP-controlled legislature — and 16 Republicans — voted against the legislation. For her part, House Minority Leader Jennifer Konfrst said there was absolutely no evidence that states with caps fared any better with medical workforce shortages than states without caps.
A version of this article originally appeared on Medscape.com.
according to a report in the Idaho Capital Sun.
The suit, which took nearly 5 years after filing to wend its way through the courts, stems from an incident that took place in the early morning of March 29, 2016. An Ada County resident peered into the family bathroom and discovered that her husband, Carl B. Stiefel, lay on the floor confused and vomiting and complaining of a severe headache. Recently, the man had experienced several of these same symptoms, plus sinus congestion, dizziness, and tinnitus.
As Mr. Stiefel’s confusion worsened, his wife called for an ambulance, which arrived at the local hospital emergency department (ED) at 4:12 AM. Within approximately 11 minutes, the patient was examined by a doctor and later underwent a cranial CT scan, which a second doctor said showed “no intracranial process.”
Mr. Stiefel’s condition improved somewhat, although his dizziness persisted, leaving him still unable to walk. At this point, his primary ED doctor admitted him to the hospital for “benign positional vertigo.” The doctor also joined colleagues in suggesting that the patient might well be a candidate for an MRI, just in case his condition failed to improve over the next few hours.
But the transfer from the ED to the main hospital reportedly took at least 3 hours, during which time Mr. Stiefel’s condition deteriorated. Once admitted, he was observed by a healthcare provider — the news report doesn’t indicate precisely who — to be “delirious without meaningful interaction.” At least 4 hours would pass before the patient was seen by still another doctor, as the plaintiffs later claimed.
The patient remained disoriented and restless as the day unfolded. The MRI contemplated earlier was finally ordered, but the scan wasn’t available for several hours, according to nursing notes cited by the plaintiffs in their lawsuit.
Finally, the scan was administered at about 5:50 PM, almost 12 hours since Mr. Stiefel had first arrived at the ED. It showed that he had a torn artery in his neck and was experiencing a stroke. This was, clearly, a very different diagnosis from the one that his admitting doctor had entered into his notes.
A surgeon operated to repair the arterial tear, but the patient’s condition continued to worsen. Over the next 3 weeks, Mr. Stiefel went from the hospital to a local rehab facility, and back to the hospital with bacterial meningitis. Ultimately, he was diagnosed with “an irreparable brain injury,” which ultimately left him disabled and unable to work.
At this point, he and his wife sued a broad range of defendants — a radiology group, individual healthcare providers employed by the hospital, the primary ED physician, and that doctor’s emergency medicine group. In the nearly 5 intervening years, each of the named defendants settled, except the ED doctor and the emergency medicine group.
The two remaining defendants vigorously contested the claims against them, denying “any and all allegations of responsibility and liability” and contending that the patient’s injuries resulted from unforeseen complications rather than the care that had been administered.
The Ada County jury disagreed, however. It found that the primary ED doctor — and by extension the group to which the doctor belonged — did in fact negligently and recklessly fail to meet the proper standard of care, leading directly to the patient’s life-altering injuries.
For this failure, the jury awarded the plaintiffs $13.5 million, well over the state’s current inflation-adjusted cap of $400,000. (To date, Idaho’s largest med-mal award is nearly $30 million, handed down more than 20 years ago.)
At press time, there was no word of an appeal.
Man sues dentist, ends up changing state medical malpractice law
In a surprise move, the Connecticut Supreme Court in mid-February reversed its own precedent regarding a 2005 law requiring certain pre-litigation steps be taken before state residents are permitted to file a medical malpractice claim, as a story in the Claims Journal reports.
In its 2011 review of that earlier law — passed to ensure that complainants had a reasonable basis for their claims — the high court went the legislature one better. It held that state courts had no “personal jurisdiction” in adjudicating malpractice claims in the absence of required supporting documents — specifically, a proper certificate and opinion letter from “a similar healthcare provider.”
For the past 12 years, this meant that any suit lacking the proper documents could not only be halted but dismissed with prejudice, meaning that such a case couldn’t be refiled.
That interpretation of the law was eventually challenged, however, by a Connecticut man who sued his dentist. Filed in 2018, the suit alleged that, during a root canal, the dentist had failed to properly diagnose and treat his patient’s dental abscess, which ultimately required surgery.
Complying with what he regarded as state law, the man attached a letter of opinion to his complaint, which testified to the merits of his claim. But, in a twist with significant consequences, the letter was written by an endodontist, not a general dentist. In response, the dentist’s attorneys submitted a motion to dismiss to the trial court, arguing that the plaintiff had breached the “similar provider” provision and that therefore the opinion letter was defective and the entire suit should be dismissed.
The trial court agreed — and the Connecticut Appellate Court went on to affirm the lower-court ruling. The case might have ended there, but the plaintiff appealed to the Connecticut Supreme Court, which agreed to review the appellate court finding.
In a 6-0 decision, the high court looked back on its 2011 interpretation of the med-mal statute, which in the intervening years had given rise to “a body of case law.” The problem with that body of law, the justices argued, was that it had “imposed substantially greater burdens on plaintiffs than the legislature intended” — and it did so “by allowing potentially curable, technical, pre-litigation defects to defeat otherwise meritorious malpractice actions, sometimes after several years of litigation.”
In short, said the justices, there was nothing in the original statute that required a court to dismiss a suit once it found a letter of opinion to be deficient. This was a “curable” defect, one that shouldn’t be allowed to derail an otherwise meritorious claim.
As for the case that prompted the high court’s latest review — that is, the Connecticut man’s suit against his dentist — the justices found that the appellate court had also erred when it tossed out the endodontist’s opinion letter. Technically, the dentist might not have been an endodontist, said the justices, but he had in fact practiced in the field during the course of a long career, so close enough.
The justices kicked the case back to the trial court, with instructions that it deny the defendant’s motion to dismiss.
Stakeholders divided over new awards cap
Last month, Iowa Gov. Kim Reynolds signed a bill into law that limits the amount of noneconomic damages a successful med-mal plaintiff can collect, explains a story posted on Radio Iowa, among other news sites.
Under the new law, the limit for suits involving hospitals is capped at $2 million — while those involving all other healthcare providers are capped at $1 million. Beginning in 2028, those caps will be adjusted annually for inflation by 2.1%.
“When mistakes happen, Iowans deserve compensation, but arbitrary multimillion-dollar awards do more than that,” said Gov. Reynolds. “They act as a tax on all Iowans by raising the cost of care. They drive medical clinics out of business and medical students out of state.”
The CEO of Knoxville Hospital and Clinics — a well-known regional provider — agreed, saying that the new law helped to make Iowa “a more attractive place to practice medicine.”
But most Democrats in the GOP-controlled legislature — and 16 Republicans — voted against the legislation. For her part, House Minority Leader Jennifer Konfrst said there was absolutely no evidence that states with caps fared any better with medical workforce shortages than states without caps.
A version of this article originally appeared on Medscape.com.
according to a report in the Idaho Capital Sun.
The suit, which took nearly 5 years after filing to wend its way through the courts, stems from an incident that took place in the early morning of March 29, 2016. An Ada County resident peered into the family bathroom and discovered that her husband, Carl B. Stiefel, lay on the floor confused and vomiting and complaining of a severe headache. Recently, the man had experienced several of these same symptoms, plus sinus congestion, dizziness, and tinnitus.
As Mr. Stiefel’s confusion worsened, his wife called for an ambulance, which arrived at the local hospital emergency department (ED) at 4:12 AM. Within approximately 11 minutes, the patient was examined by a doctor and later underwent a cranial CT scan, which a second doctor said showed “no intracranial process.”
Mr. Stiefel’s condition improved somewhat, although his dizziness persisted, leaving him still unable to walk. At this point, his primary ED doctor admitted him to the hospital for “benign positional vertigo.” The doctor also joined colleagues in suggesting that the patient might well be a candidate for an MRI, just in case his condition failed to improve over the next few hours.
But the transfer from the ED to the main hospital reportedly took at least 3 hours, during which time Mr. Stiefel’s condition deteriorated. Once admitted, he was observed by a healthcare provider — the news report doesn’t indicate precisely who — to be “delirious without meaningful interaction.” At least 4 hours would pass before the patient was seen by still another doctor, as the plaintiffs later claimed.
The patient remained disoriented and restless as the day unfolded. The MRI contemplated earlier was finally ordered, but the scan wasn’t available for several hours, according to nursing notes cited by the plaintiffs in their lawsuit.
Finally, the scan was administered at about 5:50 PM, almost 12 hours since Mr. Stiefel had first arrived at the ED. It showed that he had a torn artery in his neck and was experiencing a stroke. This was, clearly, a very different diagnosis from the one that his admitting doctor had entered into his notes.
A surgeon operated to repair the arterial tear, but the patient’s condition continued to worsen. Over the next 3 weeks, Mr. Stiefel went from the hospital to a local rehab facility, and back to the hospital with bacterial meningitis. Ultimately, he was diagnosed with “an irreparable brain injury,” which ultimately left him disabled and unable to work.
At this point, he and his wife sued a broad range of defendants — a radiology group, individual healthcare providers employed by the hospital, the primary ED physician, and that doctor’s emergency medicine group. In the nearly 5 intervening years, each of the named defendants settled, except the ED doctor and the emergency medicine group.
The two remaining defendants vigorously contested the claims against them, denying “any and all allegations of responsibility and liability” and contending that the patient’s injuries resulted from unforeseen complications rather than the care that had been administered.
The Ada County jury disagreed, however. It found that the primary ED doctor — and by extension the group to which the doctor belonged — did in fact negligently and recklessly fail to meet the proper standard of care, leading directly to the patient’s life-altering injuries.
For this failure, the jury awarded the plaintiffs $13.5 million, well over the state’s current inflation-adjusted cap of $400,000. (To date, Idaho’s largest med-mal award is nearly $30 million, handed down more than 20 years ago.)
At press time, there was no word of an appeal.
Man sues dentist, ends up changing state medical malpractice law
In a surprise move, the Connecticut Supreme Court in mid-February reversed its own precedent regarding a 2005 law requiring certain pre-litigation steps be taken before state residents are permitted to file a medical malpractice claim, as a story in the Claims Journal reports.
In its 2011 review of that earlier law — passed to ensure that complainants had a reasonable basis for their claims — the high court went the legislature one better. It held that state courts had no “personal jurisdiction” in adjudicating malpractice claims in the absence of required supporting documents — specifically, a proper certificate and opinion letter from “a similar healthcare provider.”
For the past 12 years, this meant that any suit lacking the proper documents could not only be halted but dismissed with prejudice, meaning that such a case couldn’t be refiled.
That interpretation of the law was eventually challenged, however, by a Connecticut man who sued his dentist. Filed in 2018, the suit alleged that, during a root canal, the dentist had failed to properly diagnose and treat his patient’s dental abscess, which ultimately required surgery.
Complying with what he regarded as state law, the man attached a letter of opinion to his complaint, which testified to the merits of his claim. But, in a twist with significant consequences, the letter was written by an endodontist, not a general dentist. In response, the dentist’s attorneys submitted a motion to dismiss to the trial court, arguing that the plaintiff had breached the “similar provider” provision and that therefore the opinion letter was defective and the entire suit should be dismissed.
The trial court agreed — and the Connecticut Appellate Court went on to affirm the lower-court ruling. The case might have ended there, but the plaintiff appealed to the Connecticut Supreme Court, which agreed to review the appellate court finding.
In a 6-0 decision, the high court looked back on its 2011 interpretation of the med-mal statute, which in the intervening years had given rise to “a body of case law.” The problem with that body of law, the justices argued, was that it had “imposed substantially greater burdens on plaintiffs than the legislature intended” — and it did so “by allowing potentially curable, technical, pre-litigation defects to defeat otherwise meritorious malpractice actions, sometimes after several years of litigation.”
In short, said the justices, there was nothing in the original statute that required a court to dismiss a suit once it found a letter of opinion to be deficient. This was a “curable” defect, one that shouldn’t be allowed to derail an otherwise meritorious claim.
As for the case that prompted the high court’s latest review — that is, the Connecticut man’s suit against his dentist — the justices found that the appellate court had also erred when it tossed out the endodontist’s opinion letter. Technically, the dentist might not have been an endodontist, said the justices, but he had in fact practiced in the field during the course of a long career, so close enough.
The justices kicked the case back to the trial court, with instructions that it deny the defendant’s motion to dismiss.
Stakeholders divided over new awards cap
Last month, Iowa Gov. Kim Reynolds signed a bill into law that limits the amount of noneconomic damages a successful med-mal plaintiff can collect, explains a story posted on Radio Iowa, among other news sites.
Under the new law, the limit for suits involving hospitals is capped at $2 million — while those involving all other healthcare providers are capped at $1 million. Beginning in 2028, those caps will be adjusted annually for inflation by 2.1%.
“When mistakes happen, Iowans deserve compensation, but arbitrary multimillion-dollar awards do more than that,” said Gov. Reynolds. “They act as a tax on all Iowans by raising the cost of care. They drive medical clinics out of business and medical students out of state.”
The CEO of Knoxville Hospital and Clinics — a well-known regional provider — agreed, saying that the new law helped to make Iowa “a more attractive place to practice medicine.”
But most Democrats in the GOP-controlled legislature — and 16 Republicans — voted against the legislation. For her part, House Minority Leader Jennifer Konfrst said there was absolutely no evidence that states with caps fared any better with medical workforce shortages than states without caps.
A version of this article originally appeared on Medscape.com.
Does new heart transplant method challenge definition of death?
The relatively recent innovation of heart transplantation after circulatory death of the donor is increasing the number of donor hearts available and leading to many more lives on the heart transplant waiting list being saved. Experts agree it’s a major and very welcome advance in medicine.
However, some of the processes involved in one approach to donation after circulatory death has raised ethical concerns and questions about whether they violate the “dead donor rule” – a principle that requires patients be declared dead before removal of life-sustaining organs for transplant. 
Experts in the fields of transplantation and medical ethics have yet to reach consensus, causing problems for the transplant community, who worry that this could cause a loss of confidence in the entire transplant process.
A new pathway for heart transplantation
The traditional approach to transplantation is to retrieve organs from a donor who has been declared brain dead, known as “donation after brain death (DBD).” These patients have usually suffered a catastrophic brain injury but survived to get to intensive care.
As the brain swells because of injury, it becomes evident that all brain function is lost, and the patient is declared brain dead. However, breathing is maintained by the ventilator and the heart is still beating. Because the organs are being oxygenated, there is no immediate rush to retrieve the organs and the heart can be evaluated for its suitability for transplant in a calm and methodical way before it is removed.
However, there is a massive shortage of organs, especially hearts, partially because of the limited number of donors who are declared brain dead in that setting.
In recent years, another pathway for organ transplantation has become available: “donation after circulatory death (DCD).” These patients also have suffered a catastrophic brain injury considered to be nonsurvivable, but unlike the DBD situation, the brain still has some function, so the patient does not meet the criteria for brain death.
Still, because the patient is considered to have no chance of a meaningful recovery, the family often recognizes the futility of treatment and agrees to the withdrawal of life support. When this happens, the heart normally stops beating after a period of time. There is then a “stand-off time” – normally 5 minutes – after which death is declared and the organs can be removed.
The difficulty with this approach, however, is that because the heart has been stopped, it has been deprived of oxygen, potentially causing injury. While DCD has been practiced for several years to retrieve organs such as the kidney, liver, lungs, and pancreas, the heart is more difficult as it is more susceptible to oxygen deprivation. And for the heart to be assessed for transplant suitability, it should ideally be beating, so it has to be reperfused and restarted quickly after death has been declared.
For many years it was thought the oxygen deprivation that occurs after circulatory death would be too much to provide a functional organ. But researchers in the United Kingdom and Australia developed techniques to overcome this problem, and early DCD heart transplants took place in 2014 in Australia, and in 2015 in the United Kingdom.
Heart transplantation after circulatory death has now become a routine part of the transplant program in many countries, including the United States, Spain, Belgium, the Netherlands, and Austria.
In the United States, 348 DCD heart transplants were performed in 2022, with numbers expected to reach 700 to 800 this year as more centers come online.
It is expected that most countries with heart transplant programs will follow suit and the number of donor hearts will increase by up to 30% worldwide because of DCD.
Currently, there are about 8,000 heart transplants worldwide each year and with DCD this could rise to about 10,000, potentially an extra 2,000 lives saved each year, experts estimate.
Two different approaches to DCD heart transplantation have been developed.
The direct procurement approach
The Australian group, based at St. Vincent’s Hospital in Sydney, developed a technique referred to as “direct procurement”: after the standoff period and declaration of circulatory death, the chest is opened, and the heart is removed. New technology, the Organ Care System (OCS) heart box (Transmedics), is then used to reperfuse and restart the heart outside the body so its suitability for transplant can be assessed.
The heart is kept perfused and beating in the OCS box while it is being transported to the recipient. This has enabled longer transit times than the traditional way of transporting the nonbeating heart on ice.
Peter MacDonald, MD, PhD, from the St Vincent’s group that developed this approach, said, “Most people thought a heart from a DCD donor would not survive transport – that the injury to the heart from the combination of life support withdrawal, stand-off time, and cold storage would be too much. But we modeled the process in the lab and were able to show that we were able to get the heart beating again after withdrawal of life support.”
Dr. McDonald noted that “the recipient of their first human DCD heart transplant using this machine in 2014 is still alive and well.” The Australian group has now done 85 of these DCD heart transplants, and they have increased the number of heart transplant procedures at St. Vincent’s Hospital by 25%.
Normothermic regional perfusion (NRP)
The U.K. group, based at the Royal Papworth Hospital in Cambridge, England, developed a different approach to DCD: After the standoff period and the declaration of circulatory death, the donor is connected to a heart/lung machine using extracorporeal membrane oxygenation (ECMO) so that the heart is perfused and starts beating again inside the body. This approach is known as normothermic regional perfusion (NRP).
Marius Berman, MD, surgical lead for Transplantation and Mechanical Circulatory Support at Papworth, explained that the NRP approach allows the heart to be perfused and restarted faster than direct procurement, resulting in a shorter ischemic time. The heart can be evaluated thoroughly for suitability for transplantation in situ before committing to transplantation, and because the heart is less damaged, it can be transported on ice without use of the OCS box.
“DCD is more complicated than DBD, because the heart has stopped and has to be restarted. Retrieval teams have to be very experienced,” Dr. Berman noted. “This is more of an issue for the direct procurement approach, where the chest has to be opened and the heart retrieved as fast as possible. It is a rush. The longer time without the heart being perfused correlates to an increased incidence of primary graft dysfunction. With NRP, we can get the heart started again more quickly, which is crucial.”
Stephen Large, MBBS, another cardiothoracic surgeon with the Papworth team, added that they have reduced ischemic time to about 15 minutes. “That’s considerably shorter than reperfusing the heart outside the body,” he said. “This results in a healthier organ for the recipient.”
The NRP approach is also less expensive than direct procurement as one OCS box costs about $75,000.
He pointed out that the NRP approach can also be used for heart transplants in children and even small babies, while currently the direct procurement technique is not typically suitable for children because the OCS box was not designed for small hearts.
DCD, using either technique, has increased the heart transplant rate by 40% at Papworth, and is being used at all seven transplant centers in the United Kingdom, “a world first,” noted Dr. Large.
The Papworth team recently published its 5-year experience with 25 NRP transplants and 85 direct procurement transplants. Survival in recipients was no different, although there was some suggestion that the NRP hearts may have been in slightly better condition, possibly being more resistant to immunological rejection.
Ethical concerns about NRP
Restarting the circulation during the NRP process has raised ethical concerns.
When the NRP technique was first used in the United States, these ethical questions were raised by several groups, including the American College of Physicians (ACP).
Harry Peled, MD, Providence St. Jude Medical Center, Fullerton, Calif., coauthor of a recent Viewpoint on the issue, is board-certified in both cardiology and critical care, and said he is a supporter of DCD using direct procurement, but he does not believe that NRP is ethical at present. He is not part of the ACP, but said his views align with those of the organization.
There are two ethical problems with NRP, he said. The first is whether by restarting the circulation, the NRP process violates the U.S. definition of death, and retrieval of organs would therefore violate the dead donor rule.
“American law states that death is the irreversible cessation of brain function or of circulatory function. But with NRP, the circulation is artificially restored, so the cessation of circulatory function is not irreversible,” Dr. Peled pointed out.
“I have no problem with DCD using direct procurement as we are not restarting the circulation. But NRP is restarting the circulation and that is a problem for me,” Dr. Peled said. “I would argue that by performing NRP, we are resuscitating the patient.”
The second ethical problem with NRP is concern about whether, during the process, there would be any circulation to the brain, and if so, would this be enough to restore some brain function? Before NRP is started, the main arch vessel arteries to the head are clamped to prevent flow to the brain, but there are worries that some blood flow may still be possible through small collateral vessels.
“We have established that these patients do not have enough brain function for a meaningful life, which is why a decision has been made to remove life support, but they have not been declared brain dead,” Dr. Peled said.
With direct procurement, the circulation is not restarted so there is no chance that any brain function will be restored, he said. “But with NRP, because the arch vessels have to be clamped to prevent brain circulation, that is admitting there is concern that brain function may be restored if circulation to the brain is reestablished, and brain function is compatible with life. As we do not know whether there is any meaningful circulation to the brain via the small collaterals, there is, in effect, a risk of bringing the patient back to life.”
The other major concern for some is whether even a very small amount of circulation to the brain would be enough to support consciousness, and “we don’t know that for certain,” Dr. Peled said.
The argument for NRP
Nader Moazami, MD, professor of cardiovascular surgery, NYU Langone Health, New York, is one of the more vocal proponents of NRP for DCD heart transplantation in the United States, and has coauthored responses to these ethical concerns.
“People are confusing many issues to produce an argument against NRP,” he said.
“Our position is that death has already been declared based on the lack of circulatory function for over 5 minutes and this has been with the full agreement of the family, knowing that the patient has no chance of a meaningful life. No one is thinking of trying to resuscitate the patient. It has already been established that any future efforts to resuscitate are futile. In this case, we are not resuscitating the patient by restarting the circulation. It is just regional perfusion of the organs.”
Dr. Moazami pointed out this concept was accepted for the practice of abdominal DCD when it first started in the United States in the 1990s where cold perfusion was used to preserve the abdominal organs before they were retrieved from the body.
“The new approach of using NRP is similar except that it involves circulating warm blood, which will preserve organs better and result in higher quality organs for the recipient.”
On the issue of concern about possible circulation to the brain, Dr. Moazami said: “The ethical critics of NRP are questioning whether the brain may not be dead. We are arguing that the patient has already been declared dead as they have had a circulatory death. You cannot die twice.”
He maintained that the clamping of the arch vessels to the head will ensure that when the circulation is restarted “the natural process of circulatory death leading to brain death will continue to progress.”
On the concerns about possible collateral flow to the brain, Dr. Moazami said there is no evidence that this occurs. “Prominent neurologists have said it is impossible for collaterals to provide any meaningful blood flow to the brain in this situation. And even if there is small amount of blood flow to the brain, this would be insufficient to maintain any meaningful brain function.”
But Dr. Peled argues that this has not been proved. “Even though we don’t think there is enough circulation to the brain for any function with NRP, we don’t know that with 100% certainty,” he said. “In my view, if there is a possibility of even the smallest amount of brain flow, we are going against the dead donor rule. We are rewriting the rules of death.”
Dr. Moazami countered: “Nothing in life is 100%, particularly in medicine. With that argument can you also prove with 100% certainty to me that there is absolutely no brain function with regular direct procurement DCD? We know that brain death has started, but the question is: Has it been completed? We don’t know the answer to this question with 100% certainty, but that is the case for regular direct procurement DCD as well, and that has been accepted by almost everyone.
“The whole issue revolves around when are we comfortable that death has occurred,” he said. “Those against NRP are concerned that organs are being taken before the patient is dead. But the key point is that the patient has already been declared dead.”
Since there is some concern over the ethics of NRP, why not just stick to DCD with direct procurement?
Dr. Moazami argued that NRP results in healthier organs. “NRP allows more successful heart transplants, liver transplants, lung transplants. It preserves all the organs better,” he said. “This will have a big impact on recipients – they would obviously much prefer a healthier organ. In addition, the process is easier and cheaper, so more centers will be able to do it, therefore more transplants will get done and more lives will be saved if NRP is used.”
He added: “I am a physician taking care of sick patients. I believe I have to respect the wishes of the donor and the donor family; make sure I’m not doing any harm to the donor; and ensure the best quality possible of the organ I am retrieving to best serve the recipient. I am happy I am doing this by using NRP for DCD heart transplantation.”
But Dr. Peled argued that while NRP may have some possible advantages over direct procurement, that does not justify allowing a process to go ahead that is unethical.
“The fact that NRP may result in some benefits doesn’t justify violating the dead donor rule or the possibility, however small, of causing pain to the donor. If it’s unethical, it’s unethical. Full stop,” he said.
“I feel that NRP is not respecting the rights of our patients and that the process does not have adequate transparency. We took it to our local ethics committee, and they decided not to approve NRP in our health care system. I agree with this decision,” Dr. Peled said.
“The trouble is different experts and different countries are not in agreement about this,” he added. “Reasonable, well-informed people are in disagreement. I do not believe we can have a standard of care where there is not consensus.”
Cautious nod
In a 2022 consensus statement, the International Society for Heart and Lung Transplantation (ISHLT) gave a cautious nod toward DCD and NRP, dependent on local recommendations.
The ISHLT conclusion reads: “With appropriate consideration of the ethical principles involved in organ donation, DCD can be undertaken in a morally permissible manner. In all cases, the introduction of DCD programs should be in accordance with local legal regulations. Countries lacking a DCD pathway should be encouraged to develop national ethical, professional, and legal frameworks to address both public and professional concerns.”
The author of a recent editorial on the subject, Ulrich P. Jorde, MD, head of the heart transplant program at Montefiore Medical Center, New York, said, “DCD is a great step forward. People regularly die on the heart transplant waiting list. DCD will increase the supply of donor hearts by 20% to 30%.”
However, he noted that while most societies have agreed on a protocol for organ donation based on brain death, the situation is more complicated with circulatory death.
“Different countries have different definitions of circulatory death. How long do we have to wait after the heart has stopped beating before the patient is declared dead? Most countries have agreed on 5 minutes, but other countries have imposed different periods and as such, different definitions of death.
“The ISHLT statement says that restarting the circulation is acceptable if death has been certified according to prevailing law and surgical interventions are undertaken to preclude any restoration of cerebral circulation. But our problem is that different regional societies have different definitions of circulatory, death which makes the situation confusing.”
Dr. Jorde added: “We also have to weigh the wishes of the donor and their family. If family, advocating what are presumed to be the donor’s wishes, have decided that DCD would be acceptable and they understand the concept and wish to donate the organs after circulatory death, this should be strongly considered under the concept of self-determination, a basic human right.”
Variations in practice around the world
This ethical debate has led to large variations in practice around the world, with some countries, such as Spain, allowing both methods of DCD, while Australia allows direct procurement but not NRP, and Germany currently does not allow DCD at all.
In the United States, things are even more complicated, with some states allowing NRP while others don’t. Even within states, some hospitals and transplant organizations allow NRP, and others don’t.
David A. D’Alessandro, MD, cardiac surgeon at Massachusetts General Hospital, Boston, uses only the direct procurement approach as his region does not allow NRP.
“The direct procurement approach is not controversial and to me that’s a big advantage. I believe we need to agree on the ethics first, and then get into a debate about which technique is better,” he told this news organization.
Dr. D’Alessandro and his group recently published the results of their study, with direct procurement DCD heart transplantation showing similar short-term clinical outcomes to DBD.
“We are only doing direct procurement and we are seeing good results that appear to be comparable to DBD. That is good enough for me,” he said.
Dr. D’Alessandro estimates that in the United States both types of DCD procedures are currently being done about equally.
“Anything we can do to increase the amount of hearts available for transplantation is a big deal,” he said. “At the moment, only the very sickest patients get a heart transplant, and many patients die on the transplant waiting list. Very sadly, many young people die every year from a circulatory death after having life support withdrawn. Before DCD, these beautiful functional organs were not able to be used. Now we have a way of saving lives with these organs.”
Dr. D’Alessandro noted that more and more centers in the United States are starting to perform DCD heart transplants.
“Not every transplant center may join in as the DCD procedures are very resource-intensive and time-consuming. For low-volume transplant centers, it may not be worth the expense and anguish to do DCD heart transplants. But bigger centers will need to engage in DCD to remain competitive. My guess is that 50%-70% of U.S. transplant centers will do DCD in future.”
He said he thinks it is a “medical shortcoming” that agreement cannot be reached on the ethics of NRP. “In an ideal world everyone would be on the same page. It makes me a bit uncomfortable that some people think it’s okay and some people don’t.”
Adam DeVore, MD, a cardiologist at Duke University Medical Center, Durham, N.C., the first U.S. center to perform an adult DCD heart transplant, reported that his institution uses both methods, with the choice sometimes depending on how far the heart must travel.
“If the recipient is near, NRP may be chosen as the heart is transported on ice, but if it needs to go further away we are more likely to choose direct procurement and use of the OCS box,” he said.
“I am really proud of what we’ve been able to do, helping to introduce DCD in the U.S.,” Dr. DeVore said. “This is having a massive benefit in increasing the number of hearts for donation with great outcomes.”
But he acknowledged that the whole concept of DCD is somewhat controversial.
“The idea of brain death really came about for the purpose of heart donation. The two things are very intricately tied. Trying to do heart donation without brain death having been declared is foreign to people. Also, in DCD there is the issue of [this]: When life support is removed, how long do we wait before death can be declared? That could be in conflict with how long the organ needs to remain viable. We are going through the process now of looking at these questions. There is a lot of variation in the U.S. about the withdrawal of care and the declaration of death, which is not completely standardized.
“But the concept of circulatory death itself is accepted after the withdrawal of life support. I think it’s the rush to take the organs out that makes it more difficult.”
Dr. DeVore said the field is moving forward now. “As the process has become more common, people have become more comfortable, probably because of the big difference it will make to saving lives. But we do need to try and standardize best practices.”
A recent Canadian review of the ethics of DCD concluded that the direct procurement approach would be in alignment with current medical guidelines, but that further work is required to evaluate the consistency of NRP with current Canadian death determination policy and to ensure the absence of brain perfusion during this process.
In the United Kingdom, the definition of death is brain-based, and brain death is defined on a neurological basis.
Dr. Stephen Large from Papworth explained that this recognizes the presence of brain-stem death through brain stem reflex testing after the withdrawal of life support, cardiorespiratory arrest and 5 further minutes of ischemia. As long as NRP does not restore intracranial (brainstem) perfusion after death has been confirmed, then it is consistent with laws for death determination and therefore both direct procurement and NRP are permissible.
However, the question over possible collateral flow to the brain has led the United Kingdom to pause the NRP technique as routine practice while this is investigated further. So, at the present time, the vast majority of DCD heart transplants are being conducted using the direct procurement approach.
But the United Kingdom is facing the bigger challenge: national funding that will soon end. “The DCD program in the U.K. has been extremely successful, increasing heart transplant rates by up to 28%,” Dr. Berman said. “Everybody wants it to continue. But at present the DCD program only has national funding in the U.K. until March 2023. We don’t know what will happen after that.”
The current model in the United Kingdom consists of three specialized DCD heart retrieval teams, a national protocol of direct organ procurement and delivery of DCD hearts to all seven transplant programs, both adult and pediatric.
If the national funding is not extended, “we will go back to individual hospitals trying to fund their own programs. That will be a serious threat to the program and could result in a large reduction in heart transplants,” said Dr. Berman.
Definition of death
The crux of the issue with regard to NRP seems to be variations in how death is defined and the interpretation of those definitions.
DCD donors will have had many tests indicating severe brain damage, a neurologist will have declared the prognosis is futile, and relatives will have agreed to withdraw life support, Dr. Jorde said. “The heart stops beating, and the stand-off time means that blood flow to the brain ceases completely for at least 5 minutes before circulatory death is declared. This is enough on its own to stop brain function.”
Dr. Large made the point that by the time the circulation is reestablished with NRP, more time has elapsed, and the brain will have been without perfusion for much longer than 5 minutes, so it would be “physiologically almost impossible” for there to be any blood flow to the brain.
“Because these brains are already very damaged before life support was removed, the intracranial pressure is high, which will further discourage blood flow to the brain,” he said. Then the donor goes through a period of anoxic heart arrest, up to 16 minutes at a minimum of no blood supply, enough on its own to stop meaningful brain function.
“It’s asking an awful lot to believe that there might be any brain function left,” he said. “And if, on reestablishing the circulation with NRP, there is any blood in the collaterals, the pressure of such flow is so low it won’t enter the brain.”
Dr. Large also pointed out that the fact that the United Kingdom requires a neurologic definition for brain-stem death makes the process easier.
In Australia, St. Vincent’s cardiologist Dr. MacDonald noted that death is defined as the irreversible cessation of circulation, so the NRP procedure is not allowed.
“With NRP, there is an ethical dilemma over whether the patient has legally died or not. Different countries have different ways of defining death. Perhaps society will have to review of the definition of death,” he suggested. Death is a process, “but for organ donation, we have to choose a moment in time of that process that satisfies everyone – when there is no prospect of recovery of the donor but the organs can still be utilized without harming the donor.”
Dr. MacDonald said the field is in transition. “I don’t want to argue that one technique is better than the other; I think it’s good to have access to both techniques. Anything that will increase the number of transplants we can do is a good thing.”
Collaborative decision
Everyone seems to agree that there should be an effort to try to define death in a uniform way worldwide, and that international, national and local regulations are aligned with each other.
Dr. Jorde said: “It is of critical importance that local guidelines are streamlined, firstly in any one given country and then globally, and these things must be discussed transparently within society with all stakeholders – doctors, patients, citizens.”
Dr. Peled, from Providence St. Jude in California, concurred: “There is the possibility that we could change the definition of death, but that cannot be a decision based solely on transplant organizations. It has to be a collaborative decision with a large input from groups who do not have an interest in the procurement of organs.”
He added: “The dialogue so far has been civil, and everybody is trying to do the right thing. My hope is that as a civilized society we will figure out a way forward. At present, there is significant controversy about NRP, and families need to know that. My main concern is that if there is any lack of transparency in getting informed consent, then this risks people losing trust in the donation system.”
Dr. Moazami, from NYU Langone, said the controversy has cast a cloud over the practice of NRP throughout the world. “We need to get it sorted out.”
He said he believes the way forward is to settle the question of whether there is any meaningful blood flow to the brain with the NRP technique.
“This is where the research has to focus. I believe this concern is hypothetical, but I am happy to do the studies to confirm that. Then, the issue should come to a rest. I think that is the right way forward – to do the studies rather than enforcing a moratorium on the practice because of a hypothetical concern.”
These studies on blood flow to the brain are now getting started in both the United Kingdom and the United States.
The U.K. study is being run by Antonio Rubino, MD, consultant in cardiothoracic anesthesia and intensive care at Papworth Hospital NHS Foundation and clinical lead, organ donation. Dr. Rubino explained that the study will assess cerebral blood flow using CT angiography of the brain. “We hypothesize that this will provide evidence to indicate that brain blood flow is not present during NRP and promote trust in the use of NRP in routine practice,” he said.
Dr. Large said: “Rather than having these tortured arguments, we will do the measurements. For the sake of society in this situation, I think it’s good to stop and take a breath. We must measure this, and we are doing just that.”
If there is any blood flow at all, Dr. Large said they will then have to seek expert guidance. “Say we find there is 50 mL of blood flow and normal blood flow is 1,500 mL/min. We will need expert guidance on whether it is remotely possible to be sentient on that. I would say it would be extraordinarily unlikely.”
Dr. Berman summarized the situation: “DCD is increasing the availability of hearts for transplant. This is saving lives, reducing the number of patients on the waiting list, and reducing hospital stays for patients unable to leave the hospital without a transplant. It is definitely here to stay. It is crucial that it gets funded properly, and it is also crucial that we resolve the NRP ethical issues as soon as possible.”
He is hopeful that some of these issues will be resolved this year.
Dr. MacDonald reported he has received “in-kind” support from Transmedics through provision of research modules for preclinical research studies. Dr. D’Alessandro reported he is on the speakers bureau for Abiomed, not relevant to this article. No other relevant disclosures were reported.
A version of this article first appeared on Medscape.com.
The relatively recent innovation of heart transplantation after circulatory death of the donor is increasing the number of donor hearts available and leading to many more lives on the heart transplant waiting list being saved. Experts agree it’s a major and very welcome advance in medicine.
However, some of the processes involved in one approach to donation after circulatory death has raised ethical concerns and questions about whether they violate the “dead donor rule” – a principle that requires patients be declared dead before removal of life-sustaining organs for transplant.
Experts in the fields of transplantation and medical ethics have yet to reach consensus, causing problems for the transplant community, who worry that this could cause a loss of confidence in the entire transplant process.
A new pathway for heart transplantation
The traditional approach to transplantation is to retrieve organs from a donor who has been declared brain dead, known as “donation after brain death (DBD).” These patients have usually suffered a catastrophic brain injury but survived to get to intensive care.
As the brain swells because of injury, it becomes evident that all brain function is lost, and the patient is declared brain dead. However, breathing is maintained by the ventilator and the heart is still beating. Because the organs are being oxygenated, there is no immediate rush to retrieve the organs and the heart can be evaluated for its suitability for transplant in a calm and methodical way before it is removed.
However, there is a massive shortage of organs, especially hearts, partially because of the limited number of donors who are declared brain dead in that setting.
In recent years, another pathway for organ transplantation has become available: “donation after circulatory death (DCD).” These patients also have suffered a catastrophic brain injury considered to be nonsurvivable, but unlike the DBD situation, the brain still has some function, so the patient does not meet the criteria for brain death.
Still, because the patient is considered to have no chance of a meaningful recovery, the family often recognizes the futility of treatment and agrees to the withdrawal of life support. When this happens, the heart normally stops beating after a period of time. There is then a “stand-off time” – normally 5 minutes – after which death is declared and the organs can be removed.
The difficulty with this approach, however, is that because the heart has been stopped, it has been deprived of oxygen, potentially causing injury. While DCD has been practiced for several years to retrieve organs such as the kidney, liver, lungs, and pancreas, the heart is more difficult as it is more susceptible to oxygen deprivation. And for the heart to be assessed for transplant suitability, it should ideally be beating, so it has to be reperfused and restarted quickly after death has been declared.
For many years it was thought the oxygen deprivation that occurs after circulatory death would be too much to provide a functional organ. But researchers in the United Kingdom and Australia developed techniques to overcome this problem, and early DCD heart transplants took place in 2014 in Australia, and in 2015 in the United Kingdom.
Heart transplantation after circulatory death has now become a routine part of the transplant program in many countries, including the United States, Spain, Belgium, the Netherlands, and Austria.
In the United States, 348 DCD heart transplants were performed in 2022, with numbers expected to reach 700 to 800 this year as more centers come online.
It is expected that most countries with heart transplant programs will follow suit and the number of donor hearts will increase by up to 30% worldwide because of DCD.
Currently, there are about 8,000 heart transplants worldwide each year and with DCD this could rise to about 10,000, potentially an extra 2,000 lives saved each year, experts estimate.
Two different approaches to DCD heart transplantation have been developed.
The direct procurement approach
The Australian group, based at St. Vincent’s Hospital in Sydney, developed a technique referred to as “direct procurement”: after the standoff period and declaration of circulatory death, the chest is opened, and the heart is removed. New technology, the Organ Care System (OCS) heart box (Transmedics), is then used to reperfuse and restart the heart outside the body so its suitability for transplant can be assessed.
The heart is kept perfused and beating in the OCS box while it is being transported to the recipient. This has enabled longer transit times than the traditional way of transporting the nonbeating heart on ice.
Peter MacDonald, MD, PhD, from the St Vincent’s group that developed this approach, said, “Most people thought a heart from a DCD donor would not survive transport – that the injury to the heart from the combination of life support withdrawal, stand-off time, and cold storage would be too much. But we modeled the process in the lab and were able to show that we were able to get the heart beating again after withdrawal of life support.”
Dr. McDonald noted that “the recipient of their first human DCD heart transplant using this machine in 2014 is still alive and well.” The Australian group has now done 85 of these DCD heart transplants, and they have increased the number of heart transplant procedures at St. Vincent’s Hospital by 25%.
Normothermic regional perfusion (NRP)
The U.K. group, based at the Royal Papworth Hospital in Cambridge, England, developed a different approach to DCD: After the standoff period and the declaration of circulatory death, the donor is connected to a heart/lung machine using extracorporeal membrane oxygenation (ECMO) so that the heart is perfused and starts beating again inside the body. This approach is known as normothermic regional perfusion (NRP).
Marius Berman, MD, surgical lead for Transplantation and Mechanical Circulatory Support at Papworth, explained that the NRP approach allows the heart to be perfused and restarted faster than direct procurement, resulting in a shorter ischemic time. The heart can be evaluated thoroughly for suitability for transplantation in situ before committing to transplantation, and because the heart is less damaged, it can be transported on ice without use of the OCS box.
“DCD is more complicated than DBD, because the heart has stopped and has to be restarted. Retrieval teams have to be very experienced,” Dr. Berman noted. “This is more of an issue for the direct procurement approach, where the chest has to be opened and the heart retrieved as fast as possible. It is a rush. The longer time without the heart being perfused correlates to an increased incidence of primary graft dysfunction. With NRP, we can get the heart started again more quickly, which is crucial.”
Stephen Large, MBBS, another cardiothoracic surgeon with the Papworth team, added that they have reduced ischemic time to about 15 minutes. “That’s considerably shorter than reperfusing the heart outside the body,” he said. “This results in a healthier organ for the recipient.”
The NRP approach is also less expensive than direct procurement as one OCS box costs about $75,000.
He pointed out that the NRP approach can also be used for heart transplants in children and even small babies, while currently the direct procurement technique is not typically suitable for children because the OCS box was not designed for small hearts.
DCD, using either technique, has increased the heart transplant rate by 40% at Papworth, and is being used at all seven transplant centers in the United Kingdom, “a world first,” noted Dr. Large.
The Papworth team recently published its 5-year experience with 25 NRP transplants and 85 direct procurement transplants. Survival in recipients was no different, although there was some suggestion that the NRP hearts may have been in slightly better condition, possibly being more resistant to immunological rejection.
Ethical concerns about NRP
Restarting the circulation during the NRP process has raised ethical concerns.
When the NRP technique was first used in the United States, these ethical questions were raised by several groups, including the American College of Physicians (ACP).
Harry Peled, MD, Providence St. Jude Medical Center, Fullerton, Calif., coauthor of a recent Viewpoint on the issue, is board-certified in both cardiology and critical care, and said he is a supporter of DCD using direct procurement, but he does not believe that NRP is ethical at present. He is not part of the ACP, but said his views align with those of the organization.
There are two ethical problems with NRP, he said. The first is whether by restarting the circulation, the NRP process violates the U.S. definition of death, and retrieval of organs would therefore violate the dead donor rule.
“American law states that death is the irreversible cessation of brain function or of circulatory function. But with NRP, the circulation is artificially restored, so the cessation of circulatory function is not irreversible,” Dr. Peled pointed out.
“I have no problem with DCD using direct procurement as we are not restarting the circulation. But NRP is restarting the circulation and that is a problem for me,” Dr. Peled said. “I would argue that by performing NRP, we are resuscitating the patient.”
The second ethical problem with NRP is concern about whether, during the process, there would be any circulation to the brain, and if so, would this be enough to restore some brain function? Before NRP is started, the main arch vessel arteries to the head are clamped to prevent flow to the brain, but there are worries that some blood flow may still be possible through small collateral vessels.
“We have established that these patients do not have enough brain function for a meaningful life, which is why a decision has been made to remove life support, but they have not been declared brain dead,” Dr. Peled said.
With direct procurement, the circulation is not restarted so there is no chance that any brain function will be restored, he said. “But with NRP, because the arch vessels have to be clamped to prevent brain circulation, that is admitting there is concern that brain function may be restored if circulation to the brain is reestablished, and brain function is compatible with life. As we do not know whether there is any meaningful circulation to the brain via the small collaterals, there is, in effect, a risk of bringing the patient back to life.”
The other major concern for some is whether even a very small amount of circulation to the brain would be enough to support consciousness, and “we don’t know that for certain,” Dr. Peled said.
The argument for NRP
Nader Moazami, MD, professor of cardiovascular surgery, NYU Langone Health, New York, is one of the more vocal proponents of NRP for DCD heart transplantation in the United States, and has coauthored responses to these ethical concerns.
“People are confusing many issues to produce an argument against NRP,” he said.
“Our position is that death has already been declared based on the lack of circulatory function for over 5 minutes and this has been with the full agreement of the family, knowing that the patient has no chance of a meaningful life. No one is thinking of trying to resuscitate the patient. It has already been established that any future efforts to resuscitate are futile. In this case, we are not resuscitating the patient by restarting the circulation. It is just regional perfusion of the organs.”
Dr. Moazami pointed out this concept was accepted for the practice of abdominal DCD when it first started in the United States in the 1990s where cold perfusion was used to preserve the abdominal organs before they were retrieved from the body.
“The new approach of using NRP is similar except that it involves circulating warm blood, which will preserve organs better and result in higher quality organs for the recipient.”
On the issue of concern about possible circulation to the brain, Dr. Moazami said: “The ethical critics of NRP are questioning whether the brain may not be dead. We are arguing that the patient has already been declared dead as they have had a circulatory death. You cannot die twice.”
He maintained that the clamping of the arch vessels to the head will ensure that when the circulation is restarted “the natural process of circulatory death leading to brain death will continue to progress.”
On the concerns about possible collateral flow to the brain, Dr. Moazami said there is no evidence that this occurs. “Prominent neurologists have said it is impossible for collaterals to provide any meaningful blood flow to the brain in this situation. And even if there is small amount of blood flow to the brain, this would be insufficient to maintain any meaningful brain function.”
But Dr. Peled argues that this has not been proved. “Even though we don’t think there is enough circulation to the brain for any function with NRP, we don’t know that with 100% certainty,” he said. “In my view, if there is a possibility of even the smallest amount of brain flow, we are going against the dead donor rule. We are rewriting the rules of death.”
Dr. Moazami countered: “Nothing in life is 100%, particularly in medicine. With that argument can you also prove with 100% certainty to me that there is absolutely no brain function with regular direct procurement DCD? We know that brain death has started, but the question is: Has it been completed? We don’t know the answer to this question with 100% certainty, but that is the case for regular direct procurement DCD as well, and that has been accepted by almost everyone.
“The whole issue revolves around when are we comfortable that death has occurred,” he said. “Those against NRP are concerned that organs are being taken before the patient is dead. But the key point is that the patient has already been declared dead.”
Since there is some concern over the ethics of NRP, why not just stick to DCD with direct procurement?
Dr. Moazami argued that NRP results in healthier organs. “NRP allows more successful heart transplants, liver transplants, lung transplants. It preserves all the organs better,” he said. “This will have a big impact on recipients – they would obviously much prefer a healthier organ. In addition, the process is easier and cheaper, so more centers will be able to do it, therefore more transplants will get done and more lives will be saved if NRP is used.”
He added: “I am a physician taking care of sick patients. I believe I have to respect the wishes of the donor and the donor family; make sure I’m not doing any harm to the donor; and ensure the best quality possible of the organ I am retrieving to best serve the recipient. I am happy I am doing this by using NRP for DCD heart transplantation.”
But Dr. Peled argued that while NRP may have some possible advantages over direct procurement, that does not justify allowing a process to go ahead that is unethical.
“The fact that NRP may result in some benefits doesn’t justify violating the dead donor rule or the possibility, however small, of causing pain to the donor. If it’s unethical, it’s unethical. Full stop,” he said.
“I feel that NRP is not respecting the rights of our patients and that the process does not have adequate transparency. We took it to our local ethics committee, and they decided not to approve NRP in our health care system. I agree with this decision,” Dr. Peled said.
“The trouble is different experts and different countries are not in agreement about this,” he added. “Reasonable, well-informed people are in disagreement. I do not believe we can have a standard of care where there is not consensus.”
Cautious nod
In a 2022 consensus statement, the International Society for Heart and Lung Transplantation (ISHLT) gave a cautious nod toward DCD and NRP, dependent on local recommendations.
The ISHLT conclusion reads: “With appropriate consideration of the ethical principles involved in organ donation, DCD can be undertaken in a morally permissible manner. In all cases, the introduction of DCD programs should be in accordance with local legal regulations. Countries lacking a DCD pathway should be encouraged to develop national ethical, professional, and legal frameworks to address both public and professional concerns.”
The author of a recent editorial on the subject, Ulrich P. Jorde, MD, head of the heart transplant program at Montefiore Medical Center, New York, said, “DCD is a great step forward. People regularly die on the heart transplant waiting list. DCD will increase the supply of donor hearts by 20% to 30%.”
However, he noted that while most societies have agreed on a protocol for organ donation based on brain death, the situation is more complicated with circulatory death.
“Different countries have different definitions of circulatory death. How long do we have to wait after the heart has stopped beating before the patient is declared dead? Most countries have agreed on 5 minutes, but other countries have imposed different periods and as such, different definitions of death.
“The ISHLT statement says that restarting the circulation is acceptable if death has been certified according to prevailing law and surgical interventions are undertaken to preclude any restoration of cerebral circulation. But our problem is that different regional societies have different definitions of circulatory, death which makes the situation confusing.”
Dr. Jorde added: “We also have to weigh the wishes of the donor and their family. If family, advocating what are presumed to be the donor’s wishes, have decided that DCD would be acceptable and they understand the concept and wish to donate the organs after circulatory death, this should be strongly considered under the concept of self-determination, a basic human right.”
Variations in practice around the world
This ethical debate has led to large variations in practice around the world, with some countries, such as Spain, allowing both methods of DCD, while Australia allows direct procurement but not NRP, and Germany currently does not allow DCD at all.
In the United States, things are even more complicated, with some states allowing NRP while others don’t. Even within states, some hospitals and transplant organizations allow NRP, and others don’t.
David A. D’Alessandro, MD, cardiac surgeon at Massachusetts General Hospital, Boston, uses only the direct procurement approach as his region does not allow NRP.
“The direct procurement approach is not controversial and to me that’s a big advantage. I believe we need to agree on the ethics first, and then get into a debate about which technique is better,” he told this news organization.
Dr. D’Alessandro and his group recently published the results of their study, with direct procurement DCD heart transplantation showing similar short-term clinical outcomes to DBD.
“We are only doing direct procurement and we are seeing good results that appear to be comparable to DBD. That is good enough for me,” he said.
Dr. D’Alessandro estimates that in the United States both types of DCD procedures are currently being done about equally.
“Anything we can do to increase the amount of hearts available for transplantation is a big deal,” he said. “At the moment, only the very sickest patients get a heart transplant, and many patients die on the transplant waiting list. Very sadly, many young people die every year from a circulatory death after having life support withdrawn. Before DCD, these beautiful functional organs were not able to be used. Now we have a way of saving lives with these organs.”
Dr. D’Alessandro noted that more and more centers in the United States are starting to perform DCD heart transplants.
“Not every transplant center may join in as the DCD procedures are very resource-intensive and time-consuming. For low-volume transplant centers, it may not be worth the expense and anguish to do DCD heart transplants. But bigger centers will need to engage in DCD to remain competitive. My guess is that 50%-70% of U.S. transplant centers will do DCD in future.”
He said he thinks it is a “medical shortcoming” that agreement cannot be reached on the ethics of NRP. “In an ideal world everyone would be on the same page. It makes me a bit uncomfortable that some people think it’s okay and some people don’t.”
Adam DeVore, MD, a cardiologist at Duke University Medical Center, Durham, N.C., the first U.S. center to perform an adult DCD heart transplant, reported that his institution uses both methods, with the choice sometimes depending on how far the heart must travel.
“If the recipient is near, NRP may be chosen as the heart is transported on ice, but if it needs to go further away we are more likely to choose direct procurement and use of the OCS box,” he said.
“I am really proud of what we’ve been able to do, helping to introduce DCD in the U.S.,” Dr. DeVore said. “This is having a massive benefit in increasing the number of hearts for donation with great outcomes.”
But he acknowledged that the whole concept of DCD is somewhat controversial.
“The idea of brain death really came about for the purpose of heart donation. The two things are very intricately tied. Trying to do heart donation without brain death having been declared is foreign to people. Also, in DCD there is the issue of [this]: When life support is removed, how long do we wait before death can be declared? That could be in conflict with how long the organ needs to remain viable. We are going through the process now of looking at these questions. There is a lot of variation in the U.S. about the withdrawal of care and the declaration of death, which is not completely standardized.
“But the concept of circulatory death itself is accepted after the withdrawal of life support. I think it’s the rush to take the organs out that makes it more difficult.”
Dr. DeVore said the field is moving forward now. “As the process has become more common, people have become more comfortable, probably because of the big difference it will make to saving lives. But we do need to try and standardize best practices.”
A recent Canadian review of the ethics of DCD concluded that the direct procurement approach would be in alignment with current medical guidelines, but that further work is required to evaluate the consistency of NRP with current Canadian death determination policy and to ensure the absence of brain perfusion during this process.
In the United Kingdom, the definition of death is brain-based, and brain death is defined on a neurological basis.
Dr. Stephen Large from Papworth explained that this recognizes the presence of brain-stem death through brain stem reflex testing after the withdrawal of life support, cardiorespiratory arrest and 5 further minutes of ischemia. As long as NRP does not restore intracranial (brainstem) perfusion after death has been confirmed, then it is consistent with laws for death determination and therefore both direct procurement and NRP are permissible.
However, the question over possible collateral flow to the brain has led the United Kingdom to pause the NRP technique as routine practice while this is investigated further. So, at the present time, the vast majority of DCD heart transplants are being conducted using the direct procurement approach.
But the United Kingdom is facing the bigger challenge: national funding that will soon end. “The DCD program in the U.K. has been extremely successful, increasing heart transplant rates by up to 28%,” Dr. Berman said. “Everybody wants it to continue. But at present the DCD program only has national funding in the U.K. until March 2023. We don’t know what will happen after that.”
The current model in the United Kingdom consists of three specialized DCD heart retrieval teams, a national protocol of direct organ procurement and delivery of DCD hearts to all seven transplant programs, both adult and pediatric.
If the national funding is not extended, “we will go back to individual hospitals trying to fund their own programs. That will be a serious threat to the program and could result in a large reduction in heart transplants,” said Dr. Berman.
Definition of death
The crux of the issue with regard to NRP seems to be variations in how death is defined and the interpretation of those definitions.
DCD donors will have had many tests indicating severe brain damage, a neurologist will have declared the prognosis is futile, and relatives will have agreed to withdraw life support, Dr. Jorde said. “The heart stops beating, and the stand-off time means that blood flow to the brain ceases completely for at least 5 minutes before circulatory death is declared. This is enough on its own to stop brain function.”
Dr. Large made the point that by the time the circulation is reestablished with NRP, more time has elapsed, and the brain will have been without perfusion for much longer than 5 minutes, so it would be “physiologically almost impossible” for there to be any blood flow to the brain.
“Because these brains are already very damaged before life support was removed, the intracranial pressure is high, which will further discourage blood flow to the brain,” he said. Then the donor goes through a period of anoxic heart arrest, up to 16 minutes at a minimum of no blood supply, enough on its own to stop meaningful brain function.
“It’s asking an awful lot to believe that there might be any brain function left,” he said. “And if, on reestablishing the circulation with NRP, there is any blood in the collaterals, the pressure of such flow is so low it won’t enter the brain.”
Dr. Large also pointed out that the fact that the United Kingdom requires a neurologic definition for brain-stem death makes the process easier.
In Australia, St. Vincent’s cardiologist Dr. MacDonald noted that death is defined as the irreversible cessation of circulation, so the NRP procedure is not allowed.
“With NRP, there is an ethical dilemma over whether the patient has legally died or not. Different countries have different ways of defining death. Perhaps society will have to review of the definition of death,” he suggested. Death is a process, “but for organ donation, we have to choose a moment in time of that process that satisfies everyone – when there is no prospect of recovery of the donor but the organs can still be utilized without harming the donor.”
Dr. MacDonald said the field is in transition. “I don’t want to argue that one technique is better than the other; I think it’s good to have access to both techniques. Anything that will increase the number of transplants we can do is a good thing.”
Collaborative decision
Everyone seems to agree that there should be an effort to try to define death in a uniform way worldwide, and that international, national and local regulations are aligned with each other.
Dr. Jorde said: “It is of critical importance that local guidelines are streamlined, firstly in any one given country and then globally, and these things must be discussed transparently within society with all stakeholders – doctors, patients, citizens.”
Dr. Peled, from Providence St. Jude in California, concurred: “There is the possibility that we could change the definition of death, but that cannot be a decision based solely on transplant organizations. It has to be a collaborative decision with a large input from groups who do not have an interest in the procurement of organs.”
He added: “The dialogue so far has been civil, and everybody is trying to do the right thing. My hope is that as a civilized society we will figure out a way forward. At present, there is significant controversy about NRP, and families need to know that. My main concern is that if there is any lack of transparency in getting informed consent, then this risks people losing trust in the donation system.”
Dr. Moazami, from NYU Langone, said the controversy has cast a cloud over the practice of NRP throughout the world. “We need to get it sorted out.”
He said he believes the way forward is to settle the question of whether there is any meaningful blood flow to the brain with the NRP technique.
“This is where the research has to focus. I believe this concern is hypothetical, but I am happy to do the studies to confirm that. Then, the issue should come to a rest. I think that is the right way forward – to do the studies rather than enforcing a moratorium on the practice because of a hypothetical concern.”
These studies on blood flow to the brain are now getting started in both the United Kingdom and the United States.
The U.K. study is being run by Antonio Rubino, MD, consultant in cardiothoracic anesthesia and intensive care at Papworth Hospital NHS Foundation and clinical lead, organ donation. Dr. Rubino explained that the study will assess cerebral blood flow using CT angiography of the brain. “We hypothesize that this will provide evidence to indicate that brain blood flow is not present during NRP and promote trust in the use of NRP in routine practice,” he said.
Dr. Large said: “Rather than having these tortured arguments, we will do the measurements. For the sake of society in this situation, I think it’s good to stop and take a breath. We must measure this, and we are doing just that.”
If there is any blood flow at all, Dr. Large said they will then have to seek expert guidance. “Say we find there is 50 mL of blood flow and normal blood flow is 1,500 mL/min. We will need expert guidance on whether it is remotely possible to be sentient on that. I would say it would be extraordinarily unlikely.”
Dr. Berman summarized the situation: “DCD is increasing the availability of hearts for transplant. This is saving lives, reducing the number of patients on the waiting list, and reducing hospital stays for patients unable to leave the hospital without a transplant. It is definitely here to stay. It is crucial that it gets funded properly, and it is also crucial that we resolve the NRP ethical issues as soon as possible.”
He is hopeful that some of these issues will be resolved this year.
Dr. MacDonald reported he has received “in-kind” support from Transmedics through provision of research modules for preclinical research studies. Dr. D’Alessandro reported he is on the speakers bureau for Abiomed, not relevant to this article. No other relevant disclosures were reported.
A version of this article first appeared on Medscape.com.
The relatively recent innovation of heart transplantation after circulatory death of the donor is increasing the number of donor hearts available and leading to many more lives on the heart transplant waiting list being saved. Experts agree it’s a major and very welcome advance in medicine.
However, some of the processes involved in one approach to donation after circulatory death has raised ethical concerns and questions about whether they violate the “dead donor rule” – a principle that requires patients be declared dead before removal of life-sustaining organs for transplant.
Experts in the fields of transplantation and medical ethics have yet to reach consensus, causing problems for the transplant community, who worry that this could cause a loss of confidence in the entire transplant process.
A new pathway for heart transplantation
The traditional approach to transplantation is to retrieve organs from a donor who has been declared brain dead, known as “donation after brain death (DBD).” These patients have usually suffered a catastrophic brain injury but survived to get to intensive care.
As the brain swells because of injury, it becomes evident that all brain function is lost, and the patient is declared brain dead. However, breathing is maintained by the ventilator and the heart is still beating. Because the organs are being oxygenated, there is no immediate rush to retrieve the organs and the heart can be evaluated for its suitability for transplant in a calm and methodical way before it is removed.
However, there is a massive shortage of organs, especially hearts, partially because of the limited number of donors who are declared brain dead in that setting.
In recent years, another pathway for organ transplantation has become available: “donation after circulatory death (DCD).” These patients also have suffered a catastrophic brain injury considered to be nonsurvivable, but unlike the DBD situation, the brain still has some function, so the patient does not meet the criteria for brain death.
Still, because the patient is considered to have no chance of a meaningful recovery, the family often recognizes the futility of treatment and agrees to the withdrawal of life support. When this happens, the heart normally stops beating after a period of time. There is then a “stand-off time” – normally 5 minutes – after which death is declared and the organs can be removed.
The difficulty with this approach, however, is that because the heart has been stopped, it has been deprived of oxygen, potentially causing injury. While DCD has been practiced for several years to retrieve organs such as the kidney, liver, lungs, and pancreas, the heart is more difficult as it is more susceptible to oxygen deprivation. And for the heart to be assessed for transplant suitability, it should ideally be beating, so it has to be reperfused and restarted quickly after death has been declared.
For many years it was thought the oxygen deprivation that occurs after circulatory death would be too much to provide a functional organ. But researchers in the United Kingdom and Australia developed techniques to overcome this problem, and early DCD heart transplants took place in 2014 in Australia, and in 2015 in the United Kingdom.
Heart transplantation after circulatory death has now become a routine part of the transplant program in many countries, including the United States, Spain, Belgium, the Netherlands, and Austria.
In the United States, 348 DCD heart transplants were performed in 2022, with numbers expected to reach 700 to 800 this year as more centers come online.
It is expected that most countries with heart transplant programs will follow suit and the number of donor hearts will increase by up to 30% worldwide because of DCD.
Currently, there are about 8,000 heart transplants worldwide each year and with DCD this could rise to about 10,000, potentially an extra 2,000 lives saved each year, experts estimate.
Two different approaches to DCD heart transplantation have been developed.
The direct procurement approach
The Australian group, based at St. Vincent’s Hospital in Sydney, developed a technique referred to as “direct procurement”: after the standoff period and declaration of circulatory death, the chest is opened, and the heart is removed. New technology, the Organ Care System (OCS) heart box (Transmedics), is then used to reperfuse and restart the heart outside the body so its suitability for transplant can be assessed.
The heart is kept perfused and beating in the OCS box while it is being transported to the recipient. This has enabled longer transit times than the traditional way of transporting the nonbeating heart on ice.
Peter MacDonald, MD, PhD, from the St Vincent’s group that developed this approach, said, “Most people thought a heart from a DCD donor would not survive transport – that the injury to the heart from the combination of life support withdrawal, stand-off time, and cold storage would be too much. But we modeled the process in the lab and were able to show that we were able to get the heart beating again after withdrawal of life support.”
Dr. McDonald noted that “the recipient of their first human DCD heart transplant using this machine in 2014 is still alive and well.” The Australian group has now done 85 of these DCD heart transplants, and they have increased the number of heart transplant procedures at St. Vincent’s Hospital by 25%.
Normothermic regional perfusion (NRP)
The U.K. group, based at the Royal Papworth Hospital in Cambridge, England, developed a different approach to DCD: After the standoff period and the declaration of circulatory death, the donor is connected to a heart/lung machine using extracorporeal membrane oxygenation (ECMO) so that the heart is perfused and starts beating again inside the body. This approach is known as normothermic regional perfusion (NRP).
Marius Berman, MD, surgical lead for Transplantation and Mechanical Circulatory Support at Papworth, explained that the NRP approach allows the heart to be perfused and restarted faster than direct procurement, resulting in a shorter ischemic time. The heart can be evaluated thoroughly for suitability for transplantation in situ before committing to transplantation, and because the heart is less damaged, it can be transported on ice without use of the OCS box.
“DCD is more complicated than DBD, because the heart has stopped and has to be restarted. Retrieval teams have to be very experienced,” Dr. Berman noted. “This is more of an issue for the direct procurement approach, where the chest has to be opened and the heart retrieved as fast as possible. It is a rush. The longer time without the heart being perfused correlates to an increased incidence of primary graft dysfunction. With NRP, we can get the heart started again more quickly, which is crucial.”
Stephen Large, MBBS, another cardiothoracic surgeon with the Papworth team, added that they have reduced ischemic time to about 15 minutes. “That’s considerably shorter than reperfusing the heart outside the body,” he said. “This results in a healthier organ for the recipient.”
The NRP approach is also less expensive than direct procurement as one OCS box costs about $75,000.
He pointed out that the NRP approach can also be used for heart transplants in children and even small babies, while currently the direct procurement technique is not typically suitable for children because the OCS box was not designed for small hearts.
DCD, using either technique, has increased the heart transplant rate by 40% at Papworth, and is being used at all seven transplant centers in the United Kingdom, “a world first,” noted Dr. Large.
The Papworth team recently published its 5-year experience with 25 NRP transplants and 85 direct procurement transplants. Survival in recipients was no different, although there was some suggestion that the NRP hearts may have been in slightly better condition, possibly being more resistant to immunological rejection.
Ethical concerns about NRP
Restarting the circulation during the NRP process has raised ethical concerns.
When the NRP technique was first used in the United States, these ethical questions were raised by several groups, including the American College of Physicians (ACP).
Harry Peled, MD, Providence St. Jude Medical Center, Fullerton, Calif., coauthor of a recent Viewpoint on the issue, is board-certified in both cardiology and critical care, and said he is a supporter of DCD using direct procurement, but he does not believe that NRP is ethical at present. He is not part of the ACP, but said his views align with those of the organization.
There are two ethical problems with NRP, he said. The first is whether by restarting the circulation, the NRP process violates the U.S. definition of death, and retrieval of organs would therefore violate the dead donor rule.
“American law states that death is the irreversible cessation of brain function or of circulatory function. But with NRP, the circulation is artificially restored, so the cessation of circulatory function is not irreversible,” Dr. Peled pointed out.
“I have no problem with DCD using direct procurement as we are not restarting the circulation. But NRP is restarting the circulation and that is a problem for me,” Dr. Peled said. “I would argue that by performing NRP, we are resuscitating the patient.”
The second ethical problem with NRP is concern about whether, during the process, there would be any circulation to the brain, and if so, would this be enough to restore some brain function? Before NRP is started, the main arch vessel arteries to the head are clamped to prevent flow to the brain, but there are worries that some blood flow may still be possible through small collateral vessels.
“We have established that these patients do not have enough brain function for a meaningful life, which is why a decision has been made to remove life support, but they have not been declared brain dead,” Dr. Peled said.
With direct procurement, the circulation is not restarted so there is no chance that any brain function will be restored, he said. “But with NRP, because the arch vessels have to be clamped to prevent brain circulation, that is admitting there is concern that brain function may be restored if circulation to the brain is reestablished, and brain function is compatible with life. As we do not know whether there is any meaningful circulation to the brain via the small collaterals, there is, in effect, a risk of bringing the patient back to life.”
The other major concern for some is whether even a very small amount of circulation to the brain would be enough to support consciousness, and “we don’t know that for certain,” Dr. Peled said.
The argument for NRP
Nader Moazami, MD, professor of cardiovascular surgery, NYU Langone Health, New York, is one of the more vocal proponents of NRP for DCD heart transplantation in the United States, and has coauthored responses to these ethical concerns.
“People are confusing many issues to produce an argument against NRP,” he said.
“Our position is that death has already been declared based on the lack of circulatory function for over 5 minutes and this has been with the full agreement of the family, knowing that the patient has no chance of a meaningful life. No one is thinking of trying to resuscitate the patient. It has already been established that any future efforts to resuscitate are futile. In this case, we are not resuscitating the patient by restarting the circulation. It is just regional perfusion of the organs.”
Dr. Moazami pointed out this concept was accepted for the practice of abdominal DCD when it first started in the United States in the 1990s where cold perfusion was used to preserve the abdominal organs before they were retrieved from the body.
“The new approach of using NRP is similar except that it involves circulating warm blood, which will preserve organs better and result in higher quality organs for the recipient.”
On the issue of concern about possible circulation to the brain, Dr. Moazami said: “The ethical critics of NRP are questioning whether the brain may not be dead. We are arguing that the patient has already been declared dead as they have had a circulatory death. You cannot die twice.”
He maintained that the clamping of the arch vessels to the head will ensure that when the circulation is restarted “the natural process of circulatory death leading to brain death will continue to progress.”
On the concerns about possible collateral flow to the brain, Dr. Moazami said there is no evidence that this occurs. “Prominent neurologists have said it is impossible for collaterals to provide any meaningful blood flow to the brain in this situation. And even if there is small amount of blood flow to the brain, this would be insufficient to maintain any meaningful brain function.”
But Dr. Peled argues that this has not been proved. “Even though we don’t think there is enough circulation to the brain for any function with NRP, we don’t know that with 100% certainty,” he said. “In my view, if there is a possibility of even the smallest amount of brain flow, we are going against the dead donor rule. We are rewriting the rules of death.”
Dr. Moazami countered: “Nothing in life is 100%, particularly in medicine. With that argument can you also prove with 100% certainty to me that there is absolutely no brain function with regular direct procurement DCD? We know that brain death has started, but the question is: Has it been completed? We don’t know the answer to this question with 100% certainty, but that is the case for regular direct procurement DCD as well, and that has been accepted by almost everyone.
“The whole issue revolves around when are we comfortable that death has occurred,” he said. “Those against NRP are concerned that organs are being taken before the patient is dead. But the key point is that the patient has already been declared dead.”
Since there is some concern over the ethics of NRP, why not just stick to DCD with direct procurement?
Dr. Moazami argued that NRP results in healthier organs. “NRP allows more successful heart transplants, liver transplants, lung transplants. It preserves all the organs better,” he said. “This will have a big impact on recipients – they would obviously much prefer a healthier organ. In addition, the process is easier and cheaper, so more centers will be able to do it, therefore more transplants will get done and more lives will be saved if NRP is used.”
He added: “I am a physician taking care of sick patients. I believe I have to respect the wishes of the donor and the donor family; make sure I’m not doing any harm to the donor; and ensure the best quality possible of the organ I am retrieving to best serve the recipient. I am happy I am doing this by using NRP for DCD heart transplantation.”
But Dr. Peled argued that while NRP may have some possible advantages over direct procurement, that does not justify allowing a process to go ahead that is unethical.
“The fact that NRP may result in some benefits doesn’t justify violating the dead donor rule or the possibility, however small, of causing pain to the donor. If it’s unethical, it’s unethical. Full stop,” he said.
“I feel that NRP is not respecting the rights of our patients and that the process does not have adequate transparency. We took it to our local ethics committee, and they decided not to approve NRP in our health care system. I agree with this decision,” Dr. Peled said.
“The trouble is different experts and different countries are not in agreement about this,” he added. “Reasonable, well-informed people are in disagreement. I do not believe we can have a standard of care where there is not consensus.”
Cautious nod
In a 2022 consensus statement, the International Society for Heart and Lung Transplantation (ISHLT) gave a cautious nod toward DCD and NRP, dependent on local recommendations.
The ISHLT conclusion reads: “With appropriate consideration of the ethical principles involved in organ donation, DCD can be undertaken in a morally permissible manner. In all cases, the introduction of DCD programs should be in accordance with local legal regulations. Countries lacking a DCD pathway should be encouraged to develop national ethical, professional, and legal frameworks to address both public and professional concerns.”
The author of a recent editorial on the subject, Ulrich P. Jorde, MD, head of the heart transplant program at Montefiore Medical Center, New York, said, “DCD is a great step forward. People regularly die on the heart transplant waiting list. DCD will increase the supply of donor hearts by 20% to 30%.”
However, he noted that while most societies have agreed on a protocol for organ donation based on brain death, the situation is more complicated with circulatory death.
“Different countries have different definitions of circulatory death. How long do we have to wait after the heart has stopped beating before the patient is declared dead? Most countries have agreed on 5 minutes, but other countries have imposed different periods and as such, different definitions of death.
“The ISHLT statement says that restarting the circulation is acceptable if death has been certified according to prevailing law and surgical interventions are undertaken to preclude any restoration of cerebral circulation. But our problem is that different regional societies have different definitions of circulatory, death which makes the situation confusing.”
Dr. Jorde added: “We also have to weigh the wishes of the donor and their family. If family, advocating what are presumed to be the donor’s wishes, have decided that DCD would be acceptable and they understand the concept and wish to donate the organs after circulatory death, this should be strongly considered under the concept of self-determination, a basic human right.”
Variations in practice around the world
This ethical debate has led to large variations in practice around the world, with some countries, such as Spain, allowing both methods of DCD, while Australia allows direct procurement but not NRP, and Germany currently does not allow DCD at all.
In the United States, things are even more complicated, with some states allowing NRP while others don’t. Even within states, some hospitals and transplant organizations allow NRP, and others don’t.
David A. D’Alessandro, MD, cardiac surgeon at Massachusetts General Hospital, Boston, uses only the direct procurement approach as his region does not allow NRP.
“The direct procurement approach is not controversial and to me that’s a big advantage. I believe we need to agree on the ethics first, and then get into a debate about which technique is better,” he told this news organization.
Dr. D’Alessandro and his group recently published the results of their study, with direct procurement DCD heart transplantation showing similar short-term clinical outcomes to DBD.
“We are only doing direct procurement and we are seeing good results that appear to be comparable to DBD. That is good enough for me,” he said.
Dr. D’Alessandro estimates that in the United States both types of DCD procedures are currently being done about equally.
“Anything we can do to increase the amount of hearts available for transplantation is a big deal,” he said. “At the moment, only the very sickest patients get a heart transplant, and many patients die on the transplant waiting list. Very sadly, many young people die every year from a circulatory death after having life support withdrawn. Before DCD, these beautiful functional organs were not able to be used. Now we have a way of saving lives with these organs.”
Dr. D’Alessandro noted that more and more centers in the United States are starting to perform DCD heart transplants.
“Not every transplant center may join in as the DCD procedures are very resource-intensive and time-consuming. For low-volume transplant centers, it may not be worth the expense and anguish to do DCD heart transplants. But bigger centers will need to engage in DCD to remain competitive. My guess is that 50%-70% of U.S. transplant centers will do DCD in future.”
He said he thinks it is a “medical shortcoming” that agreement cannot be reached on the ethics of NRP. “In an ideal world everyone would be on the same page. It makes me a bit uncomfortable that some people think it’s okay and some people don’t.”
Adam DeVore, MD, a cardiologist at Duke University Medical Center, Durham, N.C., the first U.S. center to perform an adult DCD heart transplant, reported that his institution uses both methods, with the choice sometimes depending on how far the heart must travel.
“If the recipient is near, NRP may be chosen as the heart is transported on ice, but if it needs to go further away we are more likely to choose direct procurement and use of the OCS box,” he said.
“I am really proud of what we’ve been able to do, helping to introduce DCD in the U.S.,” Dr. DeVore said. “This is having a massive benefit in increasing the number of hearts for donation with great outcomes.”
But he acknowledged that the whole concept of DCD is somewhat controversial.
“The idea of brain death really came about for the purpose of heart donation. The two things are very intricately tied. Trying to do heart donation without brain death having been declared is foreign to people. Also, in DCD there is the issue of [this]: When life support is removed, how long do we wait before death can be declared? That could be in conflict with how long the organ needs to remain viable. We are going through the process now of looking at these questions. There is a lot of variation in the U.S. about the withdrawal of care and the declaration of death, which is not completely standardized.
“But the concept of circulatory death itself is accepted after the withdrawal of life support. I think it’s the rush to take the organs out that makes it more difficult.”
Dr. DeVore said the field is moving forward now. “As the process has become more common, people have become more comfortable, probably because of the big difference it will make to saving lives. But we do need to try and standardize best practices.”
A recent Canadian review of the ethics of DCD concluded that the direct procurement approach would be in alignment with current medical guidelines, but that further work is required to evaluate the consistency of NRP with current Canadian death determination policy and to ensure the absence of brain perfusion during this process.
In the United Kingdom, the definition of death is brain-based, and brain death is defined on a neurological basis.
Dr. Stephen Large from Papworth explained that this recognizes the presence of brain-stem death through brain stem reflex testing after the withdrawal of life support, cardiorespiratory arrest and 5 further minutes of ischemia. As long as NRP does not restore intracranial (brainstem) perfusion after death has been confirmed, then it is consistent with laws for death determination and therefore both direct procurement and NRP are permissible.
However, the question over possible collateral flow to the brain has led the United Kingdom to pause the NRP technique as routine practice while this is investigated further. So, at the present time, the vast majority of DCD heart transplants are being conducted using the direct procurement approach.
But the United Kingdom is facing the bigger challenge: national funding that will soon end. “The DCD program in the U.K. has been extremely successful, increasing heart transplant rates by up to 28%,” Dr. Berman said. “Everybody wants it to continue. But at present the DCD program only has national funding in the U.K. until March 2023. We don’t know what will happen after that.”
The current model in the United Kingdom consists of three specialized DCD heart retrieval teams, a national protocol of direct organ procurement and delivery of DCD hearts to all seven transplant programs, both adult and pediatric.
If the national funding is not extended, “we will go back to individual hospitals trying to fund their own programs. That will be a serious threat to the program and could result in a large reduction in heart transplants,” said Dr. Berman.
Definition of death
The crux of the issue with regard to NRP seems to be variations in how death is defined and the interpretation of those definitions.
DCD donors will have had many tests indicating severe brain damage, a neurologist will have declared the prognosis is futile, and relatives will have agreed to withdraw life support, Dr. Jorde said. “The heart stops beating, and the stand-off time means that blood flow to the brain ceases completely for at least 5 minutes before circulatory death is declared. This is enough on its own to stop brain function.”
Dr. Large made the point that by the time the circulation is reestablished with NRP, more time has elapsed, and the brain will have been without perfusion for much longer than 5 minutes, so it would be “physiologically almost impossible” for there to be any blood flow to the brain.
“Because these brains are already very damaged before life support was removed, the intracranial pressure is high, which will further discourage blood flow to the brain,” he said. Then the donor goes through a period of anoxic heart arrest, up to 16 minutes at a minimum of no blood supply, enough on its own to stop meaningful brain function.
“It’s asking an awful lot to believe that there might be any brain function left,” he said. “And if, on reestablishing the circulation with NRP, there is any blood in the collaterals, the pressure of such flow is so low it won’t enter the brain.”
Dr. Large also pointed out that the fact that the United Kingdom requires a neurologic definition for brain-stem death makes the process easier.
In Australia, St. Vincent’s cardiologist Dr. MacDonald noted that death is defined as the irreversible cessation of circulation, so the NRP procedure is not allowed.
“With NRP, there is an ethical dilemma over whether the patient has legally died or not. Different countries have different ways of defining death. Perhaps society will have to review of the definition of death,” he suggested. Death is a process, “but for organ donation, we have to choose a moment in time of that process that satisfies everyone – when there is no prospect of recovery of the donor but the organs can still be utilized without harming the donor.”
Dr. MacDonald said the field is in transition. “I don’t want to argue that one technique is better than the other; I think it’s good to have access to both techniques. Anything that will increase the number of transplants we can do is a good thing.”
Collaborative decision
Everyone seems to agree that there should be an effort to try to define death in a uniform way worldwide, and that international, national and local regulations are aligned with each other.
Dr. Jorde said: “It is of critical importance that local guidelines are streamlined, firstly in any one given country and then globally, and these things must be discussed transparently within society with all stakeholders – doctors, patients, citizens.”
Dr. Peled, from Providence St. Jude in California, concurred: “There is the possibility that we could change the definition of death, but that cannot be a decision based solely on transplant organizations. It has to be a collaborative decision with a large input from groups who do not have an interest in the procurement of organs.”
He added: “The dialogue so far has been civil, and everybody is trying to do the right thing. My hope is that as a civilized society we will figure out a way forward. At present, there is significant controversy about NRP, and families need to know that. My main concern is that if there is any lack of transparency in getting informed consent, then this risks people losing trust in the donation system.”
Dr. Moazami, from NYU Langone, said the controversy has cast a cloud over the practice of NRP throughout the world. “We need to get it sorted out.”
He said he believes the way forward is to settle the question of whether there is any meaningful blood flow to the brain with the NRP technique.
“This is where the research has to focus. I believe this concern is hypothetical, but I am happy to do the studies to confirm that. Then, the issue should come to a rest. I think that is the right way forward – to do the studies rather than enforcing a moratorium on the practice because of a hypothetical concern.”
These studies on blood flow to the brain are now getting started in both the United Kingdom and the United States.
The U.K. study is being run by Antonio Rubino, MD, consultant in cardiothoracic anesthesia and intensive care at Papworth Hospital NHS Foundation and clinical lead, organ donation. Dr. Rubino explained that the study will assess cerebral blood flow using CT angiography of the brain. “We hypothesize that this will provide evidence to indicate that brain blood flow is not present during NRP and promote trust in the use of NRP in routine practice,” he said.
Dr. Large said: “Rather than having these tortured arguments, we will do the measurements. For the sake of society in this situation, I think it’s good to stop and take a breath. We must measure this, and we are doing just that.”
If there is any blood flow at all, Dr. Large said they will then have to seek expert guidance. “Say we find there is 50 mL of blood flow and normal blood flow is 1,500 mL/min. We will need expert guidance on whether it is remotely possible to be sentient on that. I would say it would be extraordinarily unlikely.”
Dr. Berman summarized the situation: “DCD is increasing the availability of hearts for transplant. This is saving lives, reducing the number of patients on the waiting list, and reducing hospital stays for patients unable to leave the hospital without a transplant. It is definitely here to stay. It is crucial that it gets funded properly, and it is also crucial that we resolve the NRP ethical issues as soon as possible.”
He is hopeful that some of these issues will be resolved this year.
Dr. MacDonald reported he has received “in-kind” support from Transmedics through provision of research modules for preclinical research studies. Dr. D’Alessandro reported he is on the speakers bureau for Abiomed, not relevant to this article. No other relevant disclosures were reported.
A version of this article first appeared on Medscape.com.
Poor bone health is a ‘robust’ dementia risk factor
After adjusting for relevant factors, adults with the lowest versus highest BMD at the femoral neck were 42% more likely to develop dementia over roughly 10 years.
“Our research has found a link between bone loss and dementia, but further studies are needed to better understand this connection between bone density and memory loss,” study investigator Mohammad Arfan Ikram, MD, PhD, with Erasmus University Medical Center in Rotterdam, the Netherlands, said in a statement.
“It’s possible that bone loss may occur already in the earliest phases of dementia, years before any clinical symptoms manifest themselves. If that were the case, bone loss could be an indicator of risk for dementia and people with bone loss could be targeted for screening and improved care,” Dr. Ikram added.
The study was published online in Neurology.
Common bedfellows
Low BMD and dementia commonly co-occur in the older population, with bone loss accelerating in dementia patients because of physical inactivity and poor nutrition. However, the extent to which bone loss already exists prior to the onset of dementia remains unclear.
The new findings are based on 3,651 adults (mean age 72 years, 58% women) in the Rotterdam Study who were free of dementia between 2002 and 2005. At that time, BMD at the femoral neck, lumbar spine, and total body were obtained using dual-energy radiography absorptiometry (DXA) and the trabecular bone score, which offers further details such as bone microarchitecture, was calculated. Participants were followed up until Jan. 1, 2020.
Analyses were adjusted for age, sex, education, physical activity, smoking status, body mass index, blood pressure, cholesterol, history of comorbidities (stroke and diabetes), and apolipoprotein E genotype.
During follow-up, 688 (19%) participants developed dementia, mostly Alzheimer’s disease (77%).
Throughout the entire follow-up period, lower BMD at the femoral neck (per standard deviation), but not at other bone sites, correlated with a higher risk for all-cause dementia (hazard ratio, 1.12; 95% confidence interval, 1.02-1.23) and Alzheimer’s disease (HR, 1.14; 95% CI, 1.02-1.28).
Within the first 10 years after baseline, the risk for dementia was greatest in individuals with the lowest BMD at the femoral neck (HR, 2.03; 95% CI, 1.39-2.96) and total body (HR, 1.42; 95% CI, 1.01-2.02) and lowest trabecular bone score (HR, 1.59; 95% CI, 1.11-2.28).
Only BMD at the femoral neck was related to incident all-cause dementia in the first 5 years of follow-up (HR, 2.13; 95% CI, 1.28-3.57).
These findings add “extra knowledge to previous findings that associations change with time, with the strength of the effect decreasing with increasing follow-up time,” the investigators noted.
They suggest that total BMD and trabecular bone score might occur as “prodromal features instead of causes of dementia and related toxic protein accumulation in the brain. In other words, persons with subclinical, incipient dementia may have poor bone health due to the dementia process instead of vice versa.”
The investigators noted that further research focusing on the predictive ability of BMD for dementia is necessary. “As an indicator of dementia risk, intervening in BMD may improve clinical care of these persons, especially considering the multicomorbidities and polypharmacy that are highly preventive in this group,” they concluded.
Little known bone-brain axis to blame?
In a comment, Shaheen Lakhan, MD, a neurologist and researcher in Boston, noted that “bone health is increasingly becoming front of mind in older adults. This study confirms an association between poor bone health – low bone mineral density and bone scores – and poor brain health.”
However, it’s unclear whether the link is causal – that is, whether poor bone health actually leads to poor brain health, and whether that can be staved off by directly supporting bone density,” Dr. Lakhan said.
“The link may very well be the little known ‘brain-bone axis’ – where our bones actually regulate our brain,” he added.
“Take for example the bone-generated hormone osteocalcin that crosses the blood-brain barrier and regulates brain functions like memory and cognition. Mice who don’t express the osteocalcin gene or are injected with antibodies that block osteocalcin actually have poor memory and worse anxiety,” Dr. Lakhan said.
“In any event, good bone health begins with healthy habits: a diet with plenty of calcium, vitamin D, and protein; a regimen of not just cardio, but also weight-bearing exercises; and staying clear of smoking and heavy alcohol intake,” he concluded.
The study was funded by Erasmus Medical Center and Erasmus University Rotterdam, the Netherlands Organization for Scientific Research, the Netherlands Organization for Health Research and Development, the Research Institute for Diseases in the Elderly, the Netherlands Genomics Initiative, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission, and the Municipality of Rotterdam. Dr. Ikram and Dr. Lakhan report no relevant disclosures.
A version of this article first appeared on Medscape.com.
After adjusting for relevant factors, adults with the lowest versus highest BMD at the femoral neck were 42% more likely to develop dementia over roughly 10 years.
“Our research has found a link between bone loss and dementia, but further studies are needed to better understand this connection between bone density and memory loss,” study investigator Mohammad Arfan Ikram, MD, PhD, with Erasmus University Medical Center in Rotterdam, the Netherlands, said in a statement.
“It’s possible that bone loss may occur already in the earliest phases of dementia, years before any clinical symptoms manifest themselves. If that were the case, bone loss could be an indicator of risk for dementia and people with bone loss could be targeted for screening and improved care,” Dr. Ikram added.
The study was published online in Neurology.
Common bedfellows
Low BMD and dementia commonly co-occur in the older population, with bone loss accelerating in dementia patients because of physical inactivity and poor nutrition. However, the extent to which bone loss already exists prior to the onset of dementia remains unclear.
The new findings are based on 3,651 adults (mean age 72 years, 58% women) in the Rotterdam Study who were free of dementia between 2002 and 2005. At that time, BMD at the femoral neck, lumbar spine, and total body were obtained using dual-energy radiography absorptiometry (DXA) and the trabecular bone score, which offers further details such as bone microarchitecture, was calculated. Participants were followed up until Jan. 1, 2020.
Analyses were adjusted for age, sex, education, physical activity, smoking status, body mass index, blood pressure, cholesterol, history of comorbidities (stroke and diabetes), and apolipoprotein E genotype.
During follow-up, 688 (19%) participants developed dementia, mostly Alzheimer’s disease (77%).
Throughout the entire follow-up period, lower BMD at the femoral neck (per standard deviation), but not at other bone sites, correlated with a higher risk for all-cause dementia (hazard ratio, 1.12; 95% confidence interval, 1.02-1.23) and Alzheimer’s disease (HR, 1.14; 95% CI, 1.02-1.28).
Within the first 10 years after baseline, the risk for dementia was greatest in individuals with the lowest BMD at the femoral neck (HR, 2.03; 95% CI, 1.39-2.96) and total body (HR, 1.42; 95% CI, 1.01-2.02) and lowest trabecular bone score (HR, 1.59; 95% CI, 1.11-2.28).
Only BMD at the femoral neck was related to incident all-cause dementia in the first 5 years of follow-up (HR, 2.13; 95% CI, 1.28-3.57).
These findings add “extra knowledge to previous findings that associations change with time, with the strength of the effect decreasing with increasing follow-up time,” the investigators noted.
They suggest that total BMD and trabecular bone score might occur as “prodromal features instead of causes of dementia and related toxic protein accumulation in the brain. In other words, persons with subclinical, incipient dementia may have poor bone health due to the dementia process instead of vice versa.”
The investigators noted that further research focusing on the predictive ability of BMD for dementia is necessary. “As an indicator of dementia risk, intervening in BMD may improve clinical care of these persons, especially considering the multicomorbidities and polypharmacy that are highly preventive in this group,” they concluded.
Little known bone-brain axis to blame?
In a comment, Shaheen Lakhan, MD, a neurologist and researcher in Boston, noted that “bone health is increasingly becoming front of mind in older adults. This study confirms an association between poor bone health – low bone mineral density and bone scores – and poor brain health.”
However, it’s unclear whether the link is causal – that is, whether poor bone health actually leads to poor brain health, and whether that can be staved off by directly supporting bone density,” Dr. Lakhan said.
“The link may very well be the little known ‘brain-bone axis’ – where our bones actually regulate our brain,” he added.
“Take for example the bone-generated hormone osteocalcin that crosses the blood-brain barrier and regulates brain functions like memory and cognition. Mice who don’t express the osteocalcin gene or are injected with antibodies that block osteocalcin actually have poor memory and worse anxiety,” Dr. Lakhan said.
“In any event, good bone health begins with healthy habits: a diet with plenty of calcium, vitamin D, and protein; a regimen of not just cardio, but also weight-bearing exercises; and staying clear of smoking and heavy alcohol intake,” he concluded.
The study was funded by Erasmus Medical Center and Erasmus University Rotterdam, the Netherlands Organization for Scientific Research, the Netherlands Organization for Health Research and Development, the Research Institute for Diseases in the Elderly, the Netherlands Genomics Initiative, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission, and the Municipality of Rotterdam. Dr. Ikram and Dr. Lakhan report no relevant disclosures.
A version of this article first appeared on Medscape.com.
After adjusting for relevant factors, adults with the lowest versus highest BMD at the femoral neck were 42% more likely to develop dementia over roughly 10 years.
“Our research has found a link between bone loss and dementia, but further studies are needed to better understand this connection between bone density and memory loss,” study investigator Mohammad Arfan Ikram, MD, PhD, with Erasmus University Medical Center in Rotterdam, the Netherlands, said in a statement.
“It’s possible that bone loss may occur already in the earliest phases of dementia, years before any clinical symptoms manifest themselves. If that were the case, bone loss could be an indicator of risk for dementia and people with bone loss could be targeted for screening and improved care,” Dr. Ikram added.
The study was published online in Neurology.
Common bedfellows
Low BMD and dementia commonly co-occur in the older population, with bone loss accelerating in dementia patients because of physical inactivity and poor nutrition. However, the extent to which bone loss already exists prior to the onset of dementia remains unclear.
The new findings are based on 3,651 adults (mean age 72 years, 58% women) in the Rotterdam Study who were free of dementia between 2002 and 2005. At that time, BMD at the femoral neck, lumbar spine, and total body were obtained using dual-energy radiography absorptiometry (DXA) and the trabecular bone score, which offers further details such as bone microarchitecture, was calculated. Participants were followed up until Jan. 1, 2020.
Analyses were adjusted for age, sex, education, physical activity, smoking status, body mass index, blood pressure, cholesterol, history of comorbidities (stroke and diabetes), and apolipoprotein E genotype.
During follow-up, 688 (19%) participants developed dementia, mostly Alzheimer’s disease (77%).
Throughout the entire follow-up period, lower BMD at the femoral neck (per standard deviation), but not at other bone sites, correlated with a higher risk for all-cause dementia (hazard ratio, 1.12; 95% confidence interval, 1.02-1.23) and Alzheimer’s disease (HR, 1.14; 95% CI, 1.02-1.28).
Within the first 10 years after baseline, the risk for dementia was greatest in individuals with the lowest BMD at the femoral neck (HR, 2.03; 95% CI, 1.39-2.96) and total body (HR, 1.42; 95% CI, 1.01-2.02) and lowest trabecular bone score (HR, 1.59; 95% CI, 1.11-2.28).
Only BMD at the femoral neck was related to incident all-cause dementia in the first 5 years of follow-up (HR, 2.13; 95% CI, 1.28-3.57).
These findings add “extra knowledge to previous findings that associations change with time, with the strength of the effect decreasing with increasing follow-up time,” the investigators noted.
They suggest that total BMD and trabecular bone score might occur as “prodromal features instead of causes of dementia and related toxic protein accumulation in the brain. In other words, persons with subclinical, incipient dementia may have poor bone health due to the dementia process instead of vice versa.”
The investigators noted that further research focusing on the predictive ability of BMD for dementia is necessary. “As an indicator of dementia risk, intervening in BMD may improve clinical care of these persons, especially considering the multicomorbidities and polypharmacy that are highly preventive in this group,” they concluded.
Little known bone-brain axis to blame?
In a comment, Shaheen Lakhan, MD, a neurologist and researcher in Boston, noted that “bone health is increasingly becoming front of mind in older adults. This study confirms an association between poor bone health – low bone mineral density and bone scores – and poor brain health.”
However, it’s unclear whether the link is causal – that is, whether poor bone health actually leads to poor brain health, and whether that can be staved off by directly supporting bone density,” Dr. Lakhan said.
“The link may very well be the little known ‘brain-bone axis’ – where our bones actually regulate our brain,” he added.
“Take for example the bone-generated hormone osteocalcin that crosses the blood-brain barrier and regulates brain functions like memory and cognition. Mice who don’t express the osteocalcin gene or are injected with antibodies that block osteocalcin actually have poor memory and worse anxiety,” Dr. Lakhan said.
“In any event, good bone health begins with healthy habits: a diet with plenty of calcium, vitamin D, and protein; a regimen of not just cardio, but also weight-bearing exercises; and staying clear of smoking and heavy alcohol intake,” he concluded.
The study was funded by Erasmus Medical Center and Erasmus University Rotterdam, the Netherlands Organization for Scientific Research, the Netherlands Organization for Health Research and Development, the Research Institute for Diseases in the Elderly, the Netherlands Genomics Initiative, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission, and the Municipality of Rotterdam. Dr. Ikram and Dr. Lakhan report no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM NEUROLOGY
Longer telomeres tied to better brain health
, new research suggests.
“This is the largest and most systematic investigation of telomere length and brain structure and function,” said Anya Topiwala, of the University of Oxford (England). “We found that longer telomeres associated with protection against dementia. The links with brain structure, we think, offer a possible mechanism for this protection. The hope is, by understanding the mechanism, new treatment targets could be uncovered,” Dr. Topiwala said.
The study was published online in PLOS ONE.
UK Biobank cohort
Telomeres form protective caps at the ends of chromosomes, and they progressively shorten with age, which may increase susceptibility to age-related diseases including Alzheimer’s disease. The mechanism underlying this risk is unclear and may involve changes in brain structure and function. However, the relationship between telomere length and neuroimaging markers is poorly characterized.
Dr. Topiwala and colleagues compared telomere length in white blood cells to brain MRI and health record data in 31,661 middle-aged and older adults in UK Biobank. They found that longer leucocyte telomere length (LTL) was associated with a larger volume of global and subcortical grey matter and a larger hippocampus – both of which shrink in patients with Alzheimer’s disease. Longer telomeres were also associated with a thicker cerebral cortex, which thins as Alzheimer’s disease progresses.
Longer LTL was also associated with reduced incidence of dementia during follow-up (hazard ratio, 0.93; 95% confidence interval, 0.91-0.96).
Dr. Topiwala noted that many of the factors related to telomere shortening, such as age, genetics, and sex, can’t be changed. However, in a previous study, her team found that drinking alcohol may shorten telomere length. “So by this logic, reducing your alcohol intake could curb the shortening,” Dr. Topiwala said.
She said that a limitation of the study is that telomere length was measured in blood rather than brain and that it’s not clear at present how closely the two relate. Also, UK Biobank participants are generally more healthy than is the general population. Also, though telomere length and brain measures were associated, “we cannot from this study prove one is causing the other,” she added.
Need for more research
Commenting on the research, Percy Griffin, PhD, Alzheimer’s Association director of scientific engagement, said that it’s been “known for some time that shortened telomeres – the caps at the end of DNA – are associated with increased aging.”
This new study is “interesting,” said Dr. Percy, in that it shows an association between longer telomere length in white blood cells and healthier brain structures in the areas associated with Alzheimer’s disease. The longer telomeres were also associated with lower incidence of all-cause dementia.
But echoing Dr. Topiwala, “association does not mean causation,” Dr. Griffin said. “More research is needed to understand how diverse mechanisms contributing to Alzheimer’s and other dementia can be targeted.”
“The Alzheimer’s Association is accelerating the discovery of novel therapies through its Part the Cloud funding program, which has invested more than $65 million to accelerate the development of 65 drug development programs,” Dr. Griffin said.
The study had no specific funding. Dr. Topiwala and Dr. Griffin report no relevant disclosures.
A version of this article first appeared on Medscape.com.
, new research suggests.
“This is the largest and most systematic investigation of telomere length and brain structure and function,” said Anya Topiwala, of the University of Oxford (England). “We found that longer telomeres associated with protection against dementia. The links with brain structure, we think, offer a possible mechanism for this protection. The hope is, by understanding the mechanism, new treatment targets could be uncovered,” Dr. Topiwala said.
The study was published online in PLOS ONE.
UK Biobank cohort
Telomeres form protective caps at the ends of chromosomes, and they progressively shorten with age, which may increase susceptibility to age-related diseases including Alzheimer’s disease. The mechanism underlying this risk is unclear and may involve changes in brain structure and function. However, the relationship between telomere length and neuroimaging markers is poorly characterized.
Dr. Topiwala and colleagues compared telomere length in white blood cells to brain MRI and health record data in 31,661 middle-aged and older adults in UK Biobank. They found that longer leucocyte telomere length (LTL) was associated with a larger volume of global and subcortical grey matter and a larger hippocampus – both of which shrink in patients with Alzheimer’s disease. Longer telomeres were also associated with a thicker cerebral cortex, which thins as Alzheimer’s disease progresses.
Longer LTL was also associated with reduced incidence of dementia during follow-up (hazard ratio, 0.93; 95% confidence interval, 0.91-0.96).
Dr. Topiwala noted that many of the factors related to telomere shortening, such as age, genetics, and sex, can’t be changed. However, in a previous study, her team found that drinking alcohol may shorten telomere length. “So by this logic, reducing your alcohol intake could curb the shortening,” Dr. Topiwala said.
She said that a limitation of the study is that telomere length was measured in blood rather than brain and that it’s not clear at present how closely the two relate. Also, UK Biobank participants are generally more healthy than is the general population. Also, though telomere length and brain measures were associated, “we cannot from this study prove one is causing the other,” she added.
Need for more research
Commenting on the research, Percy Griffin, PhD, Alzheimer’s Association director of scientific engagement, said that it’s been “known for some time that shortened telomeres – the caps at the end of DNA – are associated with increased aging.”
This new study is “interesting,” said Dr. Percy, in that it shows an association between longer telomere length in white blood cells and healthier brain structures in the areas associated with Alzheimer’s disease. The longer telomeres were also associated with lower incidence of all-cause dementia.
But echoing Dr. Topiwala, “association does not mean causation,” Dr. Griffin said. “More research is needed to understand how diverse mechanisms contributing to Alzheimer’s and other dementia can be targeted.”
“The Alzheimer’s Association is accelerating the discovery of novel therapies through its Part the Cloud funding program, which has invested more than $65 million to accelerate the development of 65 drug development programs,” Dr. Griffin said.
The study had no specific funding. Dr. Topiwala and Dr. Griffin report no relevant disclosures.
A version of this article first appeared on Medscape.com.
, new research suggests.
“This is the largest and most systematic investigation of telomere length and brain structure and function,” said Anya Topiwala, of the University of Oxford (England). “We found that longer telomeres associated with protection against dementia. The links with brain structure, we think, offer a possible mechanism for this protection. The hope is, by understanding the mechanism, new treatment targets could be uncovered,” Dr. Topiwala said.
The study was published online in PLOS ONE.
UK Biobank cohort
Telomeres form protective caps at the ends of chromosomes, and they progressively shorten with age, which may increase susceptibility to age-related diseases including Alzheimer’s disease. The mechanism underlying this risk is unclear and may involve changes in brain structure and function. However, the relationship between telomere length and neuroimaging markers is poorly characterized.
Dr. Topiwala and colleagues compared telomere length in white blood cells to brain MRI and health record data in 31,661 middle-aged and older adults in UK Biobank. They found that longer leucocyte telomere length (LTL) was associated with a larger volume of global and subcortical grey matter and a larger hippocampus – both of which shrink in patients with Alzheimer’s disease. Longer telomeres were also associated with a thicker cerebral cortex, which thins as Alzheimer’s disease progresses.
Longer LTL was also associated with reduced incidence of dementia during follow-up (hazard ratio, 0.93; 95% confidence interval, 0.91-0.96).
Dr. Topiwala noted that many of the factors related to telomere shortening, such as age, genetics, and sex, can’t be changed. However, in a previous study, her team found that drinking alcohol may shorten telomere length. “So by this logic, reducing your alcohol intake could curb the shortening,” Dr. Topiwala said.
She said that a limitation of the study is that telomere length was measured in blood rather than brain and that it’s not clear at present how closely the two relate. Also, UK Biobank participants are generally more healthy than is the general population. Also, though telomere length and brain measures were associated, “we cannot from this study prove one is causing the other,” she added.
Need for more research
Commenting on the research, Percy Griffin, PhD, Alzheimer’s Association director of scientific engagement, said that it’s been “known for some time that shortened telomeres – the caps at the end of DNA – are associated with increased aging.”
This new study is “interesting,” said Dr. Percy, in that it shows an association between longer telomere length in white blood cells and healthier brain structures in the areas associated with Alzheimer’s disease. The longer telomeres were also associated with lower incidence of all-cause dementia.
But echoing Dr. Topiwala, “association does not mean causation,” Dr. Griffin said. “More research is needed to understand how diverse mechanisms contributing to Alzheimer’s and other dementia can be targeted.”
“The Alzheimer’s Association is accelerating the discovery of novel therapies through its Part the Cloud funding program, which has invested more than $65 million to accelerate the development of 65 drug development programs,” Dr. Griffin said.
The study had no specific funding. Dr. Topiwala and Dr. Griffin report no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM PLOS ONE
The desk
Recently, Dr. Jeffrey Benabio (I don’t believe we’ve ever met), wrote an enjoyable commentary mourning the loss of letters – the wonderful paper-and-pen documents that were, for the vast majority of human history, the main method of long distance communication. Even today, he notes, there’s something special about a letter, with the time and human effort required to sit down and put pen to paper, seal it into an envelope, and entrust it to the post office.
In his piece, Dr. Benabio describes his work desk as “a small surface, perhaps just enough for the monitor and a mug ... it has no drawers. It is lean and immaculate, but it has no soul.”
With all due respect, I can’t do that. I need a desk to function. A REAL one.
I was 9 when I got my first desk, far more than a 4th-grader needed. My dad was an attorney and had an extra desk from a partner who’d retired. It was big and heavy and made of wood. It had three drawers on each side, one in the middle, and pull-outs on each side in case you needed even more writing space. I loved it. As the years went by I did homework, wrote short stories, and built models on it. I covered the pull-outs with stickers for starship controls, so on a whim I could jump to hyperspace. In 1984 a brand-new Apple Macintosh, with 128K of RAM showed up on it. I began using the computer to write college papers, but most of my work at the desk still involved books and handwriting.
My current home desk has been with me through college, medical school, residency, and fellowship, and it continues with me today.
At my office, though, is my main desk. Before 2013 I was in a small back office, with only room for a tiny three-drawer college desk.
But in 2013 I moved into my own office, for the first time in my career. Now it was time to bring in my real desk, waiting in storage since my Dad had retired.
This is my desk now. It’s huge. It’s heavy. My dad bought it when he started his law practice in 1968. It has eight drawers, and my Dad’s original leather blotter is on top. It came with his chrome and brass letter opener in the top drawer. It has space for my computer, writing pads, exam tools (for people who can’t get on the exam table across the hall), business cards, a few baubles from my kids, stapler, tape dispenser, pen cup, phone, coffee mug, and a million other things.
It takes up a lot of space, but I don’t mind. There’s a human comfort to it and the organized disorder on top of it.
Everyone practices medicine differently. What works for me isn’t going to work for another doctor, and definitely not for another specialty.
But here, the big desk is part of my personal style. Sitting there gets me into “doctor mode” each day. I hope the more casual surroundings make it comfortable for patients, too.
It’s part of the soul of my practice, and I wouldn’t have it any other way.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Recently, Dr. Jeffrey Benabio (I don’t believe we’ve ever met), wrote an enjoyable commentary mourning the loss of letters – the wonderful paper-and-pen documents that were, for the vast majority of human history, the main method of long distance communication. Even today, he notes, there’s something special about a letter, with the time and human effort required to sit down and put pen to paper, seal it into an envelope, and entrust it to the post office.
In his piece, Dr. Benabio describes his work desk as “a small surface, perhaps just enough for the monitor and a mug ... it has no drawers. It is lean and immaculate, but it has no soul.”
With all due respect, I can’t do that. I need a desk to function. A REAL one.
I was 9 when I got my first desk, far more than a 4th-grader needed. My dad was an attorney and had an extra desk from a partner who’d retired. It was big and heavy and made of wood. It had three drawers on each side, one in the middle, and pull-outs on each side in case you needed even more writing space. I loved it. As the years went by I did homework, wrote short stories, and built models on it. I covered the pull-outs with stickers for starship controls, so on a whim I could jump to hyperspace. In 1984 a brand-new Apple Macintosh, with 128K of RAM showed up on it. I began using the computer to write college papers, but most of my work at the desk still involved books and handwriting.
My current home desk has been with me through college, medical school, residency, and fellowship, and it continues with me today.
At my office, though, is my main desk. Before 2013 I was in a small back office, with only room for a tiny three-drawer college desk.
But in 2013 I moved into my own office, for the first time in my career. Now it was time to bring in my real desk, waiting in storage since my Dad had retired.
This is my desk now. It’s huge. It’s heavy. My dad bought it when he started his law practice in 1968. It has eight drawers, and my Dad’s original leather blotter is on top. It came with his chrome and brass letter opener in the top drawer. It has space for my computer, writing pads, exam tools (for people who can’t get on the exam table across the hall), business cards, a few baubles from my kids, stapler, tape dispenser, pen cup, phone, coffee mug, and a million other things.
It takes up a lot of space, but I don’t mind. There’s a human comfort to it and the organized disorder on top of it.
Everyone practices medicine differently. What works for me isn’t going to work for another doctor, and definitely not for another specialty.
But here, the big desk is part of my personal style. Sitting there gets me into “doctor mode” each day. I hope the more casual surroundings make it comfortable for patients, too.
It’s part of the soul of my practice, and I wouldn’t have it any other way.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Recently, Dr. Jeffrey Benabio (I don’t believe we’ve ever met), wrote an enjoyable commentary mourning the loss of letters – the wonderful paper-and-pen documents that were, for the vast majority of human history, the main method of long distance communication. Even today, he notes, there’s something special about a letter, with the time and human effort required to sit down and put pen to paper, seal it into an envelope, and entrust it to the post office.
In his piece, Dr. Benabio describes his work desk as “a small surface, perhaps just enough for the monitor and a mug ... it has no drawers. It is lean and immaculate, but it has no soul.”
With all due respect, I can’t do that. I need a desk to function. A REAL one.
I was 9 when I got my first desk, far more than a 4th-grader needed. My dad was an attorney and had an extra desk from a partner who’d retired. It was big and heavy and made of wood. It had three drawers on each side, one in the middle, and pull-outs on each side in case you needed even more writing space. I loved it. As the years went by I did homework, wrote short stories, and built models on it. I covered the pull-outs with stickers for starship controls, so on a whim I could jump to hyperspace. In 1984 a brand-new Apple Macintosh, with 128K of RAM showed up on it. I began using the computer to write college papers, but most of my work at the desk still involved books and handwriting.
My current home desk has been with me through college, medical school, residency, and fellowship, and it continues with me today.
At my office, though, is my main desk. Before 2013 I was in a small back office, with only room for a tiny three-drawer college desk.
But in 2013 I moved into my own office, for the first time in my career. Now it was time to bring in my real desk, waiting in storage since my Dad had retired.
This is my desk now. It’s huge. It’s heavy. My dad bought it when he started his law practice in 1968. It has eight drawers, and my Dad’s original leather blotter is on top. It came with his chrome and brass letter opener in the top drawer. It has space for my computer, writing pads, exam tools (for people who can’t get on the exam table across the hall), business cards, a few baubles from my kids, stapler, tape dispenser, pen cup, phone, coffee mug, and a million other things.
It takes up a lot of space, but I don’t mind. There’s a human comfort to it and the organized disorder on top of it.
Everyone practices medicine differently. What works for me isn’t going to work for another doctor, and definitely not for another specialty.
But here, the big desk is part of my personal style. Sitting there gets me into “doctor mode” each day. I hope the more casual surroundings make it comfortable for patients, too.
It’s part of the soul of my practice, and I wouldn’t have it any other way.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
COVID in pregnancy may affect boys’ neurodevelopment: Study
Boys born to mothers infected with SARS‐CoV‐2 during pregnancy may be more likely to receive a diagnosis of a neurodevelopmental disorder by age 12 months, according to new research.
Andrea G. Edlow, MD, MSc, with Massachusetts General Hospital and Harvard Medical School in Boston, and colleagues examined data from 18,355 births between March 1, 2020, and May 31, 2021, at eight hospitals across two health systems in Massachusetts.
Of these births, 883 (4.8%) were to individuals who tested positive for SARS‐CoV‐2 during pregnancy. Among the children exposed to SARS‐CoV‐2 in the womb, 26 (3%) received a neurodevelopmental diagnosis, including disorders of motor function, speech and language, and psychological development, by age 1 year. In the group unexposed to the virus, 1.8% received such a diagnosis.
After adjusting for factors such as race, insurance, maternal age, and preterm birth, Dr. Edlow’s group found that a positive test for SARS-CoV-2 during pregnancy was associated with an increased risk for neurodevelopmental diagnoses at 12 months among boys (adjusted odds ratio, 1.94; 95% confidence interval, 1.12-3.17; P = .01), but not among girls.
In a subset of children with data available at 18 months, the correlation among boys at that age was less pronounced and not statistically significant (aOR, 1.42; 95% CI, 0.92-2.11; P = .10).
The findings were published online in JAMA Network Open
Prior epidemiological research has suggested that maternal infection during pregnancy is associated with heightened risk for a range of neurodevelopmental disorders, including autism and schizophrenia, in offspring, the authors wrote.
“The neurodevelopmental risk associated with maternal SARS-CoV-2 infection was disproportionately high in male infants, consistent with the known increased vulnerability of males in the face of prenatal adverse exposures,” Dr. Edlow said in a news release about the findings.
Larger studies and longer follow‐up are needed to confirm and reliably estimate the risk, the researchers said.
“It is not clear that the changes we can detect at 12 and 18 months will be indicative of persistent risks for disorders such as autism spectrum disorder, intellectual disability, or schizophrenia,” they write.
New data published online by the Centers for Disease Control and Prevention show that in 11 communities in 2020, 1 in 36 (2.8%) 8-year-old children had been identified with autism spectrum disorder, an increase from 2.3% in 2018. The data also show that the early months of the pandemic may have disrupted autism detection efforts among 4-year-olds.
The investigators were supported by grants from the National Institutes of Health and the Simons Foundation Autism Research Initiative. Coauthors disclosed consulting for or receiving personal fees from biotechnology and pharmaceutical companies.
A version of this article first appeared on Medscape.com.
Boys born to mothers infected with SARS‐CoV‐2 during pregnancy may be more likely to receive a diagnosis of a neurodevelopmental disorder by age 12 months, according to new research.
Andrea G. Edlow, MD, MSc, with Massachusetts General Hospital and Harvard Medical School in Boston, and colleagues examined data from 18,355 births between March 1, 2020, and May 31, 2021, at eight hospitals across two health systems in Massachusetts.
Of these births, 883 (4.8%) were to individuals who tested positive for SARS‐CoV‐2 during pregnancy. Among the children exposed to SARS‐CoV‐2 in the womb, 26 (3%) received a neurodevelopmental diagnosis, including disorders of motor function, speech and language, and psychological development, by age 1 year. In the group unexposed to the virus, 1.8% received such a diagnosis.
After adjusting for factors such as race, insurance, maternal age, and preterm birth, Dr. Edlow’s group found that a positive test for SARS-CoV-2 during pregnancy was associated with an increased risk for neurodevelopmental diagnoses at 12 months among boys (adjusted odds ratio, 1.94; 95% confidence interval, 1.12-3.17; P = .01), but not among girls.
In a subset of children with data available at 18 months, the correlation among boys at that age was less pronounced and not statistically significant (aOR, 1.42; 95% CI, 0.92-2.11; P = .10).
The findings were published online in JAMA Network Open
Prior epidemiological research has suggested that maternal infection during pregnancy is associated with heightened risk for a range of neurodevelopmental disorders, including autism and schizophrenia, in offspring, the authors wrote.
“The neurodevelopmental risk associated with maternal SARS-CoV-2 infection was disproportionately high in male infants, consistent with the known increased vulnerability of males in the face of prenatal adverse exposures,” Dr. Edlow said in a news release about the findings.
Larger studies and longer follow‐up are needed to confirm and reliably estimate the risk, the researchers said.
“It is not clear that the changes we can detect at 12 and 18 months will be indicative of persistent risks for disorders such as autism spectrum disorder, intellectual disability, or schizophrenia,” they write.
New data published online by the Centers for Disease Control and Prevention show that in 11 communities in 2020, 1 in 36 (2.8%) 8-year-old children had been identified with autism spectrum disorder, an increase from 2.3% in 2018. The data also show that the early months of the pandemic may have disrupted autism detection efforts among 4-year-olds.
The investigators were supported by grants from the National Institutes of Health and the Simons Foundation Autism Research Initiative. Coauthors disclosed consulting for or receiving personal fees from biotechnology and pharmaceutical companies.
A version of this article first appeared on Medscape.com.
Boys born to mothers infected with SARS‐CoV‐2 during pregnancy may be more likely to receive a diagnosis of a neurodevelopmental disorder by age 12 months, according to new research.
Andrea G. Edlow, MD, MSc, with Massachusetts General Hospital and Harvard Medical School in Boston, and colleagues examined data from 18,355 births between March 1, 2020, and May 31, 2021, at eight hospitals across two health systems in Massachusetts.
Of these births, 883 (4.8%) were to individuals who tested positive for SARS‐CoV‐2 during pregnancy. Among the children exposed to SARS‐CoV‐2 in the womb, 26 (3%) received a neurodevelopmental diagnosis, including disorders of motor function, speech and language, and psychological development, by age 1 year. In the group unexposed to the virus, 1.8% received such a diagnosis.
After adjusting for factors such as race, insurance, maternal age, and preterm birth, Dr. Edlow’s group found that a positive test for SARS-CoV-2 during pregnancy was associated with an increased risk for neurodevelopmental diagnoses at 12 months among boys (adjusted odds ratio, 1.94; 95% confidence interval, 1.12-3.17; P = .01), but not among girls.
In a subset of children with data available at 18 months, the correlation among boys at that age was less pronounced and not statistically significant (aOR, 1.42; 95% CI, 0.92-2.11; P = .10).
The findings were published online in JAMA Network Open
Prior epidemiological research has suggested that maternal infection during pregnancy is associated with heightened risk for a range of neurodevelopmental disorders, including autism and schizophrenia, in offspring, the authors wrote.
“The neurodevelopmental risk associated with maternal SARS-CoV-2 infection was disproportionately high in male infants, consistent with the known increased vulnerability of males in the face of prenatal adverse exposures,” Dr. Edlow said in a news release about the findings.
Larger studies and longer follow‐up are needed to confirm and reliably estimate the risk, the researchers said.
“It is not clear that the changes we can detect at 12 and 18 months will be indicative of persistent risks for disorders such as autism spectrum disorder, intellectual disability, or schizophrenia,” they write.
New data published online by the Centers for Disease Control and Prevention show that in 11 communities in 2020, 1 in 36 (2.8%) 8-year-old children had been identified with autism spectrum disorder, an increase from 2.3% in 2018. The data also show that the early months of the pandemic may have disrupted autism detection efforts among 4-year-olds.
The investigators were supported by grants from the National Institutes of Health and the Simons Foundation Autism Research Initiative. Coauthors disclosed consulting for or receiving personal fees from biotechnology and pharmaceutical companies.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
Headache before the revolution: A clinician looks back
Headache treatment before the early 1990s was marked by decades of improvisation with mostly unapproved agents, followed by an explosion of scientific interest and new treatments developed specifically for migraine.
But this is largely thanks to the sea change that occurred 30 years ago.
In an interview, Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews, past president of the International Headache Society and clinical professor of neurology at UCLA’s David Geffen School of Medicine in Los Angeles, recalled what it was like to treat patients before and after triptan medications came onto the market.
After the first of these anti-migraine agents, sumatriptan, was approved by the Food and Drug Administration in late December 1992, headache specialists found themselves with a powerful, approved treatment that validated their commitment to solving the disorder, and helped put to rest a persistent but mistaken notion that migraine was a psychiatric condition affecting young women.
But in the 1970s and 1980s, “there wasn’t great science explaining the pathophysiology of common primary headaches like tension-type headache, cluster headache, and migraine,” Dr. Rapoport recalled. “There is often comorbid depression and anxiety with migraine, and sometimes more serious psychiatric disease, but it doesn’t mean migraine is caused by psychological issues. Now we see it clearly as a disease of the brain, but it took years of investigation to prove that.”
The early years
Dr. Rapoport’s journey with headache began in 1972, when he joined a private neurology practice in Stamford and Greenwich, Conn. Neurologists were frowned upon then for having too much interest in headache, he said. There was poor remuneration for doctors treating headache patients, who were hard to properly diagnose and effectively care for. Few medications could effectively stop a migraine attack or reliably reduce the frequency of headaches or the disability they caused.
On weekends Dr. Rapoport covered emergency departments and ICUs at three hospitals, where standard treatment for a migraine attack was injectable opiates. Not only did this treatment aggravate nausea, a common migraine symptom, “but it did not stop the migraine process.” Once the pain relief wore off, patients woke up with the same headache, Dr. Rapoport recalled. “The other drug that was available was ergotamine tartrate” – a fungal alkaloid used since medieval times to treat headache – “given sublingually. It helped the headache slightly but increased the nausea. DHE, or dihydroergotamine, was available only by injection and not used very much.”
DHE, a semi-synthetic molecule based on ergotamine, had FDA approval for migraine, but was complicated to administer. Like the opioids, it provoked vomiting when given intravenously, in patients already suffering migraine-induced nausea. But Dr. Rapoport, along with some of his colleagues, felt that there was a role for DHE for the most severe subtypes of patients, those with long histories of frequent migraines.
“We put people in the hospital and we gave them intravenous DHE. Eventually I got the idea to give it intramuscularly or subcutaneously in the emergency room or my office. When you give it that way, it doesn’t work as quickly but has fewer side effects.” Dr. Rapoport designed a cocktail by coadministering promethazine for nausea, and eventually added a steroid, dexamethasone. The triple shots worked on most patients experiencing severe daily or near-daily migraine attacks, Dr. Rapoport saw, and he began administering the drug combination at The New England Center for Headache in Stamford and Greenwich, Conn., which he opened with Dr. Fred D. Sheftell in 1979.
“The triple shots really worked,” Dr. Rapoport recalled. “There was no need to keep patients in the office or emergency room for intravenous therapy. The patients never called to complain or came back the next day,” he said, as often occurred with opioid treatment.
Dr. Rapoport had learned early in his residency, in the late 1960s, from Dr. David R. Coddon, a neurologist at Mount Sinai hospital in New York, that a tricyclic antidepressant, imipramine, could be helpful in some patients with frequent migraine attacks. As evidence trickled in that other antidepressants, beta-blockers, and antiepileptic drugs might have preventive properties, Dr. Rapoport and others prescribed them for certain patients. But of all the drugs in the headache specialists’ repertoire, few were approved for either treatment or prevention. “And this continued until the triptans,” Dr. Rapoport said.
The triptan era
Sumatriptan was developed by Glaxo for the acute treatment of migraine. The medication, first available only as self-administered subcutaneous injections, was originally designed to bind to vascular serotonin receptors to allow selective constriction of cranial vessels that dilate, causing pain, during a migraine attack. (Years later it was discovered that triptans also worked as anti-inflammatory agents that decreased the release of the neurotransmitter calcitonin gene-related peptide, or CGRP.)
Triptans “changed the world for migraine patients and for me,” Dr. Rapoport said. “I could now prescribe a medication that people could take at home to decrease or stop the migraine process in an hour or two.” The success of the triptans prompted pharmaceutical companies to search for new, more effective ways to treat migraine attacks, with better tolerability.
Seven different triptans were developed, some as injections or tablets and others as nasal sprays. “If one triptan didn’t work, we’d give a second and rarely a third,” Dr. Rapoport said. “We learned that if oral triptans did not work, the most likely issue was that it was not rapidly absorbed from the small intestine, as migraine patients have nausea, poor GI absorption, and slow transit times. This prompted the greater use of injections and nasal sprays.” Headache specialists began combining triptan treatment with nonsteroidal anti-inflammatory drugs, offering further relief for the acute care of migraine.
Medication overuse headache
The years between 1993 and 2000, which saw all the current triptan drugs come onto the market, was an exhilarating one for headache specialists. But even those who were thrilled by the possibilities of the triptans, like Dr. Rapoport, soon came to recognize their limitations, in terms of side effects and poor tolerability for some patients.
Specialists also noticed something unsettling about the triptans: that patients’ headaches seemed to recur within a day, or occur more frequently over time, with higher medication use.
Medication overuse headache (MOH) was known to occur when patients treated migraine too often with acute care medications, especially over-the-counter analgesics and prescription opioids and barbiturates. Dr. Rapoport began warning at conferences and in seminars that MOH seemed to occur with the triptans as well. “In the beginning other doctors didn’t think the triptans could cause MOH, but I observed that patients who were taking triptans daily or almost daily were having increased headache frequency and the triptans stopped being effective. If they didn’t take the drug they were overusing, they were going to get much worse, almost like a withdrawal.”
Today, all seven triptans are now generic, and they remain a mainstay of migraine treatment: “Almost all of my patients are using, or have used a triptan,” Dr. Rapoport said. Yet researchers came to recognize the need for treatments targeting different pathways, both for prevention and acute care.
The next revolution: CGRP and gepants
Studies in the early 2000s began to show a link between the release of one ubiquitous nervous system neurotransmitter, calcitonin gene-related peptide, or CGRP, and migraine. They also noticed that blocking meningeal inflammation could lead to improvement in headache. Two new drug classes emerged from this science: monoclonal antibodies against CGRP or its receptor that had to be given by injection, and oral CGRP receptor blockers that could be used both as a preventive or as an acute care medication.
In 2018 the first monoclonal antibody against the CGRP receptor, erenumab (Aimovig, marketed by Amgen), delivered by injection, was approved for migraine prevention. Three others followed, most given by autoinjector, and one by IV infusion in office or hospital settings. “Those drugs are great,” Dr. Rapoport said. “You take one shot a month or every 3 months, and your headaches drop by 50% or more with very few side effects. Some patients actually see their migraines disappear.”
The following year ubrogepant (Ubrelvy, marketed by AbbVie), the first of a novel class of oral CGRP receptor blockers known as “gepants,” was approved to treat acute migraine. The FDA soon approved another gepant, rimegepant (Nurtec, marketed by Pfizer), which received indications both for prevention and for stopping a migraine attack acutely.
Both classes of therapies – the antibodies and the gepants – are far costlier than the triptans, which are all generic, and may not be needed for every migraine patient. With the gepants, for example, insurers may restrict use to people who have not responded to triptans or for whom triptans are contraindicated or cause too many adverse events. But the CGRP-targeted therapies as a whole “have been every bit as revolutionary” as the triptans, Dr. Rapoport said. The treatments work quickly to resolve headache and disability and get the patient functioning within an hour or two, and there are fewer side effects.
In a review article published in CNS Drugs in 2021, Dr. Rapoport and his colleagues reported that the anti-CGRP treatment with gepants did not appear linked to medication overuse headache, as virtually all previous acute care medication classes did, and could be used in patients who had previously reported MOH. “I am confident that over the next few years, more people will be using them as insurance coverage will improve for patients living with migraine,” he said.
Headache treatment today
Migraine specialists and patients now have a staggering range of therapeutic options. Approved treatments now include prevention of migraine with onabotulinumtoxinA (Botox, marketed by the Allergan division of AbbVie) injections, which work alone and with other medicines; acute care treatment with ditans like lasmiditan (Reyvow, marketed by Lilly*), a category of acute care medicines that work like triptans but target different serotonin receptors. Five devices have been cleared for migraine and other types of headache by the FDA. These work alone or along with medication and can be used acutely or preventively. The devices “should be used more,” Dr. Rapoport said, but are not yet well covered by insurance.
Thirty years after the triptans, scientists and researchers continue to explore the pathophysiology of headache disorders, finding new pathways and identifying new potential targets.
“There are many parts of the brain and brain stem that are involved, as well as the thalamus and hypothalamus,” Dr. Rapoport said. “It’s interesting that the newer medications, and some of the older ones, work in the peripheral nervous system, outside the brain stem in the trigeminovascular system, to modulate the central nervous system. We also know that the CGRP system is involved with cellular second-order messengers. Stimulating and blocking this chain of reactions with newer drugs may become treatments in the future.”
Recent research has focused on a blood vessel dilating neurotransmitter, pituitary adenylate-cyclase-activating polypeptide, or PACAP-38, as a potential therapeutic target. Psychedelic medications such as psilocybin, strong pain medications such as ketamine, and even cannabinoids such as marijuana have all been investigated in migraine. Biofeedback therapies, mindfulness, and other behavioral interventions also have proved effective.
“I expect the next 2-5 years to bring us many important clinical trials on new types of pharmacological treatments,” Dr. Rapoport said. “This is a wonderful time to be a doctor or nurse treating patients living with migraine. When I started out treating headache, 51 years ago, we had only ergotamine tartrate. Today we have so many therapies and combinations of therapies that I hardly know where to start.”
Dr. Rapoport has served as a consultant to or speaker for AbbVie, Amgen, Biohaven, Cala Health, Lundbeck, Satsuma, and Teva, among others.
*Correction, 3/30/23: An earlier version of this article misstated the name of the company that markets Reyvow.
Headache treatment before the early 1990s was marked by decades of improvisation with mostly unapproved agents, followed by an explosion of scientific interest and new treatments developed specifically for migraine.
But this is largely thanks to the sea change that occurred 30 years ago.
In an interview, Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews, past president of the International Headache Society and clinical professor of neurology at UCLA’s David Geffen School of Medicine in Los Angeles, recalled what it was like to treat patients before and after triptan medications came onto the market.
After the first of these anti-migraine agents, sumatriptan, was approved by the Food and Drug Administration in late December 1992, headache specialists found themselves with a powerful, approved treatment that validated their commitment to solving the disorder, and helped put to rest a persistent but mistaken notion that migraine was a psychiatric condition affecting young women.
But in the 1970s and 1980s, “there wasn’t great science explaining the pathophysiology of common primary headaches like tension-type headache, cluster headache, and migraine,” Dr. Rapoport recalled. “There is often comorbid depression and anxiety with migraine, and sometimes more serious psychiatric disease, but it doesn’t mean migraine is caused by psychological issues. Now we see it clearly as a disease of the brain, but it took years of investigation to prove that.”
The early years
Dr. Rapoport’s journey with headache began in 1972, when he joined a private neurology practice in Stamford and Greenwich, Conn. Neurologists were frowned upon then for having too much interest in headache, he said. There was poor remuneration for doctors treating headache patients, who were hard to properly diagnose and effectively care for. Few medications could effectively stop a migraine attack or reliably reduce the frequency of headaches or the disability they caused.
On weekends Dr. Rapoport covered emergency departments and ICUs at three hospitals, where standard treatment for a migraine attack was injectable opiates. Not only did this treatment aggravate nausea, a common migraine symptom, “but it did not stop the migraine process.” Once the pain relief wore off, patients woke up with the same headache, Dr. Rapoport recalled. “The other drug that was available was ergotamine tartrate” – a fungal alkaloid used since medieval times to treat headache – “given sublingually. It helped the headache slightly but increased the nausea. DHE, or dihydroergotamine, was available only by injection and not used very much.”
DHE, a semi-synthetic molecule based on ergotamine, had FDA approval for migraine, but was complicated to administer. Like the opioids, it provoked vomiting when given intravenously, in patients already suffering migraine-induced nausea. But Dr. Rapoport, along with some of his colleagues, felt that there was a role for DHE for the most severe subtypes of patients, those with long histories of frequent migraines.
“We put people in the hospital and we gave them intravenous DHE. Eventually I got the idea to give it intramuscularly or subcutaneously in the emergency room or my office. When you give it that way, it doesn’t work as quickly but has fewer side effects.” Dr. Rapoport designed a cocktail by coadministering promethazine for nausea, and eventually added a steroid, dexamethasone. The triple shots worked on most patients experiencing severe daily or near-daily migraine attacks, Dr. Rapoport saw, and he began administering the drug combination at The New England Center for Headache in Stamford and Greenwich, Conn., which he opened with Dr. Fred D. Sheftell in 1979.
“The triple shots really worked,” Dr. Rapoport recalled. “There was no need to keep patients in the office or emergency room for intravenous therapy. The patients never called to complain or came back the next day,” he said, as often occurred with opioid treatment.
Dr. Rapoport had learned early in his residency, in the late 1960s, from Dr. David R. Coddon, a neurologist at Mount Sinai hospital in New York, that a tricyclic antidepressant, imipramine, could be helpful in some patients with frequent migraine attacks. As evidence trickled in that other antidepressants, beta-blockers, and antiepileptic drugs might have preventive properties, Dr. Rapoport and others prescribed them for certain patients. But of all the drugs in the headache specialists’ repertoire, few were approved for either treatment or prevention. “And this continued until the triptans,” Dr. Rapoport said.
The triptan era
Sumatriptan was developed by Glaxo for the acute treatment of migraine. The medication, first available only as self-administered subcutaneous injections, was originally designed to bind to vascular serotonin receptors to allow selective constriction of cranial vessels that dilate, causing pain, during a migraine attack. (Years later it was discovered that triptans also worked as anti-inflammatory agents that decreased the release of the neurotransmitter calcitonin gene-related peptide, or CGRP.)
Triptans “changed the world for migraine patients and for me,” Dr. Rapoport said. “I could now prescribe a medication that people could take at home to decrease or stop the migraine process in an hour or two.” The success of the triptans prompted pharmaceutical companies to search for new, more effective ways to treat migraine attacks, with better tolerability.
Seven different triptans were developed, some as injections or tablets and others as nasal sprays. “If one triptan didn’t work, we’d give a second and rarely a third,” Dr. Rapoport said. “We learned that if oral triptans did not work, the most likely issue was that it was not rapidly absorbed from the small intestine, as migraine patients have nausea, poor GI absorption, and slow transit times. This prompted the greater use of injections and nasal sprays.” Headache specialists began combining triptan treatment with nonsteroidal anti-inflammatory drugs, offering further relief for the acute care of migraine.
Medication overuse headache
The years between 1993 and 2000, which saw all the current triptan drugs come onto the market, was an exhilarating one for headache specialists. But even those who were thrilled by the possibilities of the triptans, like Dr. Rapoport, soon came to recognize their limitations, in terms of side effects and poor tolerability for some patients.
Specialists also noticed something unsettling about the triptans: that patients’ headaches seemed to recur within a day, or occur more frequently over time, with higher medication use.
Medication overuse headache (MOH) was known to occur when patients treated migraine too often with acute care medications, especially over-the-counter analgesics and prescription opioids and barbiturates. Dr. Rapoport began warning at conferences and in seminars that MOH seemed to occur with the triptans as well. “In the beginning other doctors didn’t think the triptans could cause MOH, but I observed that patients who were taking triptans daily or almost daily were having increased headache frequency and the triptans stopped being effective. If they didn’t take the drug they were overusing, they were going to get much worse, almost like a withdrawal.”
Today, all seven triptans are now generic, and they remain a mainstay of migraine treatment: “Almost all of my patients are using, or have used a triptan,” Dr. Rapoport said. Yet researchers came to recognize the need for treatments targeting different pathways, both for prevention and acute care.
The next revolution: CGRP and gepants
Studies in the early 2000s began to show a link between the release of one ubiquitous nervous system neurotransmitter, calcitonin gene-related peptide, or CGRP, and migraine. They also noticed that blocking meningeal inflammation could lead to improvement in headache. Two new drug classes emerged from this science: monoclonal antibodies against CGRP or its receptor that had to be given by injection, and oral CGRP receptor blockers that could be used both as a preventive or as an acute care medication.
In 2018 the first monoclonal antibody against the CGRP receptor, erenumab (Aimovig, marketed by Amgen), delivered by injection, was approved for migraine prevention. Three others followed, most given by autoinjector, and one by IV infusion in office or hospital settings. “Those drugs are great,” Dr. Rapoport said. “You take one shot a month or every 3 months, and your headaches drop by 50% or more with very few side effects. Some patients actually see their migraines disappear.”
The following year ubrogepant (Ubrelvy, marketed by AbbVie), the first of a novel class of oral CGRP receptor blockers known as “gepants,” was approved to treat acute migraine. The FDA soon approved another gepant, rimegepant (Nurtec, marketed by Pfizer), which received indications both for prevention and for stopping a migraine attack acutely.
Both classes of therapies – the antibodies and the gepants – are far costlier than the triptans, which are all generic, and may not be needed for every migraine patient. With the gepants, for example, insurers may restrict use to people who have not responded to triptans or for whom triptans are contraindicated or cause too many adverse events. But the CGRP-targeted therapies as a whole “have been every bit as revolutionary” as the triptans, Dr. Rapoport said. The treatments work quickly to resolve headache and disability and get the patient functioning within an hour or two, and there are fewer side effects.
In a review article published in CNS Drugs in 2021, Dr. Rapoport and his colleagues reported that the anti-CGRP treatment with gepants did not appear linked to medication overuse headache, as virtually all previous acute care medication classes did, and could be used in patients who had previously reported MOH. “I am confident that over the next few years, more people will be using them as insurance coverage will improve for patients living with migraine,” he said.
Headache treatment today
Migraine specialists and patients now have a staggering range of therapeutic options. Approved treatments now include prevention of migraine with onabotulinumtoxinA (Botox, marketed by the Allergan division of AbbVie) injections, which work alone and with other medicines; acute care treatment with ditans like lasmiditan (Reyvow, marketed by Lilly*), a category of acute care medicines that work like triptans but target different serotonin receptors. Five devices have been cleared for migraine and other types of headache by the FDA. These work alone or along with medication and can be used acutely or preventively. The devices “should be used more,” Dr. Rapoport said, but are not yet well covered by insurance.
Thirty years after the triptans, scientists and researchers continue to explore the pathophysiology of headache disorders, finding new pathways and identifying new potential targets.
“There are many parts of the brain and brain stem that are involved, as well as the thalamus and hypothalamus,” Dr. Rapoport said. “It’s interesting that the newer medications, and some of the older ones, work in the peripheral nervous system, outside the brain stem in the trigeminovascular system, to modulate the central nervous system. We also know that the CGRP system is involved with cellular second-order messengers. Stimulating and blocking this chain of reactions with newer drugs may become treatments in the future.”
Recent research has focused on a blood vessel dilating neurotransmitter, pituitary adenylate-cyclase-activating polypeptide, or PACAP-38, as a potential therapeutic target. Psychedelic medications such as psilocybin, strong pain medications such as ketamine, and even cannabinoids such as marijuana have all been investigated in migraine. Biofeedback therapies, mindfulness, and other behavioral interventions also have proved effective.
“I expect the next 2-5 years to bring us many important clinical trials on new types of pharmacological treatments,” Dr. Rapoport said. “This is a wonderful time to be a doctor or nurse treating patients living with migraine. When I started out treating headache, 51 years ago, we had only ergotamine tartrate. Today we have so many therapies and combinations of therapies that I hardly know where to start.”
Dr. Rapoport has served as a consultant to or speaker for AbbVie, Amgen, Biohaven, Cala Health, Lundbeck, Satsuma, and Teva, among others.
*Correction, 3/30/23: An earlier version of this article misstated the name of the company that markets Reyvow.
Headache treatment before the early 1990s was marked by decades of improvisation with mostly unapproved agents, followed by an explosion of scientific interest and new treatments developed specifically for migraine.
But this is largely thanks to the sea change that occurred 30 years ago.
In an interview, Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews, past president of the International Headache Society and clinical professor of neurology at UCLA’s David Geffen School of Medicine in Los Angeles, recalled what it was like to treat patients before and after triptan medications came onto the market.
After the first of these anti-migraine agents, sumatriptan, was approved by the Food and Drug Administration in late December 1992, headache specialists found themselves with a powerful, approved treatment that validated their commitment to solving the disorder, and helped put to rest a persistent but mistaken notion that migraine was a psychiatric condition affecting young women.
But in the 1970s and 1980s, “there wasn’t great science explaining the pathophysiology of common primary headaches like tension-type headache, cluster headache, and migraine,” Dr. Rapoport recalled. “There is often comorbid depression and anxiety with migraine, and sometimes more serious psychiatric disease, but it doesn’t mean migraine is caused by psychological issues. Now we see it clearly as a disease of the brain, but it took years of investigation to prove that.”
The early years
Dr. Rapoport’s journey with headache began in 1972, when he joined a private neurology practice in Stamford and Greenwich, Conn. Neurologists were frowned upon then for having too much interest in headache, he said. There was poor remuneration for doctors treating headache patients, who were hard to properly diagnose and effectively care for. Few medications could effectively stop a migraine attack or reliably reduce the frequency of headaches or the disability they caused.
On weekends Dr. Rapoport covered emergency departments and ICUs at three hospitals, where standard treatment for a migraine attack was injectable opiates. Not only did this treatment aggravate nausea, a common migraine symptom, “but it did not stop the migraine process.” Once the pain relief wore off, patients woke up with the same headache, Dr. Rapoport recalled. “The other drug that was available was ergotamine tartrate” – a fungal alkaloid used since medieval times to treat headache – “given sublingually. It helped the headache slightly but increased the nausea. DHE, or dihydroergotamine, was available only by injection and not used very much.”
DHE, a semi-synthetic molecule based on ergotamine, had FDA approval for migraine, but was complicated to administer. Like the opioids, it provoked vomiting when given intravenously, in patients already suffering migraine-induced nausea. But Dr. Rapoport, along with some of his colleagues, felt that there was a role for DHE for the most severe subtypes of patients, those with long histories of frequent migraines.
“We put people in the hospital and we gave them intravenous DHE. Eventually I got the idea to give it intramuscularly or subcutaneously in the emergency room or my office. When you give it that way, it doesn’t work as quickly but has fewer side effects.” Dr. Rapoport designed a cocktail by coadministering promethazine for nausea, and eventually added a steroid, dexamethasone. The triple shots worked on most patients experiencing severe daily or near-daily migraine attacks, Dr. Rapoport saw, and he began administering the drug combination at The New England Center for Headache in Stamford and Greenwich, Conn., which he opened with Dr. Fred D. Sheftell in 1979.
“The triple shots really worked,” Dr. Rapoport recalled. “There was no need to keep patients in the office or emergency room for intravenous therapy. The patients never called to complain or came back the next day,” he said, as often occurred with opioid treatment.
Dr. Rapoport had learned early in his residency, in the late 1960s, from Dr. David R. Coddon, a neurologist at Mount Sinai hospital in New York, that a tricyclic antidepressant, imipramine, could be helpful in some patients with frequent migraine attacks. As evidence trickled in that other antidepressants, beta-blockers, and antiepileptic drugs might have preventive properties, Dr. Rapoport and others prescribed them for certain patients. But of all the drugs in the headache specialists’ repertoire, few were approved for either treatment or prevention. “And this continued until the triptans,” Dr. Rapoport said.
The triptan era
Sumatriptan was developed by Glaxo for the acute treatment of migraine. The medication, first available only as self-administered subcutaneous injections, was originally designed to bind to vascular serotonin receptors to allow selective constriction of cranial vessels that dilate, causing pain, during a migraine attack. (Years later it was discovered that triptans also worked as anti-inflammatory agents that decreased the release of the neurotransmitter calcitonin gene-related peptide, or CGRP.)
Triptans “changed the world for migraine patients and for me,” Dr. Rapoport said. “I could now prescribe a medication that people could take at home to decrease or stop the migraine process in an hour or two.” The success of the triptans prompted pharmaceutical companies to search for new, more effective ways to treat migraine attacks, with better tolerability.
Seven different triptans were developed, some as injections or tablets and others as nasal sprays. “If one triptan didn’t work, we’d give a second and rarely a third,” Dr. Rapoport said. “We learned that if oral triptans did not work, the most likely issue was that it was not rapidly absorbed from the small intestine, as migraine patients have nausea, poor GI absorption, and slow transit times. This prompted the greater use of injections and nasal sprays.” Headache specialists began combining triptan treatment with nonsteroidal anti-inflammatory drugs, offering further relief for the acute care of migraine.
Medication overuse headache
The years between 1993 and 2000, which saw all the current triptan drugs come onto the market, was an exhilarating one for headache specialists. But even those who were thrilled by the possibilities of the triptans, like Dr. Rapoport, soon came to recognize their limitations, in terms of side effects and poor tolerability for some patients.
Specialists also noticed something unsettling about the triptans: that patients’ headaches seemed to recur within a day, or occur more frequently over time, with higher medication use.
Medication overuse headache (MOH) was known to occur when patients treated migraine too often with acute care medications, especially over-the-counter analgesics and prescription opioids and barbiturates. Dr. Rapoport began warning at conferences and in seminars that MOH seemed to occur with the triptans as well. “In the beginning other doctors didn’t think the triptans could cause MOH, but I observed that patients who were taking triptans daily or almost daily were having increased headache frequency and the triptans stopped being effective. If they didn’t take the drug they were overusing, they were going to get much worse, almost like a withdrawal.”
Today, all seven triptans are now generic, and they remain a mainstay of migraine treatment: “Almost all of my patients are using, or have used a triptan,” Dr. Rapoport said. Yet researchers came to recognize the need for treatments targeting different pathways, both for prevention and acute care.
The next revolution: CGRP and gepants
Studies in the early 2000s began to show a link between the release of one ubiquitous nervous system neurotransmitter, calcitonin gene-related peptide, or CGRP, and migraine. They also noticed that blocking meningeal inflammation could lead to improvement in headache. Two new drug classes emerged from this science: monoclonal antibodies against CGRP or its receptor that had to be given by injection, and oral CGRP receptor blockers that could be used both as a preventive or as an acute care medication.
In 2018 the first monoclonal antibody against the CGRP receptor, erenumab (Aimovig, marketed by Amgen), delivered by injection, was approved for migraine prevention. Three others followed, most given by autoinjector, and one by IV infusion in office or hospital settings. “Those drugs are great,” Dr. Rapoport said. “You take one shot a month or every 3 months, and your headaches drop by 50% or more with very few side effects. Some patients actually see their migraines disappear.”
The following year ubrogepant (Ubrelvy, marketed by AbbVie), the first of a novel class of oral CGRP receptor blockers known as “gepants,” was approved to treat acute migraine. The FDA soon approved another gepant, rimegepant (Nurtec, marketed by Pfizer), which received indications both for prevention and for stopping a migraine attack acutely.
Both classes of therapies – the antibodies and the gepants – are far costlier than the triptans, which are all generic, and may not be needed for every migraine patient. With the gepants, for example, insurers may restrict use to people who have not responded to triptans or for whom triptans are contraindicated or cause too many adverse events. But the CGRP-targeted therapies as a whole “have been every bit as revolutionary” as the triptans, Dr. Rapoport said. The treatments work quickly to resolve headache and disability and get the patient functioning within an hour or two, and there are fewer side effects.
In a review article published in CNS Drugs in 2021, Dr. Rapoport and his colleagues reported that the anti-CGRP treatment with gepants did not appear linked to medication overuse headache, as virtually all previous acute care medication classes did, and could be used in patients who had previously reported MOH. “I am confident that over the next few years, more people will be using them as insurance coverage will improve for patients living with migraine,” he said.
Headache treatment today
Migraine specialists and patients now have a staggering range of therapeutic options. Approved treatments now include prevention of migraine with onabotulinumtoxinA (Botox, marketed by the Allergan division of AbbVie) injections, which work alone and with other medicines; acute care treatment with ditans like lasmiditan (Reyvow, marketed by Lilly*), a category of acute care medicines that work like triptans but target different serotonin receptors. Five devices have been cleared for migraine and other types of headache by the FDA. These work alone or along with medication and can be used acutely or preventively. The devices “should be used more,” Dr. Rapoport said, but are not yet well covered by insurance.
Thirty years after the triptans, scientists and researchers continue to explore the pathophysiology of headache disorders, finding new pathways and identifying new potential targets.
“There are many parts of the brain and brain stem that are involved, as well as the thalamus and hypothalamus,” Dr. Rapoport said. “It’s interesting that the newer medications, and some of the older ones, work in the peripheral nervous system, outside the brain stem in the trigeminovascular system, to modulate the central nervous system. We also know that the CGRP system is involved with cellular second-order messengers. Stimulating and blocking this chain of reactions with newer drugs may become treatments in the future.”
Recent research has focused on a blood vessel dilating neurotransmitter, pituitary adenylate-cyclase-activating polypeptide, or PACAP-38, as a potential therapeutic target. Psychedelic medications such as psilocybin, strong pain medications such as ketamine, and even cannabinoids such as marijuana have all been investigated in migraine. Biofeedback therapies, mindfulness, and other behavioral interventions also have proved effective.
“I expect the next 2-5 years to bring us many important clinical trials on new types of pharmacological treatments,” Dr. Rapoport said. “This is a wonderful time to be a doctor or nurse treating patients living with migraine. When I started out treating headache, 51 years ago, we had only ergotamine tartrate. Today we have so many therapies and combinations of therapies that I hardly know where to start.”
Dr. Rapoport has served as a consultant to or speaker for AbbVie, Amgen, Biohaven, Cala Health, Lundbeck, Satsuma, and Teva, among others.
*Correction, 3/30/23: An earlier version of this article misstated the name of the company that markets Reyvow.