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Delayed clinical care after concussion may prolong recovery
, according to a study published Jan. 6 in JAMA Neurology.
In addition, more severe visual motion sensitivity symptoms are associated with longer recovery times, said lead author Anthony P. Kontos, PhD, and colleagues. Dr. Kontos is associate professor of orthopedic surgery at the University of Pittsburgh and the research director of the University of Pittsburgh Medical Center Sports Medicine Concussion Program.
“Without clinical guidance and behavioral management recommendations post injury, athletes may have been engaging in counterproductive recovery strategies, such as a strict rest or excessive physical activity,” the authors said. “This explanation is supported by the fact that athletes recovered in a similar amount of time after that first evaluation.”
Various factors may influence recovery after a concussion, including age, sex, and comorbidities. To examine the relationship between time since injury at the start of clinical care and recovery time, the investigators conducted a retrospective, cross-sectional study. They analyzed data from patients seen in a sports medicine clinic between August 2016 and March 2018. Eligible patients were aged 12-22 years and had a diagnosed, symptomatic, sport-related concussion. The researchers excluded patients with incomplete recovery data.
The investigators included 162 patients in their analyses; 98 of these patients were seen within 7 days of the injury, and 64 were seen 8-20 days after a concussion. Both groups had a mean age of 15 years and similar proportions of female patients (52% in the early-care group vs. 62.5% in the late-care group). At the first clinical visit, symptom severity and cognitive, ocular, and vestibular test results were similar in both groups.
The researchers defined recovery time as the number of days from injury until the date of clearance for a full return to play. Physicians cleared patients to return to play when they returned to preinjury levels of symptoms and preinjury performance on cognitive, ocular, and vestibular tests with no increase in symptoms after exertion.
Patients’ recovery times ranged from 9 to 299 days; the average recovery time was 57 days. Fifty-two percent of patients in the early-care group recovered in 30 days or fewer, compared with 19% of patients in late-care group. Patients in the early-care group had a mean recovery of 51.1 days, whereas patients in the late-care group had a mean recovery of 66 days.
In a logistic regression model, late care “was associated with a 5.8-times increased likelihood of a recovery longer than 30 days,” the researchers reported. Visual motion sensitivity symptoms also were associated with increased odds of protracted recovery (adjusted odds ratio, 4.5).
“Once care was established, time to recovery did not differ for athletes evaluated within the first week of injury compared with those evaluated 2-3 weeks post injury,” Dr. Kontos and colleagues concluded. “Education on injury and behavioral recommendations to optimize concussion recovery and earlier initiation of active rehabilitation strategies, including exertion and vestibular therapy, are plausible explanations for the association of a shorter recovery time with earlier care. However, future research should focus on the specific mechanisms by which earlier health care postconcussion promotes faster recovery and determine if these findings apply to other subpopulations, including military personnel.”
The researchers noted that they excluded from their analysis 254 patients who had incomplete recovery data but otherwise met inclusion criteria, which may have led to selection bias.
Dr. Kontos disclosed grants from the National Football League and personal fees from APA Books and University of Pittsburgh projects outside the scope of this study.
SOURCE: Kontos AP et al. JAMA Neurol. 2020 Jan 6. doi: 10.1001/jamaneurol.2019.4552.
, according to a study published Jan. 6 in JAMA Neurology.
In addition, more severe visual motion sensitivity symptoms are associated with longer recovery times, said lead author Anthony P. Kontos, PhD, and colleagues. Dr. Kontos is associate professor of orthopedic surgery at the University of Pittsburgh and the research director of the University of Pittsburgh Medical Center Sports Medicine Concussion Program.
“Without clinical guidance and behavioral management recommendations post injury, athletes may have been engaging in counterproductive recovery strategies, such as a strict rest or excessive physical activity,” the authors said. “This explanation is supported by the fact that athletes recovered in a similar amount of time after that first evaluation.”
Various factors may influence recovery after a concussion, including age, sex, and comorbidities. To examine the relationship between time since injury at the start of clinical care and recovery time, the investigators conducted a retrospective, cross-sectional study. They analyzed data from patients seen in a sports medicine clinic between August 2016 and March 2018. Eligible patients were aged 12-22 years and had a diagnosed, symptomatic, sport-related concussion. The researchers excluded patients with incomplete recovery data.
The investigators included 162 patients in their analyses; 98 of these patients were seen within 7 days of the injury, and 64 were seen 8-20 days after a concussion. Both groups had a mean age of 15 years and similar proportions of female patients (52% in the early-care group vs. 62.5% in the late-care group). At the first clinical visit, symptom severity and cognitive, ocular, and vestibular test results were similar in both groups.
The researchers defined recovery time as the number of days from injury until the date of clearance for a full return to play. Physicians cleared patients to return to play when they returned to preinjury levels of symptoms and preinjury performance on cognitive, ocular, and vestibular tests with no increase in symptoms after exertion.
Patients’ recovery times ranged from 9 to 299 days; the average recovery time was 57 days. Fifty-two percent of patients in the early-care group recovered in 30 days or fewer, compared with 19% of patients in late-care group. Patients in the early-care group had a mean recovery of 51.1 days, whereas patients in the late-care group had a mean recovery of 66 days.
In a logistic regression model, late care “was associated with a 5.8-times increased likelihood of a recovery longer than 30 days,” the researchers reported. Visual motion sensitivity symptoms also were associated with increased odds of protracted recovery (adjusted odds ratio, 4.5).
“Once care was established, time to recovery did not differ for athletes evaluated within the first week of injury compared with those evaluated 2-3 weeks post injury,” Dr. Kontos and colleagues concluded. “Education on injury and behavioral recommendations to optimize concussion recovery and earlier initiation of active rehabilitation strategies, including exertion and vestibular therapy, are plausible explanations for the association of a shorter recovery time with earlier care. However, future research should focus on the specific mechanisms by which earlier health care postconcussion promotes faster recovery and determine if these findings apply to other subpopulations, including military personnel.”
The researchers noted that they excluded from their analysis 254 patients who had incomplete recovery data but otherwise met inclusion criteria, which may have led to selection bias.
Dr. Kontos disclosed grants from the National Football League and personal fees from APA Books and University of Pittsburgh projects outside the scope of this study.
SOURCE: Kontos AP et al. JAMA Neurol. 2020 Jan 6. doi: 10.1001/jamaneurol.2019.4552.
, according to a study published Jan. 6 in JAMA Neurology.
In addition, more severe visual motion sensitivity symptoms are associated with longer recovery times, said lead author Anthony P. Kontos, PhD, and colleagues. Dr. Kontos is associate professor of orthopedic surgery at the University of Pittsburgh and the research director of the University of Pittsburgh Medical Center Sports Medicine Concussion Program.
“Without clinical guidance and behavioral management recommendations post injury, athletes may have been engaging in counterproductive recovery strategies, such as a strict rest or excessive physical activity,” the authors said. “This explanation is supported by the fact that athletes recovered in a similar amount of time after that first evaluation.”
Various factors may influence recovery after a concussion, including age, sex, and comorbidities. To examine the relationship between time since injury at the start of clinical care and recovery time, the investigators conducted a retrospective, cross-sectional study. They analyzed data from patients seen in a sports medicine clinic between August 2016 and March 2018. Eligible patients were aged 12-22 years and had a diagnosed, symptomatic, sport-related concussion. The researchers excluded patients with incomplete recovery data.
The investigators included 162 patients in their analyses; 98 of these patients were seen within 7 days of the injury, and 64 were seen 8-20 days after a concussion. Both groups had a mean age of 15 years and similar proportions of female patients (52% in the early-care group vs. 62.5% in the late-care group). At the first clinical visit, symptom severity and cognitive, ocular, and vestibular test results were similar in both groups.
The researchers defined recovery time as the number of days from injury until the date of clearance for a full return to play. Physicians cleared patients to return to play when they returned to preinjury levels of symptoms and preinjury performance on cognitive, ocular, and vestibular tests with no increase in symptoms after exertion.
Patients’ recovery times ranged from 9 to 299 days; the average recovery time was 57 days. Fifty-two percent of patients in the early-care group recovered in 30 days or fewer, compared with 19% of patients in late-care group. Patients in the early-care group had a mean recovery of 51.1 days, whereas patients in the late-care group had a mean recovery of 66 days.
In a logistic regression model, late care “was associated with a 5.8-times increased likelihood of a recovery longer than 30 days,” the researchers reported. Visual motion sensitivity symptoms also were associated with increased odds of protracted recovery (adjusted odds ratio, 4.5).
“Once care was established, time to recovery did not differ for athletes evaluated within the first week of injury compared with those evaluated 2-3 weeks post injury,” Dr. Kontos and colleagues concluded. “Education on injury and behavioral recommendations to optimize concussion recovery and earlier initiation of active rehabilitation strategies, including exertion and vestibular therapy, are plausible explanations for the association of a shorter recovery time with earlier care. However, future research should focus on the specific mechanisms by which earlier health care postconcussion promotes faster recovery and determine if these findings apply to other subpopulations, including military personnel.”
The researchers noted that they excluded from their analysis 254 patients who had incomplete recovery data but otherwise met inclusion criteria, which may have led to selection bias.
Dr. Kontos disclosed grants from the National Football League and personal fees from APA Books and University of Pittsburgh projects outside the scope of this study.
SOURCE: Kontos AP et al. JAMA Neurol. 2020 Jan 6. doi: 10.1001/jamaneurol.2019.4552.
FROM JAMA NEUROLOGY
EEG surveillance, preseizure treatment prevents TSC epilepsy, cognitive loss
BALTIMORE – Monitoring children who have tuberous sclerosis with EEG and treating them with vigabatrin (Sabril) at the first sign of preseizure abnormalities, rather than the usual practice of no surveillance and waiting until they have seizures, prevents epilepsy and cognitive decline, according to European investigators.
Early surveillance is recommended and standard practice in Europe. That’s not the case in the United States, but might be someday pending the results of the PREVENT trial (Preventing Epilepsy Using Vigabatrin In Infants With Tuberous Sclerosis Complex), an ongoing, National Institute of Neurological Disorders and Stroke–funded study to confirm the European findings.
“We are trying to convince doctors” in the United States and other “countries to do this. If you are not convinced to do early treatment,” at least “do surveillance with EEG. You will diagnose epilepsy earlier, and treat earlier, and children will do much better,” said Sergiusz Jozwiak, MD, PhD, head of pediatric neurology at Warsaw Medical University and recipient of an award from the U.S. Tuberous Sclerosis Alliance for his pioneering work.
Some U.S. physicians are already doing preventive treatment, but it’s hit and miss. “We are talking about monitoring children below the age of 2 years,” when seizures are associated with cognitive decline, he noted at the annual meeting of the American Epilepsy Society.
Dr. Jozwiak presented a follow-up at the meeting to his 2011 investigation, the first prevention study in tuberous sclerosis. Fourteen infants diagnosed within 2 months of birth underwent video-EEG monitoring every 4-6 weeks until age 2 years and were treated with vigabatrin 100-150 mg/kg per day when multifocal epileptiform discharges – a sign of impending seizures – were detected. Outcomes were compared with infants treated traditionally, with no EEG monitoring and vigabatrin only after they seized.
The children are about 9 years old now; the median IQ in the prevention arm is 94 versus 46 in the control group (P less than .03). Seven of the 14 prevention children (50%) never had a clinical seizure, while all but 1 of 25 (96%) in the control arm did (P = .001). Six of 11 prevention children (55%) versus 4 of 24 in the control group (17%), were able to come off antiepileptic drugs altogether, with no seizures (P less than .03). The work was published shortly before the epilepsy meeting.
The original 2011 report, which had similarly favorable outcomes when the children were 2 years old, led directly to the EpiStop trial, conducted at 16 mostly European centers and also reported at the meeting. Dr. Jozwiak was the senior investigator.
The design was different; all of the infants had EEG monitoring every 4 weeks until month 6, then every 6 weeks until age 12 months, then every 2 months until age 2 years. At the first detection of multifocal epileptiform discharges, infants were randomized 1:1 to vigabatrin or to the control group, with further monitoring followed by vigabatrin at the first seizure on EEG or first clinical seizure. An additional group of children – the open-label arm – also had EEG monitoring, but when to start vigabatrin was left up to the study site.
Only 50 of the original 94 children completed the trial to the full 2 years; tuberous sclerosis comorbidities drove many of them out, said lead investigator Katarzyna Kotulska-Jozwiak, MD, PhD, head of neurology at Children’s Memorial Health Institute, Warsaw.
Even so, the 25 children treated preventively in the randomized and open-label cohorts were more than three times as likely to be seizure free at 2 years (P = .01), and 74% less likely to develop drug-resistant epilepsy (P = .013). None of the prevention children developed infantile spasms versus 10 controls (40%) treated at first clinical or EEG seizure.
The incidence of neurodevelopmental delay was 34%, and autism 33%, at 24 months, and did not differ between prevention and control subjects. It’s probably because even children in the control group benefited from EEG surveillance and early treatment, the investigators said.
Historically, the rate of intellectual disability with usual treatment is around 60%, Dr. Kotulska-Jozwiak noted.
Overall, Dr. Jozwiak said that European physicians are more comfortable using vigabatrin than U.S. doctors, where the drug hasn’t been on the market as long and carries a Food and Drug Administration boxed warning of visual impairment. Its indications in the United States include infantile spasms in children 1-24 months old.
Levetiracetam (Keppra) is another option, but it’s not as effective in tuberous sclerosis. The PREVENT trial is using vigabatrin, and some U.S. doctors “are changing their minds, but it takes time,” Dr. Jozwiak said.
He noted that TSC is increasingly being diagnosed in utero, which gives a leg up on early diagnosis and prevention. The giveaways are heart tumors on ECG and cortical tubers on fetal MRI.
Dr. Jozwiak thinks the prevention approach might also help in other early seizure disorders, such as Sturge-Weber syndrome.
The work was funded by the European Commission and Polish government. Dr. Jozwiak and Dr. Kotulska-Jozwiak didn’t have any disclosures.
SOURCES: Jozwiak S et al. AES 2019, Abstract 1.218; Kotulska-Jozwiak K et al. AES 2019, Abstract 2.121.
BALTIMORE – Monitoring children who have tuberous sclerosis with EEG and treating them with vigabatrin (Sabril) at the first sign of preseizure abnormalities, rather than the usual practice of no surveillance and waiting until they have seizures, prevents epilepsy and cognitive decline, according to European investigators.
Early surveillance is recommended and standard practice in Europe. That’s not the case in the United States, but might be someday pending the results of the PREVENT trial (Preventing Epilepsy Using Vigabatrin In Infants With Tuberous Sclerosis Complex), an ongoing, National Institute of Neurological Disorders and Stroke–funded study to confirm the European findings.
“We are trying to convince doctors” in the United States and other “countries to do this. If you are not convinced to do early treatment,” at least “do surveillance with EEG. You will diagnose epilepsy earlier, and treat earlier, and children will do much better,” said Sergiusz Jozwiak, MD, PhD, head of pediatric neurology at Warsaw Medical University and recipient of an award from the U.S. Tuberous Sclerosis Alliance for his pioneering work.
Some U.S. physicians are already doing preventive treatment, but it’s hit and miss. “We are talking about monitoring children below the age of 2 years,” when seizures are associated with cognitive decline, he noted at the annual meeting of the American Epilepsy Society.
Dr. Jozwiak presented a follow-up at the meeting to his 2011 investigation, the first prevention study in tuberous sclerosis. Fourteen infants diagnosed within 2 months of birth underwent video-EEG monitoring every 4-6 weeks until age 2 years and were treated with vigabatrin 100-150 mg/kg per day when multifocal epileptiform discharges – a sign of impending seizures – were detected. Outcomes were compared with infants treated traditionally, with no EEG monitoring and vigabatrin only after they seized.
The children are about 9 years old now; the median IQ in the prevention arm is 94 versus 46 in the control group (P less than .03). Seven of the 14 prevention children (50%) never had a clinical seizure, while all but 1 of 25 (96%) in the control arm did (P = .001). Six of 11 prevention children (55%) versus 4 of 24 in the control group (17%), were able to come off antiepileptic drugs altogether, with no seizures (P less than .03). The work was published shortly before the epilepsy meeting.
The original 2011 report, which had similarly favorable outcomes when the children were 2 years old, led directly to the EpiStop trial, conducted at 16 mostly European centers and also reported at the meeting. Dr. Jozwiak was the senior investigator.
The design was different; all of the infants had EEG monitoring every 4 weeks until month 6, then every 6 weeks until age 12 months, then every 2 months until age 2 years. At the first detection of multifocal epileptiform discharges, infants were randomized 1:1 to vigabatrin or to the control group, with further monitoring followed by vigabatrin at the first seizure on EEG or first clinical seizure. An additional group of children – the open-label arm – also had EEG monitoring, but when to start vigabatrin was left up to the study site.
Only 50 of the original 94 children completed the trial to the full 2 years; tuberous sclerosis comorbidities drove many of them out, said lead investigator Katarzyna Kotulska-Jozwiak, MD, PhD, head of neurology at Children’s Memorial Health Institute, Warsaw.
Even so, the 25 children treated preventively in the randomized and open-label cohorts were more than three times as likely to be seizure free at 2 years (P = .01), and 74% less likely to develop drug-resistant epilepsy (P = .013). None of the prevention children developed infantile spasms versus 10 controls (40%) treated at first clinical or EEG seizure.
The incidence of neurodevelopmental delay was 34%, and autism 33%, at 24 months, and did not differ between prevention and control subjects. It’s probably because even children in the control group benefited from EEG surveillance and early treatment, the investigators said.
Historically, the rate of intellectual disability with usual treatment is around 60%, Dr. Kotulska-Jozwiak noted.
Overall, Dr. Jozwiak said that European physicians are more comfortable using vigabatrin than U.S. doctors, where the drug hasn’t been on the market as long and carries a Food and Drug Administration boxed warning of visual impairment. Its indications in the United States include infantile spasms in children 1-24 months old.
Levetiracetam (Keppra) is another option, but it’s not as effective in tuberous sclerosis. The PREVENT trial is using vigabatrin, and some U.S. doctors “are changing their minds, but it takes time,” Dr. Jozwiak said.
He noted that TSC is increasingly being diagnosed in utero, which gives a leg up on early diagnosis and prevention. The giveaways are heart tumors on ECG and cortical tubers on fetal MRI.
Dr. Jozwiak thinks the prevention approach might also help in other early seizure disorders, such as Sturge-Weber syndrome.
The work was funded by the European Commission and Polish government. Dr. Jozwiak and Dr. Kotulska-Jozwiak didn’t have any disclosures.
SOURCES: Jozwiak S et al. AES 2019, Abstract 1.218; Kotulska-Jozwiak K et al. AES 2019, Abstract 2.121.
BALTIMORE – Monitoring children who have tuberous sclerosis with EEG and treating them with vigabatrin (Sabril) at the first sign of preseizure abnormalities, rather than the usual practice of no surveillance and waiting until they have seizures, prevents epilepsy and cognitive decline, according to European investigators.
Early surveillance is recommended and standard practice in Europe. That’s not the case in the United States, but might be someday pending the results of the PREVENT trial (Preventing Epilepsy Using Vigabatrin In Infants With Tuberous Sclerosis Complex), an ongoing, National Institute of Neurological Disorders and Stroke–funded study to confirm the European findings.
“We are trying to convince doctors” in the United States and other “countries to do this. If you are not convinced to do early treatment,” at least “do surveillance with EEG. You will diagnose epilepsy earlier, and treat earlier, and children will do much better,” said Sergiusz Jozwiak, MD, PhD, head of pediatric neurology at Warsaw Medical University and recipient of an award from the U.S. Tuberous Sclerosis Alliance for his pioneering work.
Some U.S. physicians are already doing preventive treatment, but it’s hit and miss. “We are talking about monitoring children below the age of 2 years,” when seizures are associated with cognitive decline, he noted at the annual meeting of the American Epilepsy Society.
Dr. Jozwiak presented a follow-up at the meeting to his 2011 investigation, the first prevention study in tuberous sclerosis. Fourteen infants diagnosed within 2 months of birth underwent video-EEG monitoring every 4-6 weeks until age 2 years and were treated with vigabatrin 100-150 mg/kg per day when multifocal epileptiform discharges – a sign of impending seizures – were detected. Outcomes were compared with infants treated traditionally, with no EEG monitoring and vigabatrin only after they seized.
The children are about 9 years old now; the median IQ in the prevention arm is 94 versus 46 in the control group (P less than .03). Seven of the 14 prevention children (50%) never had a clinical seizure, while all but 1 of 25 (96%) in the control arm did (P = .001). Six of 11 prevention children (55%) versus 4 of 24 in the control group (17%), were able to come off antiepileptic drugs altogether, with no seizures (P less than .03). The work was published shortly before the epilepsy meeting.
The original 2011 report, which had similarly favorable outcomes when the children were 2 years old, led directly to the EpiStop trial, conducted at 16 mostly European centers and also reported at the meeting. Dr. Jozwiak was the senior investigator.
The design was different; all of the infants had EEG monitoring every 4 weeks until month 6, then every 6 weeks until age 12 months, then every 2 months until age 2 years. At the first detection of multifocal epileptiform discharges, infants were randomized 1:1 to vigabatrin or to the control group, with further monitoring followed by vigabatrin at the first seizure on EEG or first clinical seizure. An additional group of children – the open-label arm – also had EEG monitoring, but when to start vigabatrin was left up to the study site.
Only 50 of the original 94 children completed the trial to the full 2 years; tuberous sclerosis comorbidities drove many of them out, said lead investigator Katarzyna Kotulska-Jozwiak, MD, PhD, head of neurology at Children’s Memorial Health Institute, Warsaw.
Even so, the 25 children treated preventively in the randomized and open-label cohorts were more than three times as likely to be seizure free at 2 years (P = .01), and 74% less likely to develop drug-resistant epilepsy (P = .013). None of the prevention children developed infantile spasms versus 10 controls (40%) treated at first clinical or EEG seizure.
The incidence of neurodevelopmental delay was 34%, and autism 33%, at 24 months, and did not differ between prevention and control subjects. It’s probably because even children in the control group benefited from EEG surveillance and early treatment, the investigators said.
Historically, the rate of intellectual disability with usual treatment is around 60%, Dr. Kotulska-Jozwiak noted.
Overall, Dr. Jozwiak said that European physicians are more comfortable using vigabatrin than U.S. doctors, where the drug hasn’t been on the market as long and carries a Food and Drug Administration boxed warning of visual impairment. Its indications in the United States include infantile spasms in children 1-24 months old.
Levetiracetam (Keppra) is another option, but it’s not as effective in tuberous sclerosis. The PREVENT trial is using vigabatrin, and some U.S. doctors “are changing their minds, but it takes time,” Dr. Jozwiak said.
He noted that TSC is increasingly being diagnosed in utero, which gives a leg up on early diagnosis and prevention. The giveaways are heart tumors on ECG and cortical tubers on fetal MRI.
Dr. Jozwiak thinks the prevention approach might also help in other early seizure disorders, such as Sturge-Weber syndrome.
The work was funded by the European Commission and Polish government. Dr. Jozwiak and Dr. Kotulska-Jozwiak didn’t have any disclosures.
SOURCES: Jozwiak S et al. AES 2019, Abstract 1.218; Kotulska-Jozwiak K et al. AES 2019, Abstract 2.121.
REPORTING FROM AES 2019
Experts call to revise the Uniform Determination of Death Act
, according to an editorial published online Dec. 24, 2019, in Annals of Internal Medicine. Proposed revisions would identify the standards for determining death by neurologic criteria and address the question of whether consent is required to make this determination. If accepted, the revisions would enhance public trust in the determination of death by neurologic criteria, the authors said.
“There is a disconnect between the medical and legal standards for brain death,” said Ariane K. Lewis, MD, associate professor of neurology and neurosurgery at New York University and lead author of the editorial. The discrepancy must be remedied because it has led to lawsuits and has proved to be problematic from a societal standpoint, she added.
“We defend changing the law to match medical practice, rather than changing medical practice to match the law,” said Thaddeus Mason Pope, JD, PhD, director of the Health Law Institute at Mitchell Hamline School of Law in Saint Paul, Minnesota, and an author of the editorial.
Accepted medical standards are unclear
The UDDA was drafted in 1981 to establish a uniform legal standard for death by neurologic criteria. A person with “irreversible cessation of all functions of the entire brain, including the brainstem,” is dead, according to the statute. A determination of death, it adds, “must be made in accordance with accepted medical standards.”
But the medical standards used to determine death by neurologic cause have not been uniform. In 2015, the Supreme Court of Nevada ruled that it was not clear that the standard published by the American Academy of Neurology (AAN), which had been used in the case at issue, was the “accepted medical standard.” An AAN summit later affirmed that the accepted medical standards for determination of death by neurologic cause are the 2010 AAN standard for determination of brain death in adults and the 2011 Society of Critical Care Medicine (SCCM), American Academy of Pediatrics (AAP), and Child Neurology Society (CNS) standard for determination of brain death in children. The Nevada legislature amended the state UDDA to identify these standards as the accepted standards. A revised UDDA also should identify these standards and grant an administrative agency (i.e., the board of medicine) the power to review and update the accepted medical standards as needed, according to the editorial.
To the extent that hospitals are not following the AAN or SCCM/AAP/CNS standards for determining death by neurologic cause, “enshrining” these standards in a revised UDDA “should increase uniformity and consistency” in hospitals’ policies on brain death, Dr. Pope said.
The question of hormonal function
Lawsuits in California and Nevada raised the question of whether the pituitary gland and hypothalamus are parts of the brain. If so, then the accepted medical standards for death by neurologic cause are not consistent with the statutory requirements for the determination of death, since the former do not test for cessation of hormonal function.
The current edition of the adult standards for determining death by neurologic cause were published in 2010. “Whenever we measure brain death, we’re not measuring the cessation of all functions of the entire brain,” Dr. Pope said. “That’s not a new thing; that’s been the case for a long time.”
To address the discrepancy between medical practice and the legal statute, Dr. Lewis and colleagues proposed that the UDDA’s reference to “irreversible cessation of functions of the entire brain” be followed by the following clause: “including the brainstem, leading to unresponsive coma with loss of capacity for consciousness, brainstem areflexia, and the inability to breathe spontaneously.” An alternative revision would be to add the briefer phrase “... with the exception of hormonal function.”
Authors say consent is not required for testing
Other complications have arisen from the UDDA’s failure to specify whether consent is required for a determination of death by neurologic cause. Court rulings on this question have not been consistent. Dr. Lewis and colleagues propose adding the following text to the UDDA: “Reasonable efforts should be made to notify a patient’s legally authorized decision-maker before performing a determination of death by neurologic criteria, but consent is not required to initiate such an evaluation.”
The proposed revisions to the UDDA “might give [clinicians] more confidence to proceed with brain death testing, because it would clarify that they don’t need the parents’ [or the patient’s legally authorized decision-maker] consent to do the tests,” said Dr. Pope. “If anything, they might even have a duty to do the tests.”
The final problem with the UDDA that Dr. Lewis and colleagues cited is that it does not provide clear guidance about how to respond to religious objections to discontinuation of organ support after a determination of death by neurologic cause. “Because the issue is rather complicated, we have not advocated for a singular position related to this [question] in our revised UDDA,” Dr. Lewis said. “Rather, we recommended the need for a multidisciplinary group to come together to determine what is the best approach. In an ideal world, this [approach] would be universal throughout the country.”
Although a revised UDDA would provide greater clarity to physicians and promote uniformity of practice, it would not resolve ongoing theological and philosophical debates about whether brain death is biological death, Dr. Pope said. “The key thing is that it would give clinicians a green light or certainty and clarity that they may proceed to do the test in the first place. If the tests are positive and the patient really is dead, then they could proceed to organ procurement or to move to the morgue.”
Dr. Lewis is a member of various AAN committees and working groups but receives no compensation for her role. A coauthor received personal fees from the AAN that were unrelated to the editorial.
SOURCE: Lewis A et al. Ann Intern Med. 2019 Dec 24. doi: 10.7326/M19-2731.
, according to an editorial published online Dec. 24, 2019, in Annals of Internal Medicine. Proposed revisions would identify the standards for determining death by neurologic criteria and address the question of whether consent is required to make this determination. If accepted, the revisions would enhance public trust in the determination of death by neurologic criteria, the authors said.
“There is a disconnect between the medical and legal standards for brain death,” said Ariane K. Lewis, MD, associate professor of neurology and neurosurgery at New York University and lead author of the editorial. The discrepancy must be remedied because it has led to lawsuits and has proved to be problematic from a societal standpoint, she added.
“We defend changing the law to match medical practice, rather than changing medical practice to match the law,” said Thaddeus Mason Pope, JD, PhD, director of the Health Law Institute at Mitchell Hamline School of Law in Saint Paul, Minnesota, and an author of the editorial.
Accepted medical standards are unclear
The UDDA was drafted in 1981 to establish a uniform legal standard for death by neurologic criteria. A person with “irreversible cessation of all functions of the entire brain, including the brainstem,” is dead, according to the statute. A determination of death, it adds, “must be made in accordance with accepted medical standards.”
But the medical standards used to determine death by neurologic cause have not been uniform. In 2015, the Supreme Court of Nevada ruled that it was not clear that the standard published by the American Academy of Neurology (AAN), which had been used in the case at issue, was the “accepted medical standard.” An AAN summit later affirmed that the accepted medical standards for determination of death by neurologic cause are the 2010 AAN standard for determination of brain death in adults and the 2011 Society of Critical Care Medicine (SCCM), American Academy of Pediatrics (AAP), and Child Neurology Society (CNS) standard for determination of brain death in children. The Nevada legislature amended the state UDDA to identify these standards as the accepted standards. A revised UDDA also should identify these standards and grant an administrative agency (i.e., the board of medicine) the power to review and update the accepted medical standards as needed, according to the editorial.
To the extent that hospitals are not following the AAN or SCCM/AAP/CNS standards for determining death by neurologic cause, “enshrining” these standards in a revised UDDA “should increase uniformity and consistency” in hospitals’ policies on brain death, Dr. Pope said.
The question of hormonal function
Lawsuits in California and Nevada raised the question of whether the pituitary gland and hypothalamus are parts of the brain. If so, then the accepted medical standards for death by neurologic cause are not consistent with the statutory requirements for the determination of death, since the former do not test for cessation of hormonal function.
The current edition of the adult standards for determining death by neurologic cause were published in 2010. “Whenever we measure brain death, we’re not measuring the cessation of all functions of the entire brain,” Dr. Pope said. “That’s not a new thing; that’s been the case for a long time.”
To address the discrepancy between medical practice and the legal statute, Dr. Lewis and colleagues proposed that the UDDA’s reference to “irreversible cessation of functions of the entire brain” be followed by the following clause: “including the brainstem, leading to unresponsive coma with loss of capacity for consciousness, brainstem areflexia, and the inability to breathe spontaneously.” An alternative revision would be to add the briefer phrase “... with the exception of hormonal function.”
Authors say consent is not required for testing
Other complications have arisen from the UDDA’s failure to specify whether consent is required for a determination of death by neurologic cause. Court rulings on this question have not been consistent. Dr. Lewis and colleagues propose adding the following text to the UDDA: “Reasonable efforts should be made to notify a patient’s legally authorized decision-maker before performing a determination of death by neurologic criteria, but consent is not required to initiate such an evaluation.”
The proposed revisions to the UDDA “might give [clinicians] more confidence to proceed with brain death testing, because it would clarify that they don’t need the parents’ [or the patient’s legally authorized decision-maker] consent to do the tests,” said Dr. Pope. “If anything, they might even have a duty to do the tests.”
The final problem with the UDDA that Dr. Lewis and colleagues cited is that it does not provide clear guidance about how to respond to religious objections to discontinuation of organ support after a determination of death by neurologic cause. “Because the issue is rather complicated, we have not advocated for a singular position related to this [question] in our revised UDDA,” Dr. Lewis said. “Rather, we recommended the need for a multidisciplinary group to come together to determine what is the best approach. In an ideal world, this [approach] would be universal throughout the country.”
Although a revised UDDA would provide greater clarity to physicians and promote uniformity of practice, it would not resolve ongoing theological and philosophical debates about whether brain death is biological death, Dr. Pope said. “The key thing is that it would give clinicians a green light or certainty and clarity that they may proceed to do the test in the first place. If the tests are positive and the patient really is dead, then they could proceed to organ procurement or to move to the morgue.”
Dr. Lewis is a member of various AAN committees and working groups but receives no compensation for her role. A coauthor received personal fees from the AAN that were unrelated to the editorial.
SOURCE: Lewis A et al. Ann Intern Med. 2019 Dec 24. doi: 10.7326/M19-2731.
, according to an editorial published online Dec. 24, 2019, in Annals of Internal Medicine. Proposed revisions would identify the standards for determining death by neurologic criteria and address the question of whether consent is required to make this determination. If accepted, the revisions would enhance public trust in the determination of death by neurologic criteria, the authors said.
“There is a disconnect between the medical and legal standards for brain death,” said Ariane K. Lewis, MD, associate professor of neurology and neurosurgery at New York University and lead author of the editorial. The discrepancy must be remedied because it has led to lawsuits and has proved to be problematic from a societal standpoint, she added.
“We defend changing the law to match medical practice, rather than changing medical practice to match the law,” said Thaddeus Mason Pope, JD, PhD, director of the Health Law Institute at Mitchell Hamline School of Law in Saint Paul, Minnesota, and an author of the editorial.
Accepted medical standards are unclear
The UDDA was drafted in 1981 to establish a uniform legal standard for death by neurologic criteria. A person with “irreversible cessation of all functions of the entire brain, including the brainstem,” is dead, according to the statute. A determination of death, it adds, “must be made in accordance with accepted medical standards.”
But the medical standards used to determine death by neurologic cause have not been uniform. In 2015, the Supreme Court of Nevada ruled that it was not clear that the standard published by the American Academy of Neurology (AAN), which had been used in the case at issue, was the “accepted medical standard.” An AAN summit later affirmed that the accepted medical standards for determination of death by neurologic cause are the 2010 AAN standard for determination of brain death in adults and the 2011 Society of Critical Care Medicine (SCCM), American Academy of Pediatrics (AAP), and Child Neurology Society (CNS) standard for determination of brain death in children. The Nevada legislature amended the state UDDA to identify these standards as the accepted standards. A revised UDDA also should identify these standards and grant an administrative agency (i.e., the board of medicine) the power to review and update the accepted medical standards as needed, according to the editorial.
To the extent that hospitals are not following the AAN or SCCM/AAP/CNS standards for determining death by neurologic cause, “enshrining” these standards in a revised UDDA “should increase uniformity and consistency” in hospitals’ policies on brain death, Dr. Pope said.
The question of hormonal function
Lawsuits in California and Nevada raised the question of whether the pituitary gland and hypothalamus are parts of the brain. If so, then the accepted medical standards for death by neurologic cause are not consistent with the statutory requirements for the determination of death, since the former do not test for cessation of hormonal function.
The current edition of the adult standards for determining death by neurologic cause were published in 2010. “Whenever we measure brain death, we’re not measuring the cessation of all functions of the entire brain,” Dr. Pope said. “That’s not a new thing; that’s been the case for a long time.”
To address the discrepancy between medical practice and the legal statute, Dr. Lewis and colleagues proposed that the UDDA’s reference to “irreversible cessation of functions of the entire brain” be followed by the following clause: “including the brainstem, leading to unresponsive coma with loss of capacity for consciousness, brainstem areflexia, and the inability to breathe spontaneously.” An alternative revision would be to add the briefer phrase “... with the exception of hormonal function.”
Authors say consent is not required for testing
Other complications have arisen from the UDDA’s failure to specify whether consent is required for a determination of death by neurologic cause. Court rulings on this question have not been consistent. Dr. Lewis and colleagues propose adding the following text to the UDDA: “Reasonable efforts should be made to notify a patient’s legally authorized decision-maker before performing a determination of death by neurologic criteria, but consent is not required to initiate such an evaluation.”
The proposed revisions to the UDDA “might give [clinicians] more confidence to proceed with brain death testing, because it would clarify that they don’t need the parents’ [or the patient’s legally authorized decision-maker] consent to do the tests,” said Dr. Pope. “If anything, they might even have a duty to do the tests.”
The final problem with the UDDA that Dr. Lewis and colleagues cited is that it does not provide clear guidance about how to respond to religious objections to discontinuation of organ support after a determination of death by neurologic cause. “Because the issue is rather complicated, we have not advocated for a singular position related to this [question] in our revised UDDA,” Dr. Lewis said. “Rather, we recommended the need for a multidisciplinary group to come together to determine what is the best approach. In an ideal world, this [approach] would be universal throughout the country.”
Although a revised UDDA would provide greater clarity to physicians and promote uniformity of practice, it would not resolve ongoing theological and philosophical debates about whether brain death is biological death, Dr. Pope said. “The key thing is that it would give clinicians a green light or certainty and clarity that they may proceed to do the test in the first place. If the tests are positive and the patient really is dead, then they could proceed to organ procurement or to move to the morgue.”
Dr. Lewis is a member of various AAN committees and working groups but receives no compensation for her role. A coauthor received personal fees from the AAN that were unrelated to the editorial.
SOURCE: Lewis A et al. Ann Intern Med. 2019 Dec 24. doi: 10.7326/M19-2731.
FROM ANNALS OF INTERNAL MEDICINE
Valproic acid-induced hyperammonemic encephalopathy
Mrs. C, age 75, is transferred to our inpatient medical/surgical hospital from a psychiatric hospital after presenting with shortness of breath and altered mental status.
Eight days earlier, Mrs. C had been admitted to the psychiatric hospital for bipolar mania with psychotic features. While there, Mrs. C received quetiapine, 400 mg nightly, and an initial valproic acid (VPA) dosage of 500 mg 2 times daily. While receiving VPA 500 mg 2 times daily, her VPA total level was 62 µg/mL, which is on the lower end of the therapeutic range (50 to 125 µg/mL). This prompted the team at the psychiatric hospital to increase her VPA dosage to 500 mg 3 times daily the day before she was transferred to our hospital.
At our hospital, she is found to be in hypoxic respiratory failure secondary to pneumonia. Upon admission, her laboratory data show evidence of infection and anemia and she also has an
From hospital Day 3 to Day 6, Mrs. C experiences gradual improvement in her respiratory and mental status. However, on hospital Day 7, she has extreme somnolence and altered mental status without respiratory involvement. Our team suspects VPA toxicity and/or VPA-induced hyperammonemic encephalopathy (VHE).
VPA-induced hyperammonemia
Hyperammonemia can occur in individuals receiving VPA and is most often asymptomatic. However, elevations in ammonia may lead to VHE, which is a rare but serious adverse effect. VHE has been reported early in treatment, in acute VPA overdose, and in chronic VPA use despite normal doses and levels.1 It also can occur in the absence of clinical and laboratory evidence of hepatotoxicity. VHE is associated with significant morbidity and CNS damage. Symptoms of VHE include vomiting, lethargy, and confusion. If left untreated, VHE can lead to coma and death.
Mechanism of VHE. The exact mechanism of VHE is unknown.1-3 Ammonia is a toxic base produced by deamination of amino acids. The liver eliminates ammonia via the urea cycle.2 Valproic acid metabolites, propionate and 4-en-VPA, can directly inhibit N-acetyl glutamate, which can disrupt the urea cycle, leading to elevated ammonia levels.3 Long-term or high-dose VPA can lead to carnitine deficiency, primarily by inhibiting its biosynthesis and depleting stores.4 Carnitine deficiency leads to disturbances in mitochondrial function, causing inhibition of the urea cycle and increasing ammonia. CNS toxicity due to hyperammonemia is thought to be due to activation of glutamate receptors.3
Risk factors. Co-administration of other antiepileptic drugs (AEDs) with VPA is a risk factor for VHE.1,5 This happens because enzyme-inducing AEDs such as phenytoin, phenobarbital, and carbamazepine can increase toxic metabolites of VPA, which can lead to hyperammonemia. Topiramate can also inhibit the urea cycle, leading to increased ammonia levels. Additionally, co-administration of VPA with quetiapine, paliperidone, risperidone, or aripiprazole has been reported to increase the risk of VHE.1,5 Intellectual disability, carnitine deficiency, low albumin, and abnormal liver function have also been reported to increase the risk of VHE.1,5
Continue to: Diagnosis and management
Diagnosis and management. If a patient receiving VPA is experiencing nausea, fatigue, or somnolence, it is important to check the patient’s ammonia level (normal range: 11 to 32 µmol/L) and VPA total levels (therapeutic range: 50 to 125 µg/mL). Consider checking a VPA free level, especially in geriatric patients or patients who have low albumin; the therapeutic range of VPA free is 6 to 22 µg/mL.3 If the ammonia level is elevated, discontinue VPA immediately (Table).1-3 Clinicians may also elect to prescribe lactulose until ammonia levels return to normal range. Adding levocarnitine may also help, although evidence is limited to small case series or retrospective studies.3 Currently, there is no known advantage in combining lactulose and levocarnitine to address VHE. Severe cases of VHE (ammonia levels >400 µmol/L) may require hemodialysis.1
Prevention. Strategies to prevent VHE include avoiding polypharmacy, especially concurrent use of enzyme-inducing AEDs and possibly second-generation antipsychotics. Additionally, VPA should not be used in individuals with urea cycle disorders. It is unknown if levocarnitine supplementation is preventive, but this approach has been suggested.3
CASE CONTINUED
Mrs. C has several possible risk factors for VHE, including co-administration of quetiapine and VPA, and a low albumin level. A further laboratory workup for Mrs. C reveals a VPA free level of 19 µg/mL (21.1% free), a VPA total level of 90 µg/mL, and an ammonia level of 79 µmol/L, confirming our suspicions regarding VHE. We determine that Mrs. C’s altered mental status is likely due her elevated ammonia levels, because the infection had been improving in the days leading up to the sudden, extreme somnolence.
VPA is immediately stopped and Mrs. C receives 1 dose of lactulose. The following day, Mrs. C’s mental status improves, and her ammonia levels return to normal. On hospital Day 9, she is transferred back to the psychiatric facility for management of manic and psychotic symptoms.
Related Resources
- Brown LM, Cupples N, Moore TA. Levocarnitine for valproate-induced hyperammonemia in the psychiatric setting: a case series and literature review. Ment Health Clin. 2018;8(3):148-154.
- Aires CCP, van Cruchten A, Ijlat L, et al. New insights on the mechanisms of valproate-induced hyperammonemia: inhibition of hepatic N-acetylglutamate synthase activity by valproyl-CoA. J Hepatol. 2011;55(2):426-434.
Drug Brand Names
Aripiprazole • Abilify
Carbamazepine • Tegretol
Lactulose • Enulose
Levocarnitine • Carnitine, Carnitor
Levofloxacin • Levaquin IV
Paliperidone • Invega
Phenobarbital • Luminal
Phenytoin • Dilantin
Quetiapine • Seroquel
Risperidone • Risperdal
Topiramate • Topamax
Valproic acid • Depakene
1. Chopra A, Kolla BP, Mansukhani MP, et al. Valproate-induced hyperammonemic encephalopathy: an update on risk factors, clinical correlates, and management. Gen Hosp Psychiatry. 2012;34(3):290-298.
2. Kowalski PC, Dowben JS, Keltner NL. Ammonium: the deadly toxin you don’t want to miss when using mood stabilizers. Perspect Psychiatr Care. 2013;49(4):221-225.
3. Baddour E, Tewksbury A, Stauner N. Valproic acid-induced hyper ammonemia: incidence, clinical significance, and treatment management. Ment Health Clin. 2018;8(2):73-77.
4. Raskind JY, El-Chaar GM. The role of carnitine supplementation during valproic acid therapy. Ann Pharmacother. 2000;34(5):630-638. 5. Tseng YL, Huang CR, Lin CH, et al. Risk factors of hyperammonemia in patients with epilepsy. Medicine (Baltimore). 2014;93(11):e66. doi: 10.1097/MD.0000000000000066.
Mrs. C, age 75, is transferred to our inpatient medical/surgical hospital from a psychiatric hospital after presenting with shortness of breath and altered mental status.
Eight days earlier, Mrs. C had been admitted to the psychiatric hospital for bipolar mania with psychotic features. While there, Mrs. C received quetiapine, 400 mg nightly, and an initial valproic acid (VPA) dosage of 500 mg 2 times daily. While receiving VPA 500 mg 2 times daily, her VPA total level was 62 µg/mL, which is on the lower end of the therapeutic range (50 to 125 µg/mL). This prompted the team at the psychiatric hospital to increase her VPA dosage to 500 mg 3 times daily the day before she was transferred to our hospital.
At our hospital, she is found to be in hypoxic respiratory failure secondary to pneumonia. Upon admission, her laboratory data show evidence of infection and anemia and she also has an
From hospital Day 3 to Day 6, Mrs. C experiences gradual improvement in her respiratory and mental status. However, on hospital Day 7, she has extreme somnolence and altered mental status without respiratory involvement. Our team suspects VPA toxicity and/or VPA-induced hyperammonemic encephalopathy (VHE).
VPA-induced hyperammonemia
Hyperammonemia can occur in individuals receiving VPA and is most often asymptomatic. However, elevations in ammonia may lead to VHE, which is a rare but serious adverse effect. VHE has been reported early in treatment, in acute VPA overdose, and in chronic VPA use despite normal doses and levels.1 It also can occur in the absence of clinical and laboratory evidence of hepatotoxicity. VHE is associated with significant morbidity and CNS damage. Symptoms of VHE include vomiting, lethargy, and confusion. If left untreated, VHE can lead to coma and death.
Mechanism of VHE. The exact mechanism of VHE is unknown.1-3 Ammonia is a toxic base produced by deamination of amino acids. The liver eliminates ammonia via the urea cycle.2 Valproic acid metabolites, propionate and 4-en-VPA, can directly inhibit N-acetyl glutamate, which can disrupt the urea cycle, leading to elevated ammonia levels.3 Long-term or high-dose VPA can lead to carnitine deficiency, primarily by inhibiting its biosynthesis and depleting stores.4 Carnitine deficiency leads to disturbances in mitochondrial function, causing inhibition of the urea cycle and increasing ammonia. CNS toxicity due to hyperammonemia is thought to be due to activation of glutamate receptors.3
Risk factors. Co-administration of other antiepileptic drugs (AEDs) with VPA is a risk factor for VHE.1,5 This happens because enzyme-inducing AEDs such as phenytoin, phenobarbital, and carbamazepine can increase toxic metabolites of VPA, which can lead to hyperammonemia. Topiramate can also inhibit the urea cycle, leading to increased ammonia levels. Additionally, co-administration of VPA with quetiapine, paliperidone, risperidone, or aripiprazole has been reported to increase the risk of VHE.1,5 Intellectual disability, carnitine deficiency, low albumin, and abnormal liver function have also been reported to increase the risk of VHE.1,5
Continue to: Diagnosis and management
Diagnosis and management. If a patient receiving VPA is experiencing nausea, fatigue, or somnolence, it is important to check the patient’s ammonia level (normal range: 11 to 32 µmol/L) and VPA total levels (therapeutic range: 50 to 125 µg/mL). Consider checking a VPA free level, especially in geriatric patients or patients who have low albumin; the therapeutic range of VPA free is 6 to 22 µg/mL.3 If the ammonia level is elevated, discontinue VPA immediately (Table).1-3 Clinicians may also elect to prescribe lactulose until ammonia levels return to normal range. Adding levocarnitine may also help, although evidence is limited to small case series or retrospective studies.3 Currently, there is no known advantage in combining lactulose and levocarnitine to address VHE. Severe cases of VHE (ammonia levels >400 µmol/L) may require hemodialysis.1
Prevention. Strategies to prevent VHE include avoiding polypharmacy, especially concurrent use of enzyme-inducing AEDs and possibly second-generation antipsychotics. Additionally, VPA should not be used in individuals with urea cycle disorders. It is unknown if levocarnitine supplementation is preventive, but this approach has been suggested.3
CASE CONTINUED
Mrs. C has several possible risk factors for VHE, including co-administration of quetiapine and VPA, and a low albumin level. A further laboratory workup for Mrs. C reveals a VPA free level of 19 µg/mL (21.1% free), a VPA total level of 90 µg/mL, and an ammonia level of 79 µmol/L, confirming our suspicions regarding VHE. We determine that Mrs. C’s altered mental status is likely due her elevated ammonia levels, because the infection had been improving in the days leading up to the sudden, extreme somnolence.
VPA is immediately stopped and Mrs. C receives 1 dose of lactulose. The following day, Mrs. C’s mental status improves, and her ammonia levels return to normal. On hospital Day 9, she is transferred back to the psychiatric facility for management of manic and psychotic symptoms.
Related Resources
- Brown LM, Cupples N, Moore TA. Levocarnitine for valproate-induced hyperammonemia in the psychiatric setting: a case series and literature review. Ment Health Clin. 2018;8(3):148-154.
- Aires CCP, van Cruchten A, Ijlat L, et al. New insights on the mechanisms of valproate-induced hyperammonemia: inhibition of hepatic N-acetylglutamate synthase activity by valproyl-CoA. J Hepatol. 2011;55(2):426-434.
Drug Brand Names
Aripiprazole • Abilify
Carbamazepine • Tegretol
Lactulose • Enulose
Levocarnitine • Carnitine, Carnitor
Levofloxacin • Levaquin IV
Paliperidone • Invega
Phenobarbital • Luminal
Phenytoin • Dilantin
Quetiapine • Seroquel
Risperidone • Risperdal
Topiramate • Topamax
Valproic acid • Depakene
Mrs. C, age 75, is transferred to our inpatient medical/surgical hospital from a psychiatric hospital after presenting with shortness of breath and altered mental status.
Eight days earlier, Mrs. C had been admitted to the psychiatric hospital for bipolar mania with psychotic features. While there, Mrs. C received quetiapine, 400 mg nightly, and an initial valproic acid (VPA) dosage of 500 mg 2 times daily. While receiving VPA 500 mg 2 times daily, her VPA total level was 62 µg/mL, which is on the lower end of the therapeutic range (50 to 125 µg/mL). This prompted the team at the psychiatric hospital to increase her VPA dosage to 500 mg 3 times daily the day before she was transferred to our hospital.
At our hospital, she is found to be in hypoxic respiratory failure secondary to pneumonia. Upon admission, her laboratory data show evidence of infection and anemia and she also has an
From hospital Day 3 to Day 6, Mrs. C experiences gradual improvement in her respiratory and mental status. However, on hospital Day 7, she has extreme somnolence and altered mental status without respiratory involvement. Our team suspects VPA toxicity and/or VPA-induced hyperammonemic encephalopathy (VHE).
VPA-induced hyperammonemia
Hyperammonemia can occur in individuals receiving VPA and is most often asymptomatic. However, elevations in ammonia may lead to VHE, which is a rare but serious adverse effect. VHE has been reported early in treatment, in acute VPA overdose, and in chronic VPA use despite normal doses and levels.1 It also can occur in the absence of clinical and laboratory evidence of hepatotoxicity. VHE is associated with significant morbidity and CNS damage. Symptoms of VHE include vomiting, lethargy, and confusion. If left untreated, VHE can lead to coma and death.
Mechanism of VHE. The exact mechanism of VHE is unknown.1-3 Ammonia is a toxic base produced by deamination of amino acids. The liver eliminates ammonia via the urea cycle.2 Valproic acid metabolites, propionate and 4-en-VPA, can directly inhibit N-acetyl glutamate, which can disrupt the urea cycle, leading to elevated ammonia levels.3 Long-term or high-dose VPA can lead to carnitine deficiency, primarily by inhibiting its biosynthesis and depleting stores.4 Carnitine deficiency leads to disturbances in mitochondrial function, causing inhibition of the urea cycle and increasing ammonia. CNS toxicity due to hyperammonemia is thought to be due to activation of glutamate receptors.3
Risk factors. Co-administration of other antiepileptic drugs (AEDs) with VPA is a risk factor for VHE.1,5 This happens because enzyme-inducing AEDs such as phenytoin, phenobarbital, and carbamazepine can increase toxic metabolites of VPA, which can lead to hyperammonemia. Topiramate can also inhibit the urea cycle, leading to increased ammonia levels. Additionally, co-administration of VPA with quetiapine, paliperidone, risperidone, or aripiprazole has been reported to increase the risk of VHE.1,5 Intellectual disability, carnitine deficiency, low albumin, and abnormal liver function have also been reported to increase the risk of VHE.1,5
Continue to: Diagnosis and management
Diagnosis and management. If a patient receiving VPA is experiencing nausea, fatigue, or somnolence, it is important to check the patient’s ammonia level (normal range: 11 to 32 µmol/L) and VPA total levels (therapeutic range: 50 to 125 µg/mL). Consider checking a VPA free level, especially in geriatric patients or patients who have low albumin; the therapeutic range of VPA free is 6 to 22 µg/mL.3 If the ammonia level is elevated, discontinue VPA immediately (Table).1-3 Clinicians may also elect to prescribe lactulose until ammonia levels return to normal range. Adding levocarnitine may also help, although evidence is limited to small case series or retrospective studies.3 Currently, there is no known advantage in combining lactulose and levocarnitine to address VHE. Severe cases of VHE (ammonia levels >400 µmol/L) may require hemodialysis.1
Prevention. Strategies to prevent VHE include avoiding polypharmacy, especially concurrent use of enzyme-inducing AEDs and possibly second-generation antipsychotics. Additionally, VPA should not be used in individuals with urea cycle disorders. It is unknown if levocarnitine supplementation is preventive, but this approach has been suggested.3
CASE CONTINUED
Mrs. C has several possible risk factors for VHE, including co-administration of quetiapine and VPA, and a low albumin level. A further laboratory workup for Mrs. C reveals a VPA free level of 19 µg/mL (21.1% free), a VPA total level of 90 µg/mL, and an ammonia level of 79 µmol/L, confirming our suspicions regarding VHE. We determine that Mrs. C’s altered mental status is likely due her elevated ammonia levels, because the infection had been improving in the days leading up to the sudden, extreme somnolence.
VPA is immediately stopped and Mrs. C receives 1 dose of lactulose. The following day, Mrs. C’s mental status improves, and her ammonia levels return to normal. On hospital Day 9, she is transferred back to the psychiatric facility for management of manic and psychotic symptoms.
Related Resources
- Brown LM, Cupples N, Moore TA. Levocarnitine for valproate-induced hyperammonemia in the psychiatric setting: a case series and literature review. Ment Health Clin. 2018;8(3):148-154.
- Aires CCP, van Cruchten A, Ijlat L, et al. New insights on the mechanisms of valproate-induced hyperammonemia: inhibition of hepatic N-acetylglutamate synthase activity by valproyl-CoA. J Hepatol. 2011;55(2):426-434.
Drug Brand Names
Aripiprazole • Abilify
Carbamazepine • Tegretol
Lactulose • Enulose
Levocarnitine • Carnitine, Carnitor
Levofloxacin • Levaquin IV
Paliperidone • Invega
Phenobarbital • Luminal
Phenytoin • Dilantin
Quetiapine • Seroquel
Risperidone • Risperdal
Topiramate • Topamax
Valproic acid • Depakene
1. Chopra A, Kolla BP, Mansukhani MP, et al. Valproate-induced hyperammonemic encephalopathy: an update on risk factors, clinical correlates, and management. Gen Hosp Psychiatry. 2012;34(3):290-298.
2. Kowalski PC, Dowben JS, Keltner NL. Ammonium: the deadly toxin you don’t want to miss when using mood stabilizers. Perspect Psychiatr Care. 2013;49(4):221-225.
3. Baddour E, Tewksbury A, Stauner N. Valproic acid-induced hyper ammonemia: incidence, clinical significance, and treatment management. Ment Health Clin. 2018;8(2):73-77.
4. Raskind JY, El-Chaar GM. The role of carnitine supplementation during valproic acid therapy. Ann Pharmacother. 2000;34(5):630-638. 5. Tseng YL, Huang CR, Lin CH, et al. Risk factors of hyperammonemia in patients with epilepsy. Medicine (Baltimore). 2014;93(11):e66. doi: 10.1097/MD.0000000000000066.
1. Chopra A, Kolla BP, Mansukhani MP, et al. Valproate-induced hyperammonemic encephalopathy: an update on risk factors, clinical correlates, and management. Gen Hosp Psychiatry. 2012;34(3):290-298.
2. Kowalski PC, Dowben JS, Keltner NL. Ammonium: the deadly toxin you don’t want to miss when using mood stabilizers. Perspect Psychiatr Care. 2013;49(4):221-225.
3. Baddour E, Tewksbury A, Stauner N. Valproic acid-induced hyper ammonemia: incidence, clinical significance, and treatment management. Ment Health Clin. 2018;8(2):73-77.
4. Raskind JY, El-Chaar GM. The role of carnitine supplementation during valproic acid therapy. Ann Pharmacother. 2000;34(5):630-638. 5. Tseng YL, Huang CR, Lin CH, et al. Risk factors of hyperammonemia in patients with epilepsy. Medicine (Baltimore). 2014;93(11):e66. doi: 10.1097/MD.0000000000000066.
Data point to bidirectional link between sleep disorders and ADHD
in a large longitudinal study of adolescents in China.
Investigators twice assessed 7,072 middle and high school students participating in the larger longitudinal Shandong Adolescent Behavior & Health Cohort – in 2015 and 1 year later in 2016 – for sleep, mental health, psychosocial factors (using the self-administered Adolescent Health Questionnaire, or AHQ), and for ADHD symptoms (using the Youth Self-Report, or YSR, of the Achenbach Child Behavior Checklist).
At baseline, ADHD symptoms were reported by 7.6% of adolescents and were significantly correlated, after adjusting for adolescent and family covariates, with all the sleep variables studied: sleep duration of 7 hours or less per night, insomnia symptoms, poor sleep quality, RLS symptoms, frequent snorting, and hypnotic use, reported Xianchen Liu, MD, PhD, of Shandong (China) University, and coinvestigators. They noted a dose-response relationship between sleep duration and the odds of having ADHD symptoms.
At 1-year follow-up, 4.5% of the 6,531 participants who did not have ADHD symptoms at baseline now reported them. After adjustments for covariates, any insomnia (odds ratio, 1.48), difficulty initiating sleep (one of the insomnia symptoms) (OR, 2.09), RLS (OR, 1.47), and frequent snoring (OR, 2.30) at baseline were each significantly associated with development of incident ADHD symptoms and with ADHD severity at 1 year, they reported in Sleep.
“Given the fact that sleep disorders in adolescents are often underdiagnosed and untreated primarily in the primary care setting, our findings highlight that clinicians should assess and manage short sleep duration and sleep problems for effective treatment of ADHD in adolescents,” as well as for prevention, they wrote.
The AHQ includes questions that assess nocturnal sleep duration and sleep problems during the past month. The adolescent and family variables that were selected as covariates and controlled for include cigarette smoking, alcohol drinking, use of mental health services, chronic physical diseases, and parental education and occupation. Depression was also a covariate but was assessed through a different scale.
The YSR measures eight ADHD symptoms during the past 6 months on a 3-point scale (not true, somewhat or sometimes true, and very true or often true). The adolescent participants of this study were in grades 7, 8, and 10 at baseline. Their mean age at baseline was 15 years; half were male. They were part of the larger Shandong Adolescent and Behavioral Cohort, a longitudinal study of almost 12,000 adolescents.
Growing evidence has demonstrated a bidirectional relationship between sleep problems and ADHD symptoms in pediatric populations, the investigators wrote, and further research is needed to examine the “mediators, moderators, and biological mechanisms of the sleep-ADHD link [in adolescents].”
While there are multiple potential pathways for this link, sleep problems may sometimes result in a cluster of behavioral and cognitive symptoms that are not true ADHD but that mimic the disorder, they noted.
The investigators also noted that approximately 67% of adolescents who had clinically relevant ADHD symptoms at baseline no longer had these symptoms at 1-year follow-up – a finding that “supports the [idea]” that ADHD symptoms with onset in adolescence may be transient or episodic rather than persistent.
The study was funded in part by the National Natural Science Foundation of China. The authors reported that they have no conflicts of interest.
SOURCE: Liu X et al. Sleep. 2019 Dec 2. doi: 10.1093/sleep/zsz294.
in a large longitudinal study of adolescents in China.
Investigators twice assessed 7,072 middle and high school students participating in the larger longitudinal Shandong Adolescent Behavior & Health Cohort – in 2015 and 1 year later in 2016 – for sleep, mental health, psychosocial factors (using the self-administered Adolescent Health Questionnaire, or AHQ), and for ADHD symptoms (using the Youth Self-Report, or YSR, of the Achenbach Child Behavior Checklist).
At baseline, ADHD symptoms were reported by 7.6% of adolescents and were significantly correlated, after adjusting for adolescent and family covariates, with all the sleep variables studied: sleep duration of 7 hours or less per night, insomnia symptoms, poor sleep quality, RLS symptoms, frequent snorting, and hypnotic use, reported Xianchen Liu, MD, PhD, of Shandong (China) University, and coinvestigators. They noted a dose-response relationship between sleep duration and the odds of having ADHD symptoms.
At 1-year follow-up, 4.5% of the 6,531 participants who did not have ADHD symptoms at baseline now reported them. After adjustments for covariates, any insomnia (odds ratio, 1.48), difficulty initiating sleep (one of the insomnia symptoms) (OR, 2.09), RLS (OR, 1.47), and frequent snoring (OR, 2.30) at baseline were each significantly associated with development of incident ADHD symptoms and with ADHD severity at 1 year, they reported in Sleep.
“Given the fact that sleep disorders in adolescents are often underdiagnosed and untreated primarily in the primary care setting, our findings highlight that clinicians should assess and manage short sleep duration and sleep problems for effective treatment of ADHD in adolescents,” as well as for prevention, they wrote.
The AHQ includes questions that assess nocturnal sleep duration and sleep problems during the past month. The adolescent and family variables that were selected as covariates and controlled for include cigarette smoking, alcohol drinking, use of mental health services, chronic physical diseases, and parental education and occupation. Depression was also a covariate but was assessed through a different scale.
The YSR measures eight ADHD symptoms during the past 6 months on a 3-point scale (not true, somewhat or sometimes true, and very true or often true). The adolescent participants of this study were in grades 7, 8, and 10 at baseline. Their mean age at baseline was 15 years; half were male. They were part of the larger Shandong Adolescent and Behavioral Cohort, a longitudinal study of almost 12,000 adolescents.
Growing evidence has demonstrated a bidirectional relationship between sleep problems and ADHD symptoms in pediatric populations, the investigators wrote, and further research is needed to examine the “mediators, moderators, and biological mechanisms of the sleep-ADHD link [in adolescents].”
While there are multiple potential pathways for this link, sleep problems may sometimes result in a cluster of behavioral and cognitive symptoms that are not true ADHD but that mimic the disorder, they noted.
The investigators also noted that approximately 67% of adolescents who had clinically relevant ADHD symptoms at baseline no longer had these symptoms at 1-year follow-up – a finding that “supports the [idea]” that ADHD symptoms with onset in adolescence may be transient or episodic rather than persistent.
The study was funded in part by the National Natural Science Foundation of China. The authors reported that they have no conflicts of interest.
SOURCE: Liu X et al. Sleep. 2019 Dec 2. doi: 10.1093/sleep/zsz294.
in a large longitudinal study of adolescents in China.
Investigators twice assessed 7,072 middle and high school students participating in the larger longitudinal Shandong Adolescent Behavior & Health Cohort – in 2015 and 1 year later in 2016 – for sleep, mental health, psychosocial factors (using the self-administered Adolescent Health Questionnaire, or AHQ), and for ADHD symptoms (using the Youth Self-Report, or YSR, of the Achenbach Child Behavior Checklist).
At baseline, ADHD symptoms were reported by 7.6% of adolescents and were significantly correlated, after adjusting for adolescent and family covariates, with all the sleep variables studied: sleep duration of 7 hours or less per night, insomnia symptoms, poor sleep quality, RLS symptoms, frequent snorting, and hypnotic use, reported Xianchen Liu, MD, PhD, of Shandong (China) University, and coinvestigators. They noted a dose-response relationship between sleep duration and the odds of having ADHD symptoms.
At 1-year follow-up, 4.5% of the 6,531 participants who did not have ADHD symptoms at baseline now reported them. After adjustments for covariates, any insomnia (odds ratio, 1.48), difficulty initiating sleep (one of the insomnia symptoms) (OR, 2.09), RLS (OR, 1.47), and frequent snoring (OR, 2.30) at baseline were each significantly associated with development of incident ADHD symptoms and with ADHD severity at 1 year, they reported in Sleep.
“Given the fact that sleep disorders in adolescents are often underdiagnosed and untreated primarily in the primary care setting, our findings highlight that clinicians should assess and manage short sleep duration and sleep problems for effective treatment of ADHD in adolescents,” as well as for prevention, they wrote.
The AHQ includes questions that assess nocturnal sleep duration and sleep problems during the past month. The adolescent and family variables that were selected as covariates and controlled for include cigarette smoking, alcohol drinking, use of mental health services, chronic physical diseases, and parental education and occupation. Depression was also a covariate but was assessed through a different scale.
The YSR measures eight ADHD symptoms during the past 6 months on a 3-point scale (not true, somewhat or sometimes true, and very true or often true). The adolescent participants of this study were in grades 7, 8, and 10 at baseline. Their mean age at baseline was 15 years; half were male. They were part of the larger Shandong Adolescent and Behavioral Cohort, a longitudinal study of almost 12,000 adolescents.
Growing evidence has demonstrated a bidirectional relationship between sleep problems and ADHD symptoms in pediatric populations, the investigators wrote, and further research is needed to examine the “mediators, moderators, and biological mechanisms of the sleep-ADHD link [in adolescents].”
While there are multiple potential pathways for this link, sleep problems may sometimes result in a cluster of behavioral and cognitive symptoms that are not true ADHD but that mimic the disorder, they noted.
The investigators also noted that approximately 67% of adolescents who had clinically relevant ADHD symptoms at baseline no longer had these symptoms at 1-year follow-up – a finding that “supports the [idea]” that ADHD symptoms with onset in adolescence may be transient or episodic rather than persistent.
The study was funded in part by the National Natural Science Foundation of China. The authors reported that they have no conflicts of interest.
SOURCE: Liu X et al. Sleep. 2019 Dec 2. doi: 10.1093/sleep/zsz294.
FROM SLEEP
FDA okays ubrogepant for acute migraine treatment
The Food and Drug Administration has approved ubrogepant (Ubrelvy, Allergan) for the acute treatment of migraine with or without aura in adults.
Ubrogepant is the first drug in the class of oral calcitonin gene–related peptide receptor antagonists approved for the acute treatment of migraine. It is approved in two dose strengths (50 mg and 100 mg).
The drug is not indicated, however, for the preventive treatment of migraine.
“Migraine is an often disabling condition that affects an estimated 37 million people in the U.S.,” Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research, said in an FDA news release.
Ubrogepant represents “an important new option for the acute treatment of migraine in adults, as it is the first drug in its class approved for this indication. The FDA is pleased to approve a novel treatment for patients suffering from migraine and will continue to work with stakeholders to promote the development of new safe and effective migraine therapies,” added Dr. Dunn.
The safety and efficacy of ubrogepant for the acute treatment of migraine was demonstrated in two randomized, double-blind, placebo-controlled trials (ACHIEVE I and ACHIEVE II). In total, 1,439 adults with a history of migraine, with and without aura, received ubrogepant to treat an ongoing migraine.
“Both 50-mg and 100-mg dose strengths demonstrated significantly greater rates of pain freedom and freedom from the most bothersome migraine-associated symptom at 2 hours, compared with placebo,” Allergan said in a news release announcing approval.
The most common side effects reported by patients in the clinical trials were nausea, tiredness, and dry mouth. Ubrogepant is contraindicated for coadministration with strong CYP3A4 inhibitors.
The company expects to have ubrogepant available in the first quarter of 2020.
A version of this story originally appeared on Medscape.com.
The Food and Drug Administration has approved ubrogepant (Ubrelvy, Allergan) for the acute treatment of migraine with or without aura in adults.
Ubrogepant is the first drug in the class of oral calcitonin gene–related peptide receptor antagonists approved for the acute treatment of migraine. It is approved in two dose strengths (50 mg and 100 mg).
The drug is not indicated, however, for the preventive treatment of migraine.
“Migraine is an often disabling condition that affects an estimated 37 million people in the U.S.,” Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research, said in an FDA news release.
Ubrogepant represents “an important new option for the acute treatment of migraine in adults, as it is the first drug in its class approved for this indication. The FDA is pleased to approve a novel treatment for patients suffering from migraine and will continue to work with stakeholders to promote the development of new safe and effective migraine therapies,” added Dr. Dunn.
The safety and efficacy of ubrogepant for the acute treatment of migraine was demonstrated in two randomized, double-blind, placebo-controlled trials (ACHIEVE I and ACHIEVE II). In total, 1,439 adults with a history of migraine, with and without aura, received ubrogepant to treat an ongoing migraine.
“Both 50-mg and 100-mg dose strengths demonstrated significantly greater rates of pain freedom and freedom from the most bothersome migraine-associated symptom at 2 hours, compared with placebo,” Allergan said in a news release announcing approval.
The most common side effects reported by patients in the clinical trials were nausea, tiredness, and dry mouth. Ubrogepant is contraindicated for coadministration with strong CYP3A4 inhibitors.
The company expects to have ubrogepant available in the first quarter of 2020.
A version of this story originally appeared on Medscape.com.
The Food and Drug Administration has approved ubrogepant (Ubrelvy, Allergan) for the acute treatment of migraine with or without aura in adults.
Ubrogepant is the first drug in the class of oral calcitonin gene–related peptide receptor antagonists approved for the acute treatment of migraine. It is approved in two dose strengths (50 mg and 100 mg).
The drug is not indicated, however, for the preventive treatment of migraine.
“Migraine is an often disabling condition that affects an estimated 37 million people in the U.S.,” Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research, said in an FDA news release.
Ubrogepant represents “an important new option for the acute treatment of migraine in adults, as it is the first drug in its class approved for this indication. The FDA is pleased to approve a novel treatment for patients suffering from migraine and will continue to work with stakeholders to promote the development of new safe and effective migraine therapies,” added Dr. Dunn.
The safety and efficacy of ubrogepant for the acute treatment of migraine was demonstrated in two randomized, double-blind, placebo-controlled trials (ACHIEVE I and ACHIEVE II). In total, 1,439 adults with a history of migraine, with and without aura, received ubrogepant to treat an ongoing migraine.
“Both 50-mg and 100-mg dose strengths demonstrated significantly greater rates of pain freedom and freedom from the most bothersome migraine-associated symptom at 2 hours, compared with placebo,” Allergan said in a news release announcing approval.
The most common side effects reported by patients in the clinical trials were nausea, tiredness, and dry mouth. Ubrogepant is contraindicated for coadministration with strong CYP3A4 inhibitors.
The company expects to have ubrogepant available in the first quarter of 2020.
A version of this story originally appeared on Medscape.com.
First autoimmune epilepsy RCT supports IVIG therapy
BALTIMORE –
Although the numbers of enrolled subjects was small, it was the first double-blind, placebo-controlled randomized trial in autoimmune epilepsy, the start of a level 1 evidence base. Until now, treatment has been based mostly on case reports and expert opinion. “We’ve clearly shown that immunotherapy works and that treating early makes a difference, much more so than antiseizure medications,” said lead author Divyanshu Dubey, MBBS, from the Mayo Clinic.
The lack of data has meant that “we couldn’t get insurance approval for IVIG, so people have generally leaned towards” high-dose intravenous steroids, which are problematic because LGI-1 antibody epilepsy is a disease of older people, in whom osteoporosis, underlying infections, and other problems complicate steroid use, Dr. Dubey said.
The trial also included three people with contactin-associated-protein-like-2 (CASPR2) antibody epilepsy, but they all wound up in the placebo arm, “so it’s hard to say anything about them,” Dr. Dubey said at the American Epilepsy Society annual meeting. The work was published shortly before the meeting (Ann Neurol. 2019 Nov 28. doi: 10.1002/ana.25655).
CASPR2 and LGI-1 are proteins found in brain cells; attack by antibodies triggers encephalitis and tens to hundreds of seizures per day. The seizures tend to diminish with time, but the cognitive damage caused by the encephalitis does not. “We’ve seen patients end up in nursing homes diagnosed with Alzheimer’s disease” because the conditions weren’t recognized and treated, Dr. Dubey said.
He and his team chose LGI-1 and CASPR2 epilepsy because of the potentially devastating consequences and because they are among the most common autoimmune epilepsies for which antibodies have been identified. There was also a hope that positive results might open up insurance coverage.
The trial randomized eight people to IVIG 0.5 g/kg on day 1; 1 g/kg on day 2; and 0.6 g/kg once at 3 and 5 weeks. Nine others were randomized to volume-matched IV saline placebo on the same schedule. After enrollment of 17 patients (LGI1-IgG, 14; CASPR2-IgG, 3) over 34 months, the study was terminated because of slow enrollment.
Although none of the LGI-1 subjects in the placebo group responded, two CASPR2 patients did, yielding an IVIG response rate of 75% versus 22% (2/9) in the placebo arm after week 5 (odds ratio, 10.5; 95% confidence interval, 1.1-98.9; P = .044).
Two of the LGI-1 subjects in the IVIG arm were completely seizure free after treatment. Results in both arms, meanwhile, did not correlate with concomitant antiseizure medications among those who were on them.
All eight IVIG patients showed stabilization or improvement in cognitive function, compared with two of five in the placebo arm, as gauged by Repeatable Battery for the Assessment of Neuropsychological Status scores. Patients in the IVIG arm gained a median of 3 points, while patients in the placebo arm lost a median of 1 point (P = .077).
At week 5, six patients with persistent seizures who were in the placebo group were switched to the IVIG regimen after unblinding; four (67%) reported more than a 50% reduction in seizures.
Responses did not correlate with LGI-1/CASPR2-IgG1-4 subclass, and there were no IVIG-associated adverse events. One IVIG patients fell because of a faciobrachial dystonic seizure, a classic sign of LGI-1 disease. Antibodies were not measured in the trial because they “do not correlate with severity of autoimmune epilepsy,” Dr. Dubey said.
The original plan was to enroll 30 subjects, but the investigators terminated the study after 18 because of slow enrollment. With knowledge of autoimmune epilepsy growing at Mayo, it was increasingly difficult to find immunotherapy-naive patients, he said.
All the subjects were between 60 and 70 years old, and the majority in both arms were men, which was not surprising because the conditions skew male, Dr. Dubey said. None of the patients had underlying tumors, which are known triggers of autoimmune epilepsy.
This work was funded by Grifols Shared Services, a maker of IVIG, and Option Care, a provider of home infusion equipment. Dr. Dubey said the company had no active role in the trial, but that the lack of insurance coverage for IVIG in autoimmune epilepsy was one of the drivers of the study. He disclosed research support from Grifols; another investigator is a consultant.
SOURCE: Dubey D et al. AES 2019, Abstract 1.292.
BALTIMORE –
Although the numbers of enrolled subjects was small, it was the first double-blind, placebo-controlled randomized trial in autoimmune epilepsy, the start of a level 1 evidence base. Until now, treatment has been based mostly on case reports and expert opinion. “We’ve clearly shown that immunotherapy works and that treating early makes a difference, much more so than antiseizure medications,” said lead author Divyanshu Dubey, MBBS, from the Mayo Clinic.
The lack of data has meant that “we couldn’t get insurance approval for IVIG, so people have generally leaned towards” high-dose intravenous steroids, which are problematic because LGI-1 antibody epilepsy is a disease of older people, in whom osteoporosis, underlying infections, and other problems complicate steroid use, Dr. Dubey said.
The trial also included three people with contactin-associated-protein-like-2 (CASPR2) antibody epilepsy, but they all wound up in the placebo arm, “so it’s hard to say anything about them,” Dr. Dubey said at the American Epilepsy Society annual meeting. The work was published shortly before the meeting (Ann Neurol. 2019 Nov 28. doi: 10.1002/ana.25655).
CASPR2 and LGI-1 are proteins found in brain cells; attack by antibodies triggers encephalitis and tens to hundreds of seizures per day. The seizures tend to diminish with time, but the cognitive damage caused by the encephalitis does not. “We’ve seen patients end up in nursing homes diagnosed with Alzheimer’s disease” because the conditions weren’t recognized and treated, Dr. Dubey said.
He and his team chose LGI-1 and CASPR2 epilepsy because of the potentially devastating consequences and because they are among the most common autoimmune epilepsies for which antibodies have been identified. There was also a hope that positive results might open up insurance coverage.
The trial randomized eight people to IVIG 0.5 g/kg on day 1; 1 g/kg on day 2; and 0.6 g/kg once at 3 and 5 weeks. Nine others were randomized to volume-matched IV saline placebo on the same schedule. After enrollment of 17 patients (LGI1-IgG, 14; CASPR2-IgG, 3) over 34 months, the study was terminated because of slow enrollment.
Although none of the LGI-1 subjects in the placebo group responded, two CASPR2 patients did, yielding an IVIG response rate of 75% versus 22% (2/9) in the placebo arm after week 5 (odds ratio, 10.5; 95% confidence interval, 1.1-98.9; P = .044).
Two of the LGI-1 subjects in the IVIG arm were completely seizure free after treatment. Results in both arms, meanwhile, did not correlate with concomitant antiseizure medications among those who were on them.
All eight IVIG patients showed stabilization or improvement in cognitive function, compared with two of five in the placebo arm, as gauged by Repeatable Battery for the Assessment of Neuropsychological Status scores. Patients in the IVIG arm gained a median of 3 points, while patients in the placebo arm lost a median of 1 point (P = .077).
At week 5, six patients with persistent seizures who were in the placebo group were switched to the IVIG regimen after unblinding; four (67%) reported more than a 50% reduction in seizures.
Responses did not correlate with LGI-1/CASPR2-IgG1-4 subclass, and there were no IVIG-associated adverse events. One IVIG patients fell because of a faciobrachial dystonic seizure, a classic sign of LGI-1 disease. Antibodies were not measured in the trial because they “do not correlate with severity of autoimmune epilepsy,” Dr. Dubey said.
The original plan was to enroll 30 subjects, but the investigators terminated the study after 18 because of slow enrollment. With knowledge of autoimmune epilepsy growing at Mayo, it was increasingly difficult to find immunotherapy-naive patients, he said.
All the subjects were between 60 and 70 years old, and the majority in both arms were men, which was not surprising because the conditions skew male, Dr. Dubey said. None of the patients had underlying tumors, which are known triggers of autoimmune epilepsy.
This work was funded by Grifols Shared Services, a maker of IVIG, and Option Care, a provider of home infusion equipment. Dr. Dubey said the company had no active role in the trial, but that the lack of insurance coverage for IVIG in autoimmune epilepsy was one of the drivers of the study. He disclosed research support from Grifols; another investigator is a consultant.
SOURCE: Dubey D et al. AES 2019, Abstract 1.292.
BALTIMORE –
Although the numbers of enrolled subjects was small, it was the first double-blind, placebo-controlled randomized trial in autoimmune epilepsy, the start of a level 1 evidence base. Until now, treatment has been based mostly on case reports and expert opinion. “We’ve clearly shown that immunotherapy works and that treating early makes a difference, much more so than antiseizure medications,” said lead author Divyanshu Dubey, MBBS, from the Mayo Clinic.
The lack of data has meant that “we couldn’t get insurance approval for IVIG, so people have generally leaned towards” high-dose intravenous steroids, which are problematic because LGI-1 antibody epilepsy is a disease of older people, in whom osteoporosis, underlying infections, and other problems complicate steroid use, Dr. Dubey said.
The trial also included three people with contactin-associated-protein-like-2 (CASPR2) antibody epilepsy, but they all wound up in the placebo arm, “so it’s hard to say anything about them,” Dr. Dubey said at the American Epilepsy Society annual meeting. The work was published shortly before the meeting (Ann Neurol. 2019 Nov 28. doi: 10.1002/ana.25655).
CASPR2 and LGI-1 are proteins found in brain cells; attack by antibodies triggers encephalitis and tens to hundreds of seizures per day. The seizures tend to diminish with time, but the cognitive damage caused by the encephalitis does not. “We’ve seen patients end up in nursing homes diagnosed with Alzheimer’s disease” because the conditions weren’t recognized and treated, Dr. Dubey said.
He and his team chose LGI-1 and CASPR2 epilepsy because of the potentially devastating consequences and because they are among the most common autoimmune epilepsies for which antibodies have been identified. There was also a hope that positive results might open up insurance coverage.
The trial randomized eight people to IVIG 0.5 g/kg on day 1; 1 g/kg on day 2; and 0.6 g/kg once at 3 and 5 weeks. Nine others were randomized to volume-matched IV saline placebo on the same schedule. After enrollment of 17 patients (LGI1-IgG, 14; CASPR2-IgG, 3) over 34 months, the study was terminated because of slow enrollment.
Although none of the LGI-1 subjects in the placebo group responded, two CASPR2 patients did, yielding an IVIG response rate of 75% versus 22% (2/9) in the placebo arm after week 5 (odds ratio, 10.5; 95% confidence interval, 1.1-98.9; P = .044).
Two of the LGI-1 subjects in the IVIG arm were completely seizure free after treatment. Results in both arms, meanwhile, did not correlate with concomitant antiseizure medications among those who were on them.
All eight IVIG patients showed stabilization or improvement in cognitive function, compared with two of five in the placebo arm, as gauged by Repeatable Battery for the Assessment of Neuropsychological Status scores. Patients in the IVIG arm gained a median of 3 points, while patients in the placebo arm lost a median of 1 point (P = .077).
At week 5, six patients with persistent seizures who were in the placebo group were switched to the IVIG regimen after unblinding; four (67%) reported more than a 50% reduction in seizures.
Responses did not correlate with LGI-1/CASPR2-IgG1-4 subclass, and there were no IVIG-associated adverse events. One IVIG patients fell because of a faciobrachial dystonic seizure, a classic sign of LGI-1 disease. Antibodies were not measured in the trial because they “do not correlate with severity of autoimmune epilepsy,” Dr. Dubey said.
The original plan was to enroll 30 subjects, but the investigators terminated the study after 18 because of slow enrollment. With knowledge of autoimmune epilepsy growing at Mayo, it was increasingly difficult to find immunotherapy-naive patients, he said.
All the subjects were between 60 and 70 years old, and the majority in both arms were men, which was not surprising because the conditions skew male, Dr. Dubey said. None of the patients had underlying tumors, which are known triggers of autoimmune epilepsy.
This work was funded by Grifols Shared Services, a maker of IVIG, and Option Care, a provider of home infusion equipment. Dr. Dubey said the company had no active role in the trial, but that the lack of insurance coverage for IVIG in autoimmune epilepsy was one of the drivers of the study. He disclosed research support from Grifols; another investigator is a consultant.
SOURCE: Dubey D et al. AES 2019, Abstract 1.292.
REPORTING FROM AES 2019
A novel communication framework for inpatient pain management
Introducing the VIEW Framework
Case
A 55-year-old male with a history of diabetes mellitus, lumbar degenerative disc disease, and chronic low back pain was admitted overnight with right lower extremity cellulitis. He reported taking oral hydromorphone for chronic pain, but review of the Prescription Drug Monitoring Program (PDMP) revealed multiple short-term prescriptions from various ED providers, as well as monthly prescriptions from a variety of primary care providers.
Throughout the EHR, he is described as manipulative and narcotic-seeking with notation of multiple ED visits for pain. Multiple discharges against medical advice were noted. He was given two doses of IV hydromorphone in the ED and requested that this be continued. He was admitted for IV antibiotics for severe leg pain that he rated 15/10.
Background
The Society of Hospital Medicine published a consensus statement in the Journal of Hospital Medicine in 2018 that included 16 clinical recommendations on the safe use of opioids for the treatment of acute pain in hospitalized adults.1 In regard to communication about pain, clinicians are encouraged to set realistic goals and expectations of opioid therapy, closely monitor response to opioid therapy, and provide education about the side effects and potential risks of opioid therapy for patients and their families.
However, even when these strategies are employed, the social and behavioral complexities of individual patients can contribute to unsatisfactory interactions with health care staff. Because difficult encounters have been linked to provider burnout, enhanced communication strategies can benefit both the patient and physician.2
SHM’s Patient Experience Committee saw an opportunity to provide complementary evidence-based best-practice tips for communication about pain. Specifically, the committee worked collectively to develop a framework that can be applied to more challenging encounters.
The VIEW Framework
VISIT the patient’s chart and your own mental state.
First, visit the patient’s chart to review information relevant to the patient’s pain history. The EHR can be leveraged through filters and search functions to identify encounters, consultations, and notes relevant to pain management.
Look at the prior to admission medication list and active medication list and see if there are discrepancies. The medication administration record (MAR) can help identify adjunctive medications that the patient may be refusing. PDMP data should be screened for signs of aberrant use, including multiple pharmacies, multiple prescribers, short intervals between prescriptions, and serially prescribed, multiple, low-quantity prescriptions.
While documented pain scores can be a marker of patient distress, objective aspects of the patient’s functional status can shed light on how much his/her discomfort impairs day-to-day living. Examples of these measures include nutritional intake, sleep cycle, out of bed activity, and participation with therapy. Lastly, assess for opioid-related side-effects including constipation, decreased respiratory rate, and any notation of over sedation in narrative documentation from ancillary services.
Once this information has been accrued, it is important to take a moment of mindfulness before meeting with the patient. Take steps to minimize interruptions with electronic devices by silencing your pager/cell phone and disengaging from computers/tablets. Some examples of mindfulness-based practices include taking cycles of deep breathing, going for a short walk to appreciate hospital artwork or view points, or focusing on the sensory aspects of washing your hands prior to seeing the patient. Self-reflection on prior meaningful encounters can also help reset your state of mind. These activities can help clear prior subconscious thoughts and frustrations and prepare for the task ahead of you.3
Intense focus and awareness can enhance your recognition of patient distress, increase your ability to engage in active listening, and enable you to be more receptive to verbal and nonverbal cues.2 Additionally, mindful behaviors have been shown to contribute to decreased burnout and improved empathy.4,5
INTERVIEW the patient.
Once you enter the room, introduce yourself to the patient and others who are present. Interview the patient by eliciting subjective information. Use open-ended and nonjudgmental language, and take moments to summarize the patient’s perspective.
Inquire about the patient’s home baseline pain scores and past levels of acceptable function. Further explore the patient’s performance goals related to activities of daily living and quality of life. Ask about any prior history of addiction to any substance, and if needed, discuss your specific concerns related to substance misuse and abuse.
EMPATHIZE with the patient.
Integrate empathy into your interview by validating any frustrations and experience of pain. Identifying with loss of function and quality of life can help you connect with the patient and initiate a therapeutic relationship. Observe both verbal and nonverbal behaviors that reveal signs of emotional discomfort.6 Use open-ended questions to create space and trust for patients to share their feelings.
Pause to summarize the patient’s perspective while acknowledging and validating emotions that he or she may be experiencing such as anxiety, fear, frustration and anger.6 Statements such as “ I know it is frustrating to ... ” or “I can’t imagine what it must feel like to ... ” can help convey empathy. Multiple studies have suggested that enhanced provider empathy and positive messaging can also reduce patient pain and anxiety and increase quality of life.7,8 Empathic responses to negative emotional expressions from patients have also been associated with higher ratings of communication.9
WRAP UP.
Finally, wrap up by aligning expectations with the patient for pain control and summarize your management recommendations. Educate the patient and his/her family on the risks and benefits of recommended therapy as well as the expected course of recovery. Setting shared goals for functionality relevant to the patient’s personal values and quality of life can build connection between you and your patient.
While handing over the patient to the next provider, refrain from using stereotypical language such as “narcotic-seeking patient.” Clearly communicate the management plan and milestones to other team members, such as nurses, physical therapists, and oncoming hospitalists, to maintain consistency. This will help align patients and their care team and may stave off maladaptive patient behaviors such as splitting.
Applying the VIEW framework to the case
Visit
Upon visiting the medical chart, the physician realized that the patient’s opioid use began in his 20s when he injured his back in a traumatic motor vehicle accident. His successful athletic career came to a halt after this injury and opioid dependence ensued.
While reviewing past notes and prescription data via the PDMP, the physician noted that the patient had been visiting many different providers in order to get more pain medications. The most recent prescription was for oral hydromorphone 4 mg every 4 hours as needed, filled 1 week prior to this presentation.
She reviewed his vital signs and found that he had been persistently hypertensive and tachycardic. His nurse mentioned that he appeared to be in severe pain because of facial grimacing with standing and walking.
Prior to entering the patient’s room, the physician took a moment of mindfulness to become aware of her emotional state because she recognized that she was worried this could be a difficult encounter. She considered how hard his life has been and how much emotional and physical pain he might be experiencing. She took a deep breath, silenced her phone, and entered the room.
Interview
The physician sat at the bedside and interviewed the patient using a calm and nonjudgmental tone. It was quickly obvious to her that he was experiencing real pain. His cellulitis appeared severe and was tender to even minimal palpation. She learned that the pain in his leg had been worsening over the past week to the point that it was becoming difficult to ambulate, sleep and perform his daily hygiene routine. He was taking 4 mg tablets of hydromorphone every 2 hours, and he had run out a few days ago. He added that his mood was increasingly depressed, and he had even admitted to occasional suicidal thoughts because the pain was so unbearable.
When asked directly, he admitted that he was worried he was addicted to hydromorphone. He had first received it for low back pain after the motor vehicle accident, and it been refilled multiple times for ongoing pain over the course of a year. Importantly, she also learned that he felt he was often treated as an addict by medical professionals and felt that doctors no longer listened to him or believed him.
Empathize
As the conversation went on, the physician offered empathetic statements, recognizing the way it might feel to have your pain ignored or minimized by doctors. She expressed how frustrating it is to not be able to perform basic functions and how difficult it must be to constantly live in pain.
She said, “I don’t want you to suffer in pain. I care about you and my goal is to treat your pain so that you can return to doing the things in life that you find meaningful.” She also recognized the severity of his depression and discussed with him the role and importance of psychiatric consultation.
Wrap Up
The physician wrapped up the encounter by summarizing her plan to treat the infection and work together with him to treat his pain with the goal that he could ambulate and perform activities of daily living.
She reviewed the side effects of both acute and long-term use of opioids and discussed the risks and benefits. Given the fact that patient was on chronic baseline opioids and also had objective signs of acute pain, she started an initial regimen of hydromorphone 6 mg tablets every 4 hours as needed (a 50% increase over his home dose) and added acetaminophen 1000 mg every 6 hours and ibuprofen 600 mg every 8 hours.
She informed him that she would check on him in the afternoon and that the ultimate plan would be to taper down on his hydromorphone dose each day as his cellulitis improved. She also communicated that bidirectional respect between the patient and care team members was critical to a successful pain management.
Finally, she explained that there was going to be a different doctor covering at night and major changes to the prescription regimen would be deferred to daytime hours.
When she left the room, she summarized the plan with the patient’s nurse and shared a few details about the patient’s difficult past. At the end of the shift, the physician signed out to the overnight team that the patient had objective signs of pain and recommended a visit to the bedside if the patient’s symptoms were reported as worsening.
During his hospital stay, she monitored the patient’s nonverbal responses to movement, participation in physical therapy, and ability to sleep. She tapered the hydromorphone down each day as the patient’s cellulitis improved. At discharge, he was prescribed a 3-day supply of his home dose of hydromorphone and the same acetaminophen and ibuprofen regimen he had been on in the hospital with instructions for tapering. Finally, after coming to an agreement with the patient, she arranged for follow-up in the opioid taper clinic and communicated the plan with the patient’s primary care provider.
Dr. Horman is a hospitalist and assistant professor of medicine at UC San Diego Health. Dr. Richards is a hospitalist and assistant professor of medicine at the University of Nebraska Medical Center in Omaha. Dr. Horman and Dr. Richards note that they wrote this article in collaboration with the Society of Hospital Medicine Patient Experience Committee.
Key points
- Spend adequate time to fully visit patients’ history as it relates to their current pain complaints.
- Review notes and prescription data to better understand past and current pain regimen.
- Be vigilant about taking a mindful moment to visit your thoughts and potential biases.
- Interview patients using a calm tone and nonjudgmental, reassuring words.
- Empathize with patients and validate any frustrations and experience of pain.
- Wrap-up by summarizing your recommendations with patients, their families, the care team, and subsequent providers.
References
1. Herzig SJ et al. Safe opioid prescribing for acute noncancer pain in hospitalized adults: A Systematic Review of Existing Guidelines. J Hosp Med. 2018;13(4):256-62.
2. An PG et al. (MEM Investigators). Burden of difficult encounters in primary care: data from the minimizing error, maximizing outcomes study. Arch Intern Med. 2009;169(4):410-4.
3. Sanyer O, Fortenberry K. Using Mindfulness Techniques to improve difficult clinical encounters. Am Fam Physician. 2013;87(6):402.
4. Beckman HB et al. The impact of a program in mindful communication on primary care physicians. Acad Med. 2012;87(6):815-8.
5. Krasner MS et al. Association of an educational program in mindful communication with burnout, empathy, and attitudes among primary care physicians. JAMA. 2009;302(12):1284-93.
6. Dean M, Street R. A 3-Stage model of patient centered communication for addressing cancer patients’ emotional distress. Patient Educ Couns. 2014;94(2):143-8.
7. Howick J et al. Effects of empathic and positive communication in healthcare consultations: A systematic review and meta-analysis. J R Soc Med. 2018;111(7):240-52.
8. Mistiaen P et al. The effect of patient-practitioner communication on pain: A systematic review. Eur J Pain. 2016;20:675-88.
9. Weiss R et al. Associations of physician empathy with patient anxiety and ratings of communication in hospital admission encounters. J Hosp Med. 2017;12(10):805-10.
Introducing the VIEW Framework
Introducing the VIEW Framework
Case
A 55-year-old male with a history of diabetes mellitus, lumbar degenerative disc disease, and chronic low back pain was admitted overnight with right lower extremity cellulitis. He reported taking oral hydromorphone for chronic pain, but review of the Prescription Drug Monitoring Program (PDMP) revealed multiple short-term prescriptions from various ED providers, as well as monthly prescriptions from a variety of primary care providers.
Throughout the EHR, he is described as manipulative and narcotic-seeking with notation of multiple ED visits for pain. Multiple discharges against medical advice were noted. He was given two doses of IV hydromorphone in the ED and requested that this be continued. He was admitted for IV antibiotics for severe leg pain that he rated 15/10.
Background
The Society of Hospital Medicine published a consensus statement in the Journal of Hospital Medicine in 2018 that included 16 clinical recommendations on the safe use of opioids for the treatment of acute pain in hospitalized adults.1 In regard to communication about pain, clinicians are encouraged to set realistic goals and expectations of opioid therapy, closely monitor response to opioid therapy, and provide education about the side effects and potential risks of opioid therapy for patients and their families.
However, even when these strategies are employed, the social and behavioral complexities of individual patients can contribute to unsatisfactory interactions with health care staff. Because difficult encounters have been linked to provider burnout, enhanced communication strategies can benefit both the patient and physician.2
SHM’s Patient Experience Committee saw an opportunity to provide complementary evidence-based best-practice tips for communication about pain. Specifically, the committee worked collectively to develop a framework that can be applied to more challenging encounters.
The VIEW Framework
VISIT the patient’s chart and your own mental state.
First, visit the patient’s chart to review information relevant to the patient’s pain history. The EHR can be leveraged through filters and search functions to identify encounters, consultations, and notes relevant to pain management.
Look at the prior to admission medication list and active medication list and see if there are discrepancies. The medication administration record (MAR) can help identify adjunctive medications that the patient may be refusing. PDMP data should be screened for signs of aberrant use, including multiple pharmacies, multiple prescribers, short intervals between prescriptions, and serially prescribed, multiple, low-quantity prescriptions.
While documented pain scores can be a marker of patient distress, objective aspects of the patient’s functional status can shed light on how much his/her discomfort impairs day-to-day living. Examples of these measures include nutritional intake, sleep cycle, out of bed activity, and participation with therapy. Lastly, assess for opioid-related side-effects including constipation, decreased respiratory rate, and any notation of over sedation in narrative documentation from ancillary services.
Once this information has been accrued, it is important to take a moment of mindfulness before meeting with the patient. Take steps to minimize interruptions with electronic devices by silencing your pager/cell phone and disengaging from computers/tablets. Some examples of mindfulness-based practices include taking cycles of deep breathing, going for a short walk to appreciate hospital artwork or view points, or focusing on the sensory aspects of washing your hands prior to seeing the patient. Self-reflection on prior meaningful encounters can also help reset your state of mind. These activities can help clear prior subconscious thoughts and frustrations and prepare for the task ahead of you.3
Intense focus and awareness can enhance your recognition of patient distress, increase your ability to engage in active listening, and enable you to be more receptive to verbal and nonverbal cues.2 Additionally, mindful behaviors have been shown to contribute to decreased burnout and improved empathy.4,5
INTERVIEW the patient.
Once you enter the room, introduce yourself to the patient and others who are present. Interview the patient by eliciting subjective information. Use open-ended and nonjudgmental language, and take moments to summarize the patient’s perspective.
Inquire about the patient’s home baseline pain scores and past levels of acceptable function. Further explore the patient’s performance goals related to activities of daily living and quality of life. Ask about any prior history of addiction to any substance, and if needed, discuss your specific concerns related to substance misuse and abuse.
EMPATHIZE with the patient.
Integrate empathy into your interview by validating any frustrations and experience of pain. Identifying with loss of function and quality of life can help you connect with the patient and initiate a therapeutic relationship. Observe both verbal and nonverbal behaviors that reveal signs of emotional discomfort.6 Use open-ended questions to create space and trust for patients to share their feelings.
Pause to summarize the patient’s perspective while acknowledging and validating emotions that he or she may be experiencing such as anxiety, fear, frustration and anger.6 Statements such as “ I know it is frustrating to ... ” or “I can’t imagine what it must feel like to ... ” can help convey empathy. Multiple studies have suggested that enhanced provider empathy and positive messaging can also reduce patient pain and anxiety and increase quality of life.7,8 Empathic responses to negative emotional expressions from patients have also been associated with higher ratings of communication.9
WRAP UP.
Finally, wrap up by aligning expectations with the patient for pain control and summarize your management recommendations. Educate the patient and his/her family on the risks and benefits of recommended therapy as well as the expected course of recovery. Setting shared goals for functionality relevant to the patient’s personal values and quality of life can build connection between you and your patient.
While handing over the patient to the next provider, refrain from using stereotypical language such as “narcotic-seeking patient.” Clearly communicate the management plan and milestones to other team members, such as nurses, physical therapists, and oncoming hospitalists, to maintain consistency. This will help align patients and their care team and may stave off maladaptive patient behaviors such as splitting.
Applying the VIEW framework to the case
Visit
Upon visiting the medical chart, the physician realized that the patient’s opioid use began in his 20s when he injured his back in a traumatic motor vehicle accident. His successful athletic career came to a halt after this injury and opioid dependence ensued.
While reviewing past notes and prescription data via the PDMP, the physician noted that the patient had been visiting many different providers in order to get more pain medications. The most recent prescription was for oral hydromorphone 4 mg every 4 hours as needed, filled 1 week prior to this presentation.
She reviewed his vital signs and found that he had been persistently hypertensive and tachycardic. His nurse mentioned that he appeared to be in severe pain because of facial grimacing with standing and walking.
Prior to entering the patient’s room, the physician took a moment of mindfulness to become aware of her emotional state because she recognized that she was worried this could be a difficult encounter. She considered how hard his life has been and how much emotional and physical pain he might be experiencing. She took a deep breath, silenced her phone, and entered the room.
Interview
The physician sat at the bedside and interviewed the patient using a calm and nonjudgmental tone. It was quickly obvious to her that he was experiencing real pain. His cellulitis appeared severe and was tender to even minimal palpation. She learned that the pain in his leg had been worsening over the past week to the point that it was becoming difficult to ambulate, sleep and perform his daily hygiene routine. He was taking 4 mg tablets of hydromorphone every 2 hours, and he had run out a few days ago. He added that his mood was increasingly depressed, and he had even admitted to occasional suicidal thoughts because the pain was so unbearable.
When asked directly, he admitted that he was worried he was addicted to hydromorphone. He had first received it for low back pain after the motor vehicle accident, and it been refilled multiple times for ongoing pain over the course of a year. Importantly, she also learned that he felt he was often treated as an addict by medical professionals and felt that doctors no longer listened to him or believed him.
Empathize
As the conversation went on, the physician offered empathetic statements, recognizing the way it might feel to have your pain ignored or minimized by doctors. She expressed how frustrating it is to not be able to perform basic functions and how difficult it must be to constantly live in pain.
She said, “I don’t want you to suffer in pain. I care about you and my goal is to treat your pain so that you can return to doing the things in life that you find meaningful.” She also recognized the severity of his depression and discussed with him the role and importance of psychiatric consultation.
Wrap Up
The physician wrapped up the encounter by summarizing her plan to treat the infection and work together with him to treat his pain with the goal that he could ambulate and perform activities of daily living.
She reviewed the side effects of both acute and long-term use of opioids and discussed the risks and benefits. Given the fact that patient was on chronic baseline opioids and also had objective signs of acute pain, she started an initial regimen of hydromorphone 6 mg tablets every 4 hours as needed (a 50% increase over his home dose) and added acetaminophen 1000 mg every 6 hours and ibuprofen 600 mg every 8 hours.
She informed him that she would check on him in the afternoon and that the ultimate plan would be to taper down on his hydromorphone dose each day as his cellulitis improved. She also communicated that bidirectional respect between the patient and care team members was critical to a successful pain management.
Finally, she explained that there was going to be a different doctor covering at night and major changes to the prescription regimen would be deferred to daytime hours.
When she left the room, she summarized the plan with the patient’s nurse and shared a few details about the patient’s difficult past. At the end of the shift, the physician signed out to the overnight team that the patient had objective signs of pain and recommended a visit to the bedside if the patient’s symptoms were reported as worsening.
During his hospital stay, she monitored the patient’s nonverbal responses to movement, participation in physical therapy, and ability to sleep. She tapered the hydromorphone down each day as the patient’s cellulitis improved. At discharge, he was prescribed a 3-day supply of his home dose of hydromorphone and the same acetaminophen and ibuprofen regimen he had been on in the hospital with instructions for tapering. Finally, after coming to an agreement with the patient, she arranged for follow-up in the opioid taper clinic and communicated the plan with the patient’s primary care provider.
Dr. Horman is a hospitalist and assistant professor of medicine at UC San Diego Health. Dr. Richards is a hospitalist and assistant professor of medicine at the University of Nebraska Medical Center in Omaha. Dr. Horman and Dr. Richards note that they wrote this article in collaboration with the Society of Hospital Medicine Patient Experience Committee.
Key points
- Spend adequate time to fully visit patients’ history as it relates to their current pain complaints.
- Review notes and prescription data to better understand past and current pain regimen.
- Be vigilant about taking a mindful moment to visit your thoughts and potential biases.
- Interview patients using a calm tone and nonjudgmental, reassuring words.
- Empathize with patients and validate any frustrations and experience of pain.
- Wrap-up by summarizing your recommendations with patients, their families, the care team, and subsequent providers.
References
1. Herzig SJ et al. Safe opioid prescribing for acute noncancer pain in hospitalized adults: A Systematic Review of Existing Guidelines. J Hosp Med. 2018;13(4):256-62.
2. An PG et al. (MEM Investigators). Burden of difficult encounters in primary care: data from the minimizing error, maximizing outcomes study. Arch Intern Med. 2009;169(4):410-4.
3. Sanyer O, Fortenberry K. Using Mindfulness Techniques to improve difficult clinical encounters. Am Fam Physician. 2013;87(6):402.
4. Beckman HB et al. The impact of a program in mindful communication on primary care physicians. Acad Med. 2012;87(6):815-8.
5. Krasner MS et al. Association of an educational program in mindful communication with burnout, empathy, and attitudes among primary care physicians. JAMA. 2009;302(12):1284-93.
6. Dean M, Street R. A 3-Stage model of patient centered communication for addressing cancer patients’ emotional distress. Patient Educ Couns. 2014;94(2):143-8.
7. Howick J et al. Effects of empathic and positive communication in healthcare consultations: A systematic review and meta-analysis. J R Soc Med. 2018;111(7):240-52.
8. Mistiaen P et al. The effect of patient-practitioner communication on pain: A systematic review. Eur J Pain. 2016;20:675-88.
9. Weiss R et al. Associations of physician empathy with patient anxiety and ratings of communication in hospital admission encounters. J Hosp Med. 2017;12(10):805-10.
Case
A 55-year-old male with a history of diabetes mellitus, lumbar degenerative disc disease, and chronic low back pain was admitted overnight with right lower extremity cellulitis. He reported taking oral hydromorphone for chronic pain, but review of the Prescription Drug Monitoring Program (PDMP) revealed multiple short-term prescriptions from various ED providers, as well as monthly prescriptions from a variety of primary care providers.
Throughout the EHR, he is described as manipulative and narcotic-seeking with notation of multiple ED visits for pain. Multiple discharges against medical advice were noted. He was given two doses of IV hydromorphone in the ED and requested that this be continued. He was admitted for IV antibiotics for severe leg pain that he rated 15/10.
Background
The Society of Hospital Medicine published a consensus statement in the Journal of Hospital Medicine in 2018 that included 16 clinical recommendations on the safe use of opioids for the treatment of acute pain in hospitalized adults.1 In regard to communication about pain, clinicians are encouraged to set realistic goals and expectations of opioid therapy, closely monitor response to opioid therapy, and provide education about the side effects and potential risks of opioid therapy for patients and their families.
However, even when these strategies are employed, the social and behavioral complexities of individual patients can contribute to unsatisfactory interactions with health care staff. Because difficult encounters have been linked to provider burnout, enhanced communication strategies can benefit both the patient and physician.2
SHM’s Patient Experience Committee saw an opportunity to provide complementary evidence-based best-practice tips for communication about pain. Specifically, the committee worked collectively to develop a framework that can be applied to more challenging encounters.
The VIEW Framework
VISIT the patient’s chart and your own mental state.
First, visit the patient’s chart to review information relevant to the patient’s pain history. The EHR can be leveraged through filters and search functions to identify encounters, consultations, and notes relevant to pain management.
Look at the prior to admission medication list and active medication list and see if there are discrepancies. The medication administration record (MAR) can help identify adjunctive medications that the patient may be refusing. PDMP data should be screened for signs of aberrant use, including multiple pharmacies, multiple prescribers, short intervals between prescriptions, and serially prescribed, multiple, low-quantity prescriptions.
While documented pain scores can be a marker of patient distress, objective aspects of the patient’s functional status can shed light on how much his/her discomfort impairs day-to-day living. Examples of these measures include nutritional intake, sleep cycle, out of bed activity, and participation with therapy. Lastly, assess for opioid-related side-effects including constipation, decreased respiratory rate, and any notation of over sedation in narrative documentation from ancillary services.
Once this information has been accrued, it is important to take a moment of mindfulness before meeting with the patient. Take steps to minimize interruptions with electronic devices by silencing your pager/cell phone and disengaging from computers/tablets. Some examples of mindfulness-based practices include taking cycles of deep breathing, going for a short walk to appreciate hospital artwork or view points, or focusing on the sensory aspects of washing your hands prior to seeing the patient. Self-reflection on prior meaningful encounters can also help reset your state of mind. These activities can help clear prior subconscious thoughts and frustrations and prepare for the task ahead of you.3
Intense focus and awareness can enhance your recognition of patient distress, increase your ability to engage in active listening, and enable you to be more receptive to verbal and nonverbal cues.2 Additionally, mindful behaviors have been shown to contribute to decreased burnout and improved empathy.4,5
INTERVIEW the patient.
Once you enter the room, introduce yourself to the patient and others who are present. Interview the patient by eliciting subjective information. Use open-ended and nonjudgmental language, and take moments to summarize the patient’s perspective.
Inquire about the patient’s home baseline pain scores and past levels of acceptable function. Further explore the patient’s performance goals related to activities of daily living and quality of life. Ask about any prior history of addiction to any substance, and if needed, discuss your specific concerns related to substance misuse and abuse.
EMPATHIZE with the patient.
Integrate empathy into your interview by validating any frustrations and experience of pain. Identifying with loss of function and quality of life can help you connect with the patient and initiate a therapeutic relationship. Observe both verbal and nonverbal behaviors that reveal signs of emotional discomfort.6 Use open-ended questions to create space and trust for patients to share their feelings.
Pause to summarize the patient’s perspective while acknowledging and validating emotions that he or she may be experiencing such as anxiety, fear, frustration and anger.6 Statements such as “ I know it is frustrating to ... ” or “I can’t imagine what it must feel like to ... ” can help convey empathy. Multiple studies have suggested that enhanced provider empathy and positive messaging can also reduce patient pain and anxiety and increase quality of life.7,8 Empathic responses to negative emotional expressions from patients have also been associated with higher ratings of communication.9
WRAP UP.
Finally, wrap up by aligning expectations with the patient for pain control and summarize your management recommendations. Educate the patient and his/her family on the risks and benefits of recommended therapy as well as the expected course of recovery. Setting shared goals for functionality relevant to the patient’s personal values and quality of life can build connection between you and your patient.
While handing over the patient to the next provider, refrain from using stereotypical language such as “narcotic-seeking patient.” Clearly communicate the management plan and milestones to other team members, such as nurses, physical therapists, and oncoming hospitalists, to maintain consistency. This will help align patients and their care team and may stave off maladaptive patient behaviors such as splitting.
Applying the VIEW framework to the case
Visit
Upon visiting the medical chart, the physician realized that the patient’s opioid use began in his 20s when he injured his back in a traumatic motor vehicle accident. His successful athletic career came to a halt after this injury and opioid dependence ensued.
While reviewing past notes and prescription data via the PDMP, the physician noted that the patient had been visiting many different providers in order to get more pain medications. The most recent prescription was for oral hydromorphone 4 mg every 4 hours as needed, filled 1 week prior to this presentation.
She reviewed his vital signs and found that he had been persistently hypertensive and tachycardic. His nurse mentioned that he appeared to be in severe pain because of facial grimacing with standing and walking.
Prior to entering the patient’s room, the physician took a moment of mindfulness to become aware of her emotional state because she recognized that she was worried this could be a difficult encounter. She considered how hard his life has been and how much emotional and physical pain he might be experiencing. She took a deep breath, silenced her phone, and entered the room.
Interview
The physician sat at the bedside and interviewed the patient using a calm and nonjudgmental tone. It was quickly obvious to her that he was experiencing real pain. His cellulitis appeared severe and was tender to even minimal palpation. She learned that the pain in his leg had been worsening over the past week to the point that it was becoming difficult to ambulate, sleep and perform his daily hygiene routine. He was taking 4 mg tablets of hydromorphone every 2 hours, and he had run out a few days ago. He added that his mood was increasingly depressed, and he had even admitted to occasional suicidal thoughts because the pain was so unbearable.
When asked directly, he admitted that he was worried he was addicted to hydromorphone. He had first received it for low back pain after the motor vehicle accident, and it been refilled multiple times for ongoing pain over the course of a year. Importantly, she also learned that he felt he was often treated as an addict by medical professionals and felt that doctors no longer listened to him or believed him.
Empathize
As the conversation went on, the physician offered empathetic statements, recognizing the way it might feel to have your pain ignored or minimized by doctors. She expressed how frustrating it is to not be able to perform basic functions and how difficult it must be to constantly live in pain.
She said, “I don’t want you to suffer in pain. I care about you and my goal is to treat your pain so that you can return to doing the things in life that you find meaningful.” She also recognized the severity of his depression and discussed with him the role and importance of psychiatric consultation.
Wrap Up
The physician wrapped up the encounter by summarizing her plan to treat the infection and work together with him to treat his pain with the goal that he could ambulate and perform activities of daily living.
She reviewed the side effects of both acute and long-term use of opioids and discussed the risks and benefits. Given the fact that patient was on chronic baseline opioids and also had objective signs of acute pain, she started an initial regimen of hydromorphone 6 mg tablets every 4 hours as needed (a 50% increase over his home dose) and added acetaminophen 1000 mg every 6 hours and ibuprofen 600 mg every 8 hours.
She informed him that she would check on him in the afternoon and that the ultimate plan would be to taper down on his hydromorphone dose each day as his cellulitis improved. She also communicated that bidirectional respect between the patient and care team members was critical to a successful pain management.
Finally, she explained that there was going to be a different doctor covering at night and major changes to the prescription regimen would be deferred to daytime hours.
When she left the room, she summarized the plan with the patient’s nurse and shared a few details about the patient’s difficult past. At the end of the shift, the physician signed out to the overnight team that the patient had objective signs of pain and recommended a visit to the bedside if the patient’s symptoms were reported as worsening.
During his hospital stay, she monitored the patient’s nonverbal responses to movement, participation in physical therapy, and ability to sleep. She tapered the hydromorphone down each day as the patient’s cellulitis improved. At discharge, he was prescribed a 3-day supply of his home dose of hydromorphone and the same acetaminophen and ibuprofen regimen he had been on in the hospital with instructions for tapering. Finally, after coming to an agreement with the patient, she arranged for follow-up in the opioid taper clinic and communicated the plan with the patient’s primary care provider.
Dr. Horman is a hospitalist and assistant professor of medicine at UC San Diego Health. Dr. Richards is a hospitalist and assistant professor of medicine at the University of Nebraska Medical Center in Omaha. Dr. Horman and Dr. Richards note that they wrote this article in collaboration with the Society of Hospital Medicine Patient Experience Committee.
Key points
- Spend adequate time to fully visit patients’ history as it relates to their current pain complaints.
- Review notes and prescription data to better understand past and current pain regimen.
- Be vigilant about taking a mindful moment to visit your thoughts and potential biases.
- Interview patients using a calm tone and nonjudgmental, reassuring words.
- Empathize with patients and validate any frustrations and experience of pain.
- Wrap-up by summarizing your recommendations with patients, their families, the care team, and subsequent providers.
References
1. Herzig SJ et al. Safe opioid prescribing for acute noncancer pain in hospitalized adults: A Systematic Review of Existing Guidelines. J Hosp Med. 2018;13(4):256-62.
2. An PG et al. (MEM Investigators). Burden of difficult encounters in primary care: data from the minimizing error, maximizing outcomes study. Arch Intern Med. 2009;169(4):410-4.
3. Sanyer O, Fortenberry K. Using Mindfulness Techniques to improve difficult clinical encounters. Am Fam Physician. 2013;87(6):402.
4. Beckman HB et al. The impact of a program in mindful communication on primary care physicians. Acad Med. 2012;87(6):815-8.
5. Krasner MS et al. Association of an educational program in mindful communication with burnout, empathy, and attitudes among primary care physicians. JAMA. 2009;302(12):1284-93.
6. Dean M, Street R. A 3-Stage model of patient centered communication for addressing cancer patients’ emotional distress. Patient Educ Couns. 2014;94(2):143-8.
7. Howick J et al. Effects of empathic and positive communication in healthcare consultations: A systematic review and meta-analysis. J R Soc Med. 2018;111(7):240-52.
8. Mistiaen P et al. The effect of patient-practitioner communication on pain: A systematic review. Eur J Pain. 2016;20:675-88.
9. Weiss R et al. Associations of physician empathy with patient anxiety and ratings of communication in hospital admission encounters. J Hosp Med. 2017;12(10):805-10.
FDA warns gabapentin, pregabalin may cause serious breathing problems
Elderly patients who take these drugs also are at increased risk of breathing problems, the announcement said.
Gabapentin (marketed as Neurontin, Gralise, and Horizant) and pregabalin (Lyrica and Lyrica CR) are used to treat seizures, nerve pain, and restless legs syndrome. Physicians increasingly are prescribing these medications, and people are misusing and abusing these drugs more frequently, the agency said. Gabapentin and pregabalin often are combined with central nervous system depressants such as opioids, antianxiety medicines, antidepressants, and antihistamines, which increases the risk of respiratory depression.
Conditions that reduce lung function, including chronic obstructive pulmonary disease (COPD), also increase the likelihood of breathing problems when taking gabapentin and pregabalin.
“There is less evidence supporting the risk of serious breathing difficulties in healthy individuals taking gabapentinoids alone. We will continue to monitor these medicines as part of our routine monitoring of all FDA-approved drugs,” the announcement said.
The FDA is requiring new warnings about the risk of respiratory depression in the prescribing information of gabapentinoids. In addition, drug manufacturers must further assess the abuse potential of these drugs, particularly in combination with opioids.
Patients and caregivers should seek immediate medical attention for respiratory problems, which can be life threatening. Symptoms include confusion or disorientation; unusual dizziness or lightheadedness; extreme sleepiness or lethargy; slowed, shallow, or difficult breathing; unresponsiveness; and bluish-colored or tinted skin, especially on the lips, fingers, and toes.
Physicians should start gabapentinoids at the lowest dose and monitor patients for symptoms of respiratory depression and sedation when coprescribing these drugs with an opioid or other central nervous system depressant such as a benzodiazepine, according to the FDA.
The agency reviewed 49 case reports that were submitted between 2012 and 2017. Among these cases, 12 people died from respiratory depression with gabapentinoids. All of the patients who died had at least one risk factor.
Gabapentin first was approved in 1993, and pregabalin was approved in 2004. Drug adverse events and side effects can be reported online, the agency noted.
Elderly patients who take these drugs also are at increased risk of breathing problems, the announcement said.
Gabapentin (marketed as Neurontin, Gralise, and Horizant) and pregabalin (Lyrica and Lyrica CR) are used to treat seizures, nerve pain, and restless legs syndrome. Physicians increasingly are prescribing these medications, and people are misusing and abusing these drugs more frequently, the agency said. Gabapentin and pregabalin often are combined with central nervous system depressants such as opioids, antianxiety medicines, antidepressants, and antihistamines, which increases the risk of respiratory depression.
Conditions that reduce lung function, including chronic obstructive pulmonary disease (COPD), also increase the likelihood of breathing problems when taking gabapentin and pregabalin.
“There is less evidence supporting the risk of serious breathing difficulties in healthy individuals taking gabapentinoids alone. We will continue to monitor these medicines as part of our routine monitoring of all FDA-approved drugs,” the announcement said.
The FDA is requiring new warnings about the risk of respiratory depression in the prescribing information of gabapentinoids. In addition, drug manufacturers must further assess the abuse potential of these drugs, particularly in combination with opioids.
Patients and caregivers should seek immediate medical attention for respiratory problems, which can be life threatening. Symptoms include confusion or disorientation; unusual dizziness or lightheadedness; extreme sleepiness or lethargy; slowed, shallow, or difficult breathing; unresponsiveness; and bluish-colored or tinted skin, especially on the lips, fingers, and toes.
Physicians should start gabapentinoids at the lowest dose and monitor patients for symptoms of respiratory depression and sedation when coprescribing these drugs with an opioid or other central nervous system depressant such as a benzodiazepine, according to the FDA.
The agency reviewed 49 case reports that were submitted between 2012 and 2017. Among these cases, 12 people died from respiratory depression with gabapentinoids. All of the patients who died had at least one risk factor.
Gabapentin first was approved in 1993, and pregabalin was approved in 2004. Drug adverse events and side effects can be reported online, the agency noted.
Elderly patients who take these drugs also are at increased risk of breathing problems, the announcement said.
Gabapentin (marketed as Neurontin, Gralise, and Horizant) and pregabalin (Lyrica and Lyrica CR) are used to treat seizures, nerve pain, and restless legs syndrome. Physicians increasingly are prescribing these medications, and people are misusing and abusing these drugs more frequently, the agency said. Gabapentin and pregabalin often are combined with central nervous system depressants such as opioids, antianxiety medicines, antidepressants, and antihistamines, which increases the risk of respiratory depression.
Conditions that reduce lung function, including chronic obstructive pulmonary disease (COPD), also increase the likelihood of breathing problems when taking gabapentin and pregabalin.
“There is less evidence supporting the risk of serious breathing difficulties in healthy individuals taking gabapentinoids alone. We will continue to monitor these medicines as part of our routine monitoring of all FDA-approved drugs,” the announcement said.
The FDA is requiring new warnings about the risk of respiratory depression in the prescribing information of gabapentinoids. In addition, drug manufacturers must further assess the abuse potential of these drugs, particularly in combination with opioids.
Patients and caregivers should seek immediate medical attention for respiratory problems, which can be life threatening. Symptoms include confusion or disorientation; unusual dizziness or lightheadedness; extreme sleepiness or lethargy; slowed, shallow, or difficult breathing; unresponsiveness; and bluish-colored or tinted skin, especially on the lips, fingers, and toes.
Physicians should start gabapentinoids at the lowest dose and monitor patients for symptoms of respiratory depression and sedation when coprescribing these drugs with an opioid or other central nervous system depressant such as a benzodiazepine, according to the FDA.
The agency reviewed 49 case reports that were submitted between 2012 and 2017. Among these cases, 12 people died from respiratory depression with gabapentinoids. All of the patients who died had at least one risk factor.
Gabapentin first was approved in 1993, and pregabalin was approved in 2004. Drug adverse events and side effects can be reported online, the agency noted.
California researchers work to update EMS status epilepticus protocols
BALTIMORE – Investigators from the University of California, San Francisco, are working with medical directors across the state to update county emergency medical services protocols to ensure patients in status epilepticus get 10 mg IM midazolam in the field, per national treatment guidelines from the American Epilepsy Society.
The work comes in the wake of a recent research letter in JAMA where the UCSF team reported that, across 33 emergency medical services (EMS) in California, only 2 included 10 mg midazolam IM per the guidelines, advice based on randomized, controlled clinical trials that found it to be safe and effective for stopping prehospital seizures in adults.
“Making people aware of the problem [is having] an impact,” said investigator Elan Guterman, MD, a neurology hospitalist and assistant professor of neurology at the university.
In a follow-up review at the annual meeting of the American Epilepsy Society, the team took a deep dive into the situation in Alameda County, just east of San Francisco and including the city of Oakland, as an indicator of what’s been going on across the state.
Patients had to have an EMS record of active seizures, meaning more than two within 5 minutes or a single seizure lasting more than 5 minutes. Alameda ambulance crews, like most, carry intramuscular midazolam because it’s more shelf stable than the two other first-line options, lorazepam and diazepam, and doesn’t require an intravenous line.
Among the 2,494 adults treated for status epilepticus from 2013 to 2018, just 62% received intramuscular midazolam, and only 39% got a dose of 5 mg or more. Not a single patient received the recommended 10-mg IM injection.
In short, “at the time when it’s the most important to act quickly, patients were not receiving the care they needed,” and the problem isn’t likely limited to California, Dr. Guterman said.
When patients did get 5 mg or more, they were less likely to reseize and require additional doses (adjusted odds ratio, 0.59; 95% CI, 0.4-0.86). Also – and counterintuitively given the concern about benzodiazepines and respiratory depression – the team found that higher initial doses of 5 mg or more were actually associated with a lower need for respiratory support, including intubation (OR, 0.81; 95% CI, 0.67-0.99).
It’s possible ambulance crews were erring on the side of caution. People who got midazolam were more likely to have an established diagnosis of epilepsy (68% vs. 62%; P less than .01) and less likely to have been abusing drugs or alcohol (12.5% vs. 16.3%; P less than .01).
But an abundance of caution doesn’t fully explain it; even among people known to have epilepsy, many weren’t treated with midazolam and none at the appropriate dose.
Dr. Guterman thinks the bigger issue is what was reported in the research letter: Local EMS protocols simply haven’t been updated to include current best practices. EMS services might not even be aware of them, which is why she and her colleagues have been meeting with county medical directors.
“The first step is making sure the EMS world is aware of this gap in care, and motivating them to address it,” she said.
Patients in the study were a mean of 53 years old, and just over half were men.
There was no industry funding for the study, and Dr. Guterman didn’t report any relevant disclosures.
SOURCE: Guterman E et al. AES 2019, Abstract 1.394.
BALTIMORE – Investigators from the University of California, San Francisco, are working with medical directors across the state to update county emergency medical services protocols to ensure patients in status epilepticus get 10 mg IM midazolam in the field, per national treatment guidelines from the American Epilepsy Society.
The work comes in the wake of a recent research letter in JAMA where the UCSF team reported that, across 33 emergency medical services (EMS) in California, only 2 included 10 mg midazolam IM per the guidelines, advice based on randomized, controlled clinical trials that found it to be safe and effective for stopping prehospital seizures in adults.
“Making people aware of the problem [is having] an impact,” said investigator Elan Guterman, MD, a neurology hospitalist and assistant professor of neurology at the university.
In a follow-up review at the annual meeting of the American Epilepsy Society, the team took a deep dive into the situation in Alameda County, just east of San Francisco and including the city of Oakland, as an indicator of what’s been going on across the state.
Patients had to have an EMS record of active seizures, meaning more than two within 5 minutes or a single seizure lasting more than 5 minutes. Alameda ambulance crews, like most, carry intramuscular midazolam because it’s more shelf stable than the two other first-line options, lorazepam and diazepam, and doesn’t require an intravenous line.
Among the 2,494 adults treated for status epilepticus from 2013 to 2018, just 62% received intramuscular midazolam, and only 39% got a dose of 5 mg or more. Not a single patient received the recommended 10-mg IM injection.
In short, “at the time when it’s the most important to act quickly, patients were not receiving the care they needed,” and the problem isn’t likely limited to California, Dr. Guterman said.
When patients did get 5 mg or more, they were less likely to reseize and require additional doses (adjusted odds ratio, 0.59; 95% CI, 0.4-0.86). Also – and counterintuitively given the concern about benzodiazepines and respiratory depression – the team found that higher initial doses of 5 mg or more were actually associated with a lower need for respiratory support, including intubation (OR, 0.81; 95% CI, 0.67-0.99).
It’s possible ambulance crews were erring on the side of caution. People who got midazolam were more likely to have an established diagnosis of epilepsy (68% vs. 62%; P less than .01) and less likely to have been abusing drugs or alcohol (12.5% vs. 16.3%; P less than .01).
But an abundance of caution doesn’t fully explain it; even among people known to have epilepsy, many weren’t treated with midazolam and none at the appropriate dose.
Dr. Guterman thinks the bigger issue is what was reported in the research letter: Local EMS protocols simply haven’t been updated to include current best practices. EMS services might not even be aware of them, which is why she and her colleagues have been meeting with county medical directors.
“The first step is making sure the EMS world is aware of this gap in care, and motivating them to address it,” she said.
Patients in the study were a mean of 53 years old, and just over half were men.
There was no industry funding for the study, and Dr. Guterman didn’t report any relevant disclosures.
SOURCE: Guterman E et al. AES 2019, Abstract 1.394.
BALTIMORE – Investigators from the University of California, San Francisco, are working with medical directors across the state to update county emergency medical services protocols to ensure patients in status epilepticus get 10 mg IM midazolam in the field, per national treatment guidelines from the American Epilepsy Society.
The work comes in the wake of a recent research letter in JAMA where the UCSF team reported that, across 33 emergency medical services (EMS) in California, only 2 included 10 mg midazolam IM per the guidelines, advice based on randomized, controlled clinical trials that found it to be safe and effective for stopping prehospital seizures in adults.
“Making people aware of the problem [is having] an impact,” said investigator Elan Guterman, MD, a neurology hospitalist and assistant professor of neurology at the university.
In a follow-up review at the annual meeting of the American Epilepsy Society, the team took a deep dive into the situation in Alameda County, just east of San Francisco and including the city of Oakland, as an indicator of what’s been going on across the state.
Patients had to have an EMS record of active seizures, meaning more than two within 5 minutes or a single seizure lasting more than 5 minutes. Alameda ambulance crews, like most, carry intramuscular midazolam because it’s more shelf stable than the two other first-line options, lorazepam and diazepam, and doesn’t require an intravenous line.
Among the 2,494 adults treated for status epilepticus from 2013 to 2018, just 62% received intramuscular midazolam, and only 39% got a dose of 5 mg or more. Not a single patient received the recommended 10-mg IM injection.
In short, “at the time when it’s the most important to act quickly, patients were not receiving the care they needed,” and the problem isn’t likely limited to California, Dr. Guterman said.
When patients did get 5 mg or more, they were less likely to reseize and require additional doses (adjusted odds ratio, 0.59; 95% CI, 0.4-0.86). Also – and counterintuitively given the concern about benzodiazepines and respiratory depression – the team found that higher initial doses of 5 mg or more were actually associated with a lower need for respiratory support, including intubation (OR, 0.81; 95% CI, 0.67-0.99).
It’s possible ambulance crews were erring on the side of caution. People who got midazolam were more likely to have an established diagnosis of epilepsy (68% vs. 62%; P less than .01) and less likely to have been abusing drugs or alcohol (12.5% vs. 16.3%; P less than .01).
But an abundance of caution doesn’t fully explain it; even among people known to have epilepsy, many weren’t treated with midazolam and none at the appropriate dose.
Dr. Guterman thinks the bigger issue is what was reported in the research letter: Local EMS protocols simply haven’t been updated to include current best practices. EMS services might not even be aware of them, which is why she and her colleagues have been meeting with county medical directors.
“The first step is making sure the EMS world is aware of this gap in care, and motivating them to address it,” she said.
Patients in the study were a mean of 53 years old, and just over half were men.
There was no industry funding for the study, and Dr. Guterman didn’t report any relevant disclosures.
SOURCE: Guterman E et al. AES 2019, Abstract 1.394.
REPORTING FROM AES 2019
