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First EDition: Emergency Physicians’ Rates of Opioid Prescribing, more
BY JEFF BAUER
A large retrospective analysis found a wide variation in opioid prescribing among emergency physicians (EPs) working within the same ED. The study also found that Medicare patients treated by EPs who wrote the most prescriptions for opioids were more likely to use opioids for 6 months after their ED visit than were those treated by EPs who wrote fewer opioid prescriptions.
Researchers evaluated initial visits to an ED by approximately 378,000 Medicare beneficiaries (average age: 68 years) from 2008 through 2011. None of these patients had received a prescription for an opioid in the 6 months before the ED visit, and none of the visits resulted in a hospital admission. Prescriptions for opioids (excluding methadone) were identified by the national drug code in the Medicare Part D database. An opioid prescription was attributed to the treating EP if the patient filled the prescription within 3 days after the ED visit.
Investigators categorized the treating EPs in this study as “high-intensity” or “low-intensity” opioid prescribers by calculating the proportion of all ED visits that resulted in an opioid prescription being filled. They then grouped the EPs into quartiles of opioid prescribing within each hospital. High-intensity prescribers were those in the top quartile of opioid prescribing rates, and low-intensity prescribers were those in the bottom quartile.
The primary outcome was long-term opioid use, defined as 6 months or more of opioids supplied in the 12 months after the initial ED visit. This did not include prescriptions filled within 30 days of the initial visit.
Overall, approximately 215,700 patients were treated by low-intensity prescribers and 162,000 by high-intensity prescribers. In general, the patient characteristics and diagnoses were similar in both groups. The rate of opioid prescribing of high-intensity prescribers was approximately triple the rate of low-intensity prescribers. High-intensity prescribers provided an opioid prescription for 21.4% of ED visits, compared to 7.3% among low-intensity prescribers.
Long-term opioid use at 12 months was significantly higher among patients who had been initially treated by high-intensity prescribers compared to those who had been treated by low-intensity prescribers (1.51% vs 1.16%; unadjusted odds ratio [OR], 1.31). There was minimal change in this difference after the results were adjusted for the patients’ age, race, sex, disability status, and presence of chronic conditions (OR, 1.30). The number needed to harm was calculated as 49, meaning theoretically, for every 49 patients who received a new opioid prescription in the ED, one would become a long-term user. The authors noted, however, that “…prescriptions provided by other physicians in the months after an [ED] visit are necessary for long-term opioid use to take hold.”
Researchers pointed out several limitations to their study. Because the study was observational, it could not establish causality. Researchers were not able to directly attribute opioid prescriptions to the treating EPs, but instead used prescriptions filled within 3 days of an ED visits as a surrogate; some opioid prescriptions could have been written by another clinician, such as the patient’s primary care physician during a follow-up visit. Because the study focused on Medicare patients, the results may not be applicable to younger patients. Based on their analysis, researchers could not determine whether an opioid prescription was appropriate, and therefore they could not quantify the extent of opioid overprescribing.
For more on EPs and opioid prescribing, see “The New Opioid Epidemic and the Law of Unintended Consequences” by Emergency Medicine Editor in Chief Neal Flomenbaum, MD (Emergency Medicine. 2017;49[2]:52) and “The New Opioid Epidemic: Prescriptions, Synthetics, and Street Drugs” by Rama B. Rao, MD and Emergency Medicine Associate Editor, Toxicology Lewis S. Nelson, MD (Emergency Medicine. 2017;49[2]:64-70).
Barnett ML, Olenski AR, Jena AB. Opioid-prescribing patterns of emergency physicians and risk of long-term use. N Engl J Med. 2017;376(7):663-673. doi:10.1056/NEJMsa1610524.
Lower Admission Rates, Other Factors Tied to High Rate of Death Soon After ED Discharge Among Older Adults
BY JEFF BAUER
Each year, approximately 10,000 older adult patients die within 7 days of discharge from an ED in the United States, despite having no obvious life-threatening illness, according to a large retrospective study. Emergency departments with lower rates of inpatient admission from the ED, lower patient volumes, and lower charges had significantly higher rates of death after discharge.
Researchers evaluated Medicare claims data related to slightly more than 10 million ED visits from 2007 to 2012. Because the goal was to study generally healthy patients, the following patients were excluded: individuals who were age 90 years and older; were receiving palliative or hospice care; or had received a life-limiting diagnosis, such as a myocardial infarction (MI) or a malignancy, either in the ED or in the year prior to the ED visit. The primary outcome was death within 7 days after discharge from an ED. The cause of death was determined by linking claims to death certificates; this information was available only for a subset of patients who visited an ED in 2007 or 2008.
Overall, during the 6-year study, 0.12% of discharged patients died within 7 days of discharge; this translates to more than 10,000 early deaths per year nationally. The leading causes of death were atherosclerotic heart disease (13.6%), MI (10.3%), and chronic obstructive pulmonary disease (9.6%).
Emergency departments ranked in the lowest fifth for admission rates admitted 15% of patients, compared to 56% of patients at EDs with the highest admission rates. The early death rate of patients treated at EDs with the lowest rates of inpatient admissions from the ED was 3.4 times higher than the death rate seen in EDs with the highest inpatient admission rates (0.27% vs 0.08%, respectively). This was true despite the fact that EDs with low-admission rates treated healthier patients, as evidenced by the overall 7-day mortality rate of all patients treated in the ED, whether they were admitted or discharged. Emergency departments that saw higher volumes of patients and had higher charges for visits had significantly fewer deaths.
Obermeyer Z, Cohn B, Wilson M, Jena AB, Cutler DM. Early death after discharge from emergency departments: analysis of national US insurance claims data. BMJ. 2017;356:j239. doi:10.1136/bmj.j239.
Tertiary Center Repeat Computed Tomography Scans Find Additional Injuries
MICHELE G. SULLIVAN
FRONTLINE MEDICAL NEWS
Imaging obtained at nontertiary trauma centers (NTCs) probably does not tell the whole story of a trauma patient’s injuries, according to a new retrospective study.
Repeat scans done at a Level 1 trauma center identified new injuries in 76% of patients who were transferred, Morgan Bonds, MD, reported at the annual scientific assembly of the Eastern Association for the Surgery of Trauma. About half of these previously unobserved injuries were considered clinically significant, said Dr Bonds, a surgical resident at the University of Oklahoma, Oklahoma City.
Her study examined imaging and clinical assessment of 203 trauma patients who were initially worked up at an NTC, and then transferred to the Level 1 University of Oklahoma tertiary trauma center (TTC). The facility’s primary radiologist reviewed all of the initial computed tomography (CT) scans while blinded to the NTC interpretation. The initial scans and interpretations were then compared with those done at the TTC.
The team split imaging and interpretation disconnects into four categories:
- Type A errors: A missed injury on the NTC scan. “This represents the expertise and experience of our primary radiologist,” Dr Bonds said.
- Type B errors: Missed injuries on scans where NTC radiologists saw other injuries that the TTC radiologist did not confirm. “This represents the experience of our radiologist and also the inexperience and overreaction of the NTC radiologists.”
- Type C errors: New injuries seen on additional TTC imaging of the same body area. “This represents the quality of the image.”
- Type D errors: New injuries found upon any new imaging, whether of a previously scanned or newly scanned body area. “This represents quality of work-up—the decision of the trauma team to more fully investigate the patient’s injuries, as well as the quality of the CT tech performing the scan.”
During the study period, 203 patients presented at the TTC with prior scans conducted at an NTC.
The mean age of the patients was 43 years; most (67%) were men. The mean Injury Severity Score was 16; 97% had experienced blunt trauma. Shock was present in 3% and a traumatic brain injury in 8%. Repeat scans were most common for neck and cervical spine injuries (54%) and thoracic/lumbar spine injuries (53%), and least common for chest injuries (32%).
An inadequate NTC work-up as judged by the TTC attending was the most common reason for obtaining new images (76%). Poor image quality was the next most common reason (31%).
Among the 203 patients, 99 (49%) had a type A error. Of these injuries missed on the initial scan, 90% were considered to be clinically significant.
Type B errors occurred in 15% of patients. Type C errors (new injuries in different body area) occurred in 54% of patients and, of these, 76% were considered clinically significant. Type D errors (new injuries seen in any imaging of any area) occurred in 73% of patients.
“This study confirms that images are often repeated or completed after having images done at NTCs,” Dr Bonds said. “Relying on NTC image interpretation can lead to undertreating our patients. One potential solution to this issue could be image sharing between NTCs and TTCs. This might reduce both the rate of missed injuries and the need for repeat scans.”
Cutaneous Eruption Reported in Pregnant Woman With Locally Acquired Zika Virus
M. ALEXANDER OTTO
FRONTLINE MEDICAL NEWS
Zika presented in a young, pregnant Florida woman as erythematous follicular macules and papules on the trunk and arms, scattered tender pink papules on the palms, and a few petechiae on the hard palate, according to a report in the New England Journal of Medicine.
The report advises how Zika virus may present during pregnancy. “Medical providers on the front line should be aware of the constellation of symptoms in patients reporting travel to endemic areas, including areas in Southern Florida, where other non-travel-associated cases have been confirmed,” wrote investigators led by Lucy Chen, MD, of the University of Miami.
The 23-year-old woman presented on July 7, 2016 at 23 weeks and 3 days’ gestation with a 3-day history of fever, widespread pruritic rash, and sore throat, which were followed by myalgias and joint pain 2 days later. The cutaneous eruption was noted on physical examination; neither conjunctivitis nor lymphadenopathy was present. The patient and her partner said they had not traveled outside the United States for 2 years.
Zika virus RNA was detected in the woman’s urine and serum specimens with the use of reverse-transcriptase polymerase chain reaction and persisted for 2 weeks in urine samples and for 6 weeks in serum samples. On histopathology, skin lesions revealed a mild perivascular lymphocytic infiltration in the upper dermis, admixed with some neutrophils. Liver and renal functions were normal.
Fetal ultrasonography performed on the day of presentation showed an estimated fetal weight of 644 g (53rd percentile), an estimated head circumference of 221 mm (63rd percentile), and normal intracranial anatomy. Fevers and rash subsided after 3 days of supportive care. Screening for measles, varicella, rubella, syphilis, Epstein-Barr virus, influenza, hepatitis B, hepatitis C, mumps, and dengue was negative.
An initial immunoglobulin M test on July 7 was negative; seroconversion occurred 1 week after presentation and remained positive through delivery.
A full-term infant weighing 2,990 g was delivered vaginally. Neonatal ultrasonography and magnetic resonance imaging of the head showed a normal head size and intracranial anatomy, with no calcifications. Placental tissue was negative for Zika virus, and neonatal laboratory testing revealed no evidence of infection.
The case was confirmed by the Miami-Dade County Department of Health as the first non-travel-associated Zika infection in the United States.
Chen L, Hafeez F, Curry CL, Elgart G. Cutaneous eruption in a U.S. woman with locally acquired Zika virus infection. N Engl J Med. 2017;376(4):400-401. doi:10.1056/NEJMc1610614.
Lab Values Poor Surrogate for Detecting Pediatric Rocky Mountain Spotted Fever in Children
WHITNEY MCKNIGHT
FRONTLINE MEDICAL NEWS
Three fatalities observed in a retrospective analysis of six cases of Rocky Mountain spotted fever (RMSF) in children were associated with either a delayed diagnosis pending laboratory findings or delayed anti-rickettsia treatment, researchers said.
“The fact that all fatal cases died before the convalescent period emphasizes that diagnosis should be based on clinical findings instead of RMSF serologic and histologic testing,” wrote the authors of a study published online in Pediatric Dermatology.
Rechelle Tull of the department of dermatology, Wake Forest University, Winston-Salem, NC, and her colleagues conducted a retrospective review of 3,912 inpatient dermatology consultations over a period of 10 years at a tertiary care center, and identified six patients aged 22 months to 2 years (mean, 5.1 years) diagnosed with RMSF. The patients were evaluated in the months of April, May, and June, and three of the six patients infected with the vector-borne obligate intracellular bacterium, Rickettsia rickettsii, had died within 4 days of hospitalization, according to the authors.
Two of the fatal cases involved delayed anti-rickettsial therapy after the patients were misdiagnosed with group A Streptococcus. None of the six children were initially evaluated for R rickettsii; they averaged three encounters with their clinician before being admitted for acute inpatient care, where they received intravenous doxycycline after nearly a week of symptoms.
“All fatal cases were complicated by neurologic manifestations, including seizures, obtundation, and uncal herniation,” a finding that is consistent with the literature, the authors said.
Although the high-fatality rate might be the result of the small study size, Ms Tull and her coinvestigators concluded that the disease should be considered in all differential diagnoses for children who present with a fever and rash during the summer months in endemic areas, particularly since pediatric cases of the disease are associated with poorer outcomes than adult cases.
Given that RMSF often remains subclinical in its early stages, and typically presents with nonspecific symptoms of fever, rash, headache, and abdominal pain when it does emerge, physicians might be tempted to defer treatment until after serological and histological results are in, as is the standard method. Concerns over doxycycline’s tendency to stain teeth and cause enamel hypoplasia are also common. However, empirical administration could mean the difference between life and death, since treatment within the first 5 days following infection is associated with better outcomes—an algorithm complicated by the fact that symptoms caused by R rickettsii have been known to take as long as 21 days to appear.
In the study, Ms Tull and her colleagues found that the average time between exposure to the tick and the onset of symptoms was 6.6 days (range, 1-21 days).
Currently, there are no diagnostic tests “that reliably diagnose RMSF during the first 7 days of illness,” and most patients “do not develop detectable antibodies until the second week of illness,” the investigators reported. Even then, sensitivity of indirect fluorescent antibody serum testing after the second week of illness is only between 86% and 94%, they noted. Further, the sensitivity of immunohistochemical (IHC) tissue staining has been reported at 70%, and false-negative IHC results are common in acute disease when antibody response is harder to detect.
Ms Tull and her colleagues found that five of the six patients in their study had negative IHC testing; two of the six had positive serum antibody titers. For this reason, they concluded that RMSF diagnosis should be based on “clinical history, examination, and laboratory abnormalities” rather than laboratory testing, and urged that “prompt treatment should be instituted empirically.”
Tull R, Ahn C, Daniel A, Yosipovitch G, Strowd LC. Retrospective study of Rocky Mountain spotted fever in children. Pediatr Dermatol. 2016 Dec 19. doi:10.1111/pde.13053. [Epub ahead of print]
BY JEFF BAUER
A large retrospective analysis found a wide variation in opioid prescribing among emergency physicians (EPs) working within the same ED. The study also found that Medicare patients treated by EPs who wrote the most prescriptions for opioids were more likely to use opioids for 6 months after their ED visit than were those treated by EPs who wrote fewer opioid prescriptions.
Researchers evaluated initial visits to an ED by approximately 378,000 Medicare beneficiaries (average age: 68 years) from 2008 through 2011. None of these patients had received a prescription for an opioid in the 6 months before the ED visit, and none of the visits resulted in a hospital admission. Prescriptions for opioids (excluding methadone) were identified by the national drug code in the Medicare Part D database. An opioid prescription was attributed to the treating EP if the patient filled the prescription within 3 days after the ED visit.
Investigators categorized the treating EPs in this study as “high-intensity” or “low-intensity” opioid prescribers by calculating the proportion of all ED visits that resulted in an opioid prescription being filled. They then grouped the EPs into quartiles of opioid prescribing within each hospital. High-intensity prescribers were those in the top quartile of opioid prescribing rates, and low-intensity prescribers were those in the bottom quartile.
The primary outcome was long-term opioid use, defined as 6 months or more of opioids supplied in the 12 months after the initial ED visit. This did not include prescriptions filled within 30 days of the initial visit.
Overall, approximately 215,700 patients were treated by low-intensity prescribers and 162,000 by high-intensity prescribers. In general, the patient characteristics and diagnoses were similar in both groups. The rate of opioid prescribing of high-intensity prescribers was approximately triple the rate of low-intensity prescribers. High-intensity prescribers provided an opioid prescription for 21.4% of ED visits, compared to 7.3% among low-intensity prescribers.
Long-term opioid use at 12 months was significantly higher among patients who had been initially treated by high-intensity prescribers compared to those who had been treated by low-intensity prescribers (1.51% vs 1.16%; unadjusted odds ratio [OR], 1.31). There was minimal change in this difference after the results were adjusted for the patients’ age, race, sex, disability status, and presence of chronic conditions (OR, 1.30). The number needed to harm was calculated as 49, meaning theoretically, for every 49 patients who received a new opioid prescription in the ED, one would become a long-term user. The authors noted, however, that “…prescriptions provided by other physicians in the months after an [ED] visit are necessary for long-term opioid use to take hold.”
Researchers pointed out several limitations to their study. Because the study was observational, it could not establish causality. Researchers were not able to directly attribute opioid prescriptions to the treating EPs, but instead used prescriptions filled within 3 days of an ED visits as a surrogate; some opioid prescriptions could have been written by another clinician, such as the patient’s primary care physician during a follow-up visit. Because the study focused on Medicare patients, the results may not be applicable to younger patients. Based on their analysis, researchers could not determine whether an opioid prescription was appropriate, and therefore they could not quantify the extent of opioid overprescribing.
For more on EPs and opioid prescribing, see “The New Opioid Epidemic and the Law of Unintended Consequences” by Emergency Medicine Editor in Chief Neal Flomenbaum, MD (Emergency Medicine. 2017;49[2]:52) and “The New Opioid Epidemic: Prescriptions, Synthetics, and Street Drugs” by Rama B. Rao, MD and Emergency Medicine Associate Editor, Toxicology Lewis S. Nelson, MD (Emergency Medicine. 2017;49[2]:64-70).
Barnett ML, Olenski AR, Jena AB. Opioid-prescribing patterns of emergency physicians and risk of long-term use. N Engl J Med. 2017;376(7):663-673. doi:10.1056/NEJMsa1610524.
Lower Admission Rates, Other Factors Tied to High Rate of Death Soon After ED Discharge Among Older Adults
BY JEFF BAUER
Each year, approximately 10,000 older adult patients die within 7 days of discharge from an ED in the United States, despite having no obvious life-threatening illness, according to a large retrospective study. Emergency departments with lower rates of inpatient admission from the ED, lower patient volumes, and lower charges had significantly higher rates of death after discharge.
Researchers evaluated Medicare claims data related to slightly more than 10 million ED visits from 2007 to 2012. Because the goal was to study generally healthy patients, the following patients were excluded: individuals who were age 90 years and older; were receiving palliative or hospice care; or had received a life-limiting diagnosis, such as a myocardial infarction (MI) or a malignancy, either in the ED or in the year prior to the ED visit. The primary outcome was death within 7 days after discharge from an ED. The cause of death was determined by linking claims to death certificates; this information was available only for a subset of patients who visited an ED in 2007 or 2008.
Overall, during the 6-year study, 0.12% of discharged patients died within 7 days of discharge; this translates to more than 10,000 early deaths per year nationally. The leading causes of death were atherosclerotic heart disease (13.6%), MI (10.3%), and chronic obstructive pulmonary disease (9.6%).
Emergency departments ranked in the lowest fifth for admission rates admitted 15% of patients, compared to 56% of patients at EDs with the highest admission rates. The early death rate of patients treated at EDs with the lowest rates of inpatient admissions from the ED was 3.4 times higher than the death rate seen in EDs with the highest inpatient admission rates (0.27% vs 0.08%, respectively). This was true despite the fact that EDs with low-admission rates treated healthier patients, as evidenced by the overall 7-day mortality rate of all patients treated in the ED, whether they were admitted or discharged. Emergency departments that saw higher volumes of patients and had higher charges for visits had significantly fewer deaths.
Obermeyer Z, Cohn B, Wilson M, Jena AB, Cutler DM. Early death after discharge from emergency departments: analysis of national US insurance claims data. BMJ. 2017;356:j239. doi:10.1136/bmj.j239.
Tertiary Center Repeat Computed Tomography Scans Find Additional Injuries
MICHELE G. SULLIVAN
FRONTLINE MEDICAL NEWS
Imaging obtained at nontertiary trauma centers (NTCs) probably does not tell the whole story of a trauma patient’s injuries, according to a new retrospective study.
Repeat scans done at a Level 1 trauma center identified new injuries in 76% of patients who were transferred, Morgan Bonds, MD, reported at the annual scientific assembly of the Eastern Association for the Surgery of Trauma. About half of these previously unobserved injuries were considered clinically significant, said Dr Bonds, a surgical resident at the University of Oklahoma, Oklahoma City.
Her study examined imaging and clinical assessment of 203 trauma patients who were initially worked up at an NTC, and then transferred to the Level 1 University of Oklahoma tertiary trauma center (TTC). The facility’s primary radiologist reviewed all of the initial computed tomography (CT) scans while blinded to the NTC interpretation. The initial scans and interpretations were then compared with those done at the TTC.
The team split imaging and interpretation disconnects into four categories:
- Type A errors: A missed injury on the NTC scan. “This represents the expertise and experience of our primary radiologist,” Dr Bonds said.
- Type B errors: Missed injuries on scans where NTC radiologists saw other injuries that the TTC radiologist did not confirm. “This represents the experience of our radiologist and also the inexperience and overreaction of the NTC radiologists.”
- Type C errors: New injuries seen on additional TTC imaging of the same body area. “This represents the quality of the image.”
- Type D errors: New injuries found upon any new imaging, whether of a previously scanned or newly scanned body area. “This represents quality of work-up—the decision of the trauma team to more fully investigate the patient’s injuries, as well as the quality of the CT tech performing the scan.”
During the study period, 203 patients presented at the TTC with prior scans conducted at an NTC.
The mean age of the patients was 43 years; most (67%) were men. The mean Injury Severity Score was 16; 97% had experienced blunt trauma. Shock was present in 3% and a traumatic brain injury in 8%. Repeat scans were most common for neck and cervical spine injuries (54%) and thoracic/lumbar spine injuries (53%), and least common for chest injuries (32%).
An inadequate NTC work-up as judged by the TTC attending was the most common reason for obtaining new images (76%). Poor image quality was the next most common reason (31%).
Among the 203 patients, 99 (49%) had a type A error. Of these injuries missed on the initial scan, 90% were considered to be clinically significant.
Type B errors occurred in 15% of patients. Type C errors (new injuries in different body area) occurred in 54% of patients and, of these, 76% were considered clinically significant. Type D errors (new injuries seen in any imaging of any area) occurred in 73% of patients.
“This study confirms that images are often repeated or completed after having images done at NTCs,” Dr Bonds said. “Relying on NTC image interpretation can lead to undertreating our patients. One potential solution to this issue could be image sharing between NTCs and TTCs. This might reduce both the rate of missed injuries and the need for repeat scans.”
Cutaneous Eruption Reported in Pregnant Woman With Locally Acquired Zika Virus
M. ALEXANDER OTTO
FRONTLINE MEDICAL NEWS
Zika presented in a young, pregnant Florida woman as erythematous follicular macules and papules on the trunk and arms, scattered tender pink papules on the palms, and a few petechiae on the hard palate, according to a report in the New England Journal of Medicine.
The report advises how Zika virus may present during pregnancy. “Medical providers on the front line should be aware of the constellation of symptoms in patients reporting travel to endemic areas, including areas in Southern Florida, where other non-travel-associated cases have been confirmed,” wrote investigators led by Lucy Chen, MD, of the University of Miami.
The 23-year-old woman presented on July 7, 2016 at 23 weeks and 3 days’ gestation with a 3-day history of fever, widespread pruritic rash, and sore throat, which were followed by myalgias and joint pain 2 days later. The cutaneous eruption was noted on physical examination; neither conjunctivitis nor lymphadenopathy was present. The patient and her partner said they had not traveled outside the United States for 2 years.
Zika virus RNA was detected in the woman’s urine and serum specimens with the use of reverse-transcriptase polymerase chain reaction and persisted for 2 weeks in urine samples and for 6 weeks in serum samples. On histopathology, skin lesions revealed a mild perivascular lymphocytic infiltration in the upper dermis, admixed with some neutrophils. Liver and renal functions were normal.
Fetal ultrasonography performed on the day of presentation showed an estimated fetal weight of 644 g (53rd percentile), an estimated head circumference of 221 mm (63rd percentile), and normal intracranial anatomy. Fevers and rash subsided after 3 days of supportive care. Screening for measles, varicella, rubella, syphilis, Epstein-Barr virus, influenza, hepatitis B, hepatitis C, mumps, and dengue was negative.
An initial immunoglobulin M test on July 7 was negative; seroconversion occurred 1 week after presentation and remained positive through delivery.
A full-term infant weighing 2,990 g was delivered vaginally. Neonatal ultrasonography and magnetic resonance imaging of the head showed a normal head size and intracranial anatomy, with no calcifications. Placental tissue was negative for Zika virus, and neonatal laboratory testing revealed no evidence of infection.
The case was confirmed by the Miami-Dade County Department of Health as the first non-travel-associated Zika infection in the United States.
Chen L, Hafeez F, Curry CL, Elgart G. Cutaneous eruption in a U.S. woman with locally acquired Zika virus infection. N Engl J Med. 2017;376(4):400-401. doi:10.1056/NEJMc1610614.
Lab Values Poor Surrogate for Detecting Pediatric Rocky Mountain Spotted Fever in Children
WHITNEY MCKNIGHT
FRONTLINE MEDICAL NEWS
Three fatalities observed in a retrospective analysis of six cases of Rocky Mountain spotted fever (RMSF) in children were associated with either a delayed diagnosis pending laboratory findings or delayed anti-rickettsia treatment, researchers said.
“The fact that all fatal cases died before the convalescent period emphasizes that diagnosis should be based on clinical findings instead of RMSF serologic and histologic testing,” wrote the authors of a study published online in Pediatric Dermatology.
Rechelle Tull of the department of dermatology, Wake Forest University, Winston-Salem, NC, and her colleagues conducted a retrospective review of 3,912 inpatient dermatology consultations over a period of 10 years at a tertiary care center, and identified six patients aged 22 months to 2 years (mean, 5.1 years) diagnosed with RMSF. The patients were evaluated in the months of April, May, and June, and three of the six patients infected with the vector-borne obligate intracellular bacterium, Rickettsia rickettsii, had died within 4 days of hospitalization, according to the authors.
Two of the fatal cases involved delayed anti-rickettsial therapy after the patients were misdiagnosed with group A Streptococcus. None of the six children were initially evaluated for R rickettsii; they averaged three encounters with their clinician before being admitted for acute inpatient care, where they received intravenous doxycycline after nearly a week of symptoms.
“All fatal cases were complicated by neurologic manifestations, including seizures, obtundation, and uncal herniation,” a finding that is consistent with the literature, the authors said.
Although the high-fatality rate might be the result of the small study size, Ms Tull and her coinvestigators concluded that the disease should be considered in all differential diagnoses for children who present with a fever and rash during the summer months in endemic areas, particularly since pediatric cases of the disease are associated with poorer outcomes than adult cases.
Given that RMSF often remains subclinical in its early stages, and typically presents with nonspecific symptoms of fever, rash, headache, and abdominal pain when it does emerge, physicians might be tempted to defer treatment until after serological and histological results are in, as is the standard method. Concerns over doxycycline’s tendency to stain teeth and cause enamel hypoplasia are also common. However, empirical administration could mean the difference between life and death, since treatment within the first 5 days following infection is associated with better outcomes—an algorithm complicated by the fact that symptoms caused by R rickettsii have been known to take as long as 21 days to appear.
In the study, Ms Tull and her colleagues found that the average time between exposure to the tick and the onset of symptoms was 6.6 days (range, 1-21 days).
Currently, there are no diagnostic tests “that reliably diagnose RMSF during the first 7 days of illness,” and most patients “do not develop detectable antibodies until the second week of illness,” the investigators reported. Even then, sensitivity of indirect fluorescent antibody serum testing after the second week of illness is only between 86% and 94%, they noted. Further, the sensitivity of immunohistochemical (IHC) tissue staining has been reported at 70%, and false-negative IHC results are common in acute disease when antibody response is harder to detect.
Ms Tull and her colleagues found that five of the six patients in their study had negative IHC testing; two of the six had positive serum antibody titers. For this reason, they concluded that RMSF diagnosis should be based on “clinical history, examination, and laboratory abnormalities” rather than laboratory testing, and urged that “prompt treatment should be instituted empirically.”
Tull R, Ahn C, Daniel A, Yosipovitch G, Strowd LC. Retrospective study of Rocky Mountain spotted fever in children. Pediatr Dermatol. 2016 Dec 19. doi:10.1111/pde.13053. [Epub ahead of print]
BY JEFF BAUER
A large retrospective analysis found a wide variation in opioid prescribing among emergency physicians (EPs) working within the same ED. The study also found that Medicare patients treated by EPs who wrote the most prescriptions for opioids were more likely to use opioids for 6 months after their ED visit than were those treated by EPs who wrote fewer opioid prescriptions.
Researchers evaluated initial visits to an ED by approximately 378,000 Medicare beneficiaries (average age: 68 years) from 2008 through 2011. None of these patients had received a prescription for an opioid in the 6 months before the ED visit, and none of the visits resulted in a hospital admission. Prescriptions for opioids (excluding methadone) were identified by the national drug code in the Medicare Part D database. An opioid prescription was attributed to the treating EP if the patient filled the prescription within 3 days after the ED visit.
Investigators categorized the treating EPs in this study as “high-intensity” or “low-intensity” opioid prescribers by calculating the proportion of all ED visits that resulted in an opioid prescription being filled. They then grouped the EPs into quartiles of opioid prescribing within each hospital. High-intensity prescribers were those in the top quartile of opioid prescribing rates, and low-intensity prescribers were those in the bottom quartile.
The primary outcome was long-term opioid use, defined as 6 months or more of opioids supplied in the 12 months after the initial ED visit. This did not include prescriptions filled within 30 days of the initial visit.
Overall, approximately 215,700 patients were treated by low-intensity prescribers and 162,000 by high-intensity prescribers. In general, the patient characteristics and diagnoses were similar in both groups. The rate of opioid prescribing of high-intensity prescribers was approximately triple the rate of low-intensity prescribers. High-intensity prescribers provided an opioid prescription for 21.4% of ED visits, compared to 7.3% among low-intensity prescribers.
Long-term opioid use at 12 months was significantly higher among patients who had been initially treated by high-intensity prescribers compared to those who had been treated by low-intensity prescribers (1.51% vs 1.16%; unadjusted odds ratio [OR], 1.31). There was minimal change in this difference after the results were adjusted for the patients’ age, race, sex, disability status, and presence of chronic conditions (OR, 1.30). The number needed to harm was calculated as 49, meaning theoretically, for every 49 patients who received a new opioid prescription in the ED, one would become a long-term user. The authors noted, however, that “…prescriptions provided by other physicians in the months after an [ED] visit are necessary for long-term opioid use to take hold.”
Researchers pointed out several limitations to their study. Because the study was observational, it could not establish causality. Researchers were not able to directly attribute opioid prescriptions to the treating EPs, but instead used prescriptions filled within 3 days of an ED visits as a surrogate; some opioid prescriptions could have been written by another clinician, such as the patient’s primary care physician during a follow-up visit. Because the study focused on Medicare patients, the results may not be applicable to younger patients. Based on their analysis, researchers could not determine whether an opioid prescription was appropriate, and therefore they could not quantify the extent of opioid overprescribing.
For more on EPs and opioid prescribing, see “The New Opioid Epidemic and the Law of Unintended Consequences” by Emergency Medicine Editor in Chief Neal Flomenbaum, MD (Emergency Medicine. 2017;49[2]:52) and “The New Opioid Epidemic: Prescriptions, Synthetics, and Street Drugs” by Rama B. Rao, MD and Emergency Medicine Associate Editor, Toxicology Lewis S. Nelson, MD (Emergency Medicine. 2017;49[2]:64-70).
Barnett ML, Olenski AR, Jena AB. Opioid-prescribing patterns of emergency physicians and risk of long-term use. N Engl J Med. 2017;376(7):663-673. doi:10.1056/NEJMsa1610524.
Lower Admission Rates, Other Factors Tied to High Rate of Death Soon After ED Discharge Among Older Adults
BY JEFF BAUER
Each year, approximately 10,000 older adult patients die within 7 days of discharge from an ED in the United States, despite having no obvious life-threatening illness, according to a large retrospective study. Emergency departments with lower rates of inpatient admission from the ED, lower patient volumes, and lower charges had significantly higher rates of death after discharge.
Researchers evaluated Medicare claims data related to slightly more than 10 million ED visits from 2007 to 2012. Because the goal was to study generally healthy patients, the following patients were excluded: individuals who were age 90 years and older; were receiving palliative or hospice care; or had received a life-limiting diagnosis, such as a myocardial infarction (MI) or a malignancy, either in the ED or in the year prior to the ED visit. The primary outcome was death within 7 days after discharge from an ED. The cause of death was determined by linking claims to death certificates; this information was available only for a subset of patients who visited an ED in 2007 or 2008.
Overall, during the 6-year study, 0.12% of discharged patients died within 7 days of discharge; this translates to more than 10,000 early deaths per year nationally. The leading causes of death were atherosclerotic heart disease (13.6%), MI (10.3%), and chronic obstructive pulmonary disease (9.6%).
Emergency departments ranked in the lowest fifth for admission rates admitted 15% of patients, compared to 56% of patients at EDs with the highest admission rates. The early death rate of patients treated at EDs with the lowest rates of inpatient admissions from the ED was 3.4 times higher than the death rate seen in EDs with the highest inpatient admission rates (0.27% vs 0.08%, respectively). This was true despite the fact that EDs with low-admission rates treated healthier patients, as evidenced by the overall 7-day mortality rate of all patients treated in the ED, whether they were admitted or discharged. Emergency departments that saw higher volumes of patients and had higher charges for visits had significantly fewer deaths.
Obermeyer Z, Cohn B, Wilson M, Jena AB, Cutler DM. Early death after discharge from emergency departments: analysis of national US insurance claims data. BMJ. 2017;356:j239. doi:10.1136/bmj.j239.
Tertiary Center Repeat Computed Tomography Scans Find Additional Injuries
MICHELE G. SULLIVAN
FRONTLINE MEDICAL NEWS
Imaging obtained at nontertiary trauma centers (NTCs) probably does not tell the whole story of a trauma patient’s injuries, according to a new retrospective study.
Repeat scans done at a Level 1 trauma center identified new injuries in 76% of patients who were transferred, Morgan Bonds, MD, reported at the annual scientific assembly of the Eastern Association for the Surgery of Trauma. About half of these previously unobserved injuries were considered clinically significant, said Dr Bonds, a surgical resident at the University of Oklahoma, Oklahoma City.
Her study examined imaging and clinical assessment of 203 trauma patients who were initially worked up at an NTC, and then transferred to the Level 1 University of Oklahoma tertiary trauma center (TTC). The facility’s primary radiologist reviewed all of the initial computed tomography (CT) scans while blinded to the NTC interpretation. The initial scans and interpretations were then compared with those done at the TTC.
The team split imaging and interpretation disconnects into four categories:
- Type A errors: A missed injury on the NTC scan. “This represents the expertise and experience of our primary radiologist,” Dr Bonds said.
- Type B errors: Missed injuries on scans where NTC radiologists saw other injuries that the TTC radiologist did not confirm. “This represents the experience of our radiologist and also the inexperience and overreaction of the NTC radiologists.”
- Type C errors: New injuries seen on additional TTC imaging of the same body area. “This represents the quality of the image.”
- Type D errors: New injuries found upon any new imaging, whether of a previously scanned or newly scanned body area. “This represents quality of work-up—the decision of the trauma team to more fully investigate the patient’s injuries, as well as the quality of the CT tech performing the scan.”
During the study period, 203 patients presented at the TTC with prior scans conducted at an NTC.
The mean age of the patients was 43 years; most (67%) were men. The mean Injury Severity Score was 16; 97% had experienced blunt trauma. Shock was present in 3% and a traumatic brain injury in 8%. Repeat scans were most common for neck and cervical spine injuries (54%) and thoracic/lumbar spine injuries (53%), and least common for chest injuries (32%).
An inadequate NTC work-up as judged by the TTC attending was the most common reason for obtaining new images (76%). Poor image quality was the next most common reason (31%).
Among the 203 patients, 99 (49%) had a type A error. Of these injuries missed on the initial scan, 90% were considered to be clinically significant.
Type B errors occurred in 15% of patients. Type C errors (new injuries in different body area) occurred in 54% of patients and, of these, 76% were considered clinically significant. Type D errors (new injuries seen in any imaging of any area) occurred in 73% of patients.
“This study confirms that images are often repeated or completed after having images done at NTCs,” Dr Bonds said. “Relying on NTC image interpretation can lead to undertreating our patients. One potential solution to this issue could be image sharing between NTCs and TTCs. This might reduce both the rate of missed injuries and the need for repeat scans.”
Cutaneous Eruption Reported in Pregnant Woman With Locally Acquired Zika Virus
M. ALEXANDER OTTO
FRONTLINE MEDICAL NEWS
Zika presented in a young, pregnant Florida woman as erythematous follicular macules and papules on the trunk and arms, scattered tender pink papules on the palms, and a few petechiae on the hard palate, according to a report in the New England Journal of Medicine.
The report advises how Zika virus may present during pregnancy. “Medical providers on the front line should be aware of the constellation of symptoms in patients reporting travel to endemic areas, including areas in Southern Florida, where other non-travel-associated cases have been confirmed,” wrote investigators led by Lucy Chen, MD, of the University of Miami.
The 23-year-old woman presented on July 7, 2016 at 23 weeks and 3 days’ gestation with a 3-day history of fever, widespread pruritic rash, and sore throat, which were followed by myalgias and joint pain 2 days later. The cutaneous eruption was noted on physical examination; neither conjunctivitis nor lymphadenopathy was present. The patient and her partner said they had not traveled outside the United States for 2 years.
Zika virus RNA was detected in the woman’s urine and serum specimens with the use of reverse-transcriptase polymerase chain reaction and persisted for 2 weeks in urine samples and for 6 weeks in serum samples. On histopathology, skin lesions revealed a mild perivascular lymphocytic infiltration in the upper dermis, admixed with some neutrophils. Liver and renal functions were normal.
Fetal ultrasonography performed on the day of presentation showed an estimated fetal weight of 644 g (53rd percentile), an estimated head circumference of 221 mm (63rd percentile), and normal intracranial anatomy. Fevers and rash subsided after 3 days of supportive care. Screening for measles, varicella, rubella, syphilis, Epstein-Barr virus, influenza, hepatitis B, hepatitis C, mumps, and dengue was negative.
An initial immunoglobulin M test on July 7 was negative; seroconversion occurred 1 week after presentation and remained positive through delivery.
A full-term infant weighing 2,990 g was delivered vaginally. Neonatal ultrasonography and magnetic resonance imaging of the head showed a normal head size and intracranial anatomy, with no calcifications. Placental tissue was negative for Zika virus, and neonatal laboratory testing revealed no evidence of infection.
The case was confirmed by the Miami-Dade County Department of Health as the first non-travel-associated Zika infection in the United States.
Chen L, Hafeez F, Curry CL, Elgart G. Cutaneous eruption in a U.S. woman with locally acquired Zika virus infection. N Engl J Med. 2017;376(4):400-401. doi:10.1056/NEJMc1610614.
Lab Values Poor Surrogate for Detecting Pediatric Rocky Mountain Spotted Fever in Children
WHITNEY MCKNIGHT
FRONTLINE MEDICAL NEWS
Three fatalities observed in a retrospective analysis of six cases of Rocky Mountain spotted fever (RMSF) in children were associated with either a delayed diagnosis pending laboratory findings or delayed anti-rickettsia treatment, researchers said.
“The fact that all fatal cases died before the convalescent period emphasizes that diagnosis should be based on clinical findings instead of RMSF serologic and histologic testing,” wrote the authors of a study published online in Pediatric Dermatology.
Rechelle Tull of the department of dermatology, Wake Forest University, Winston-Salem, NC, and her colleagues conducted a retrospective review of 3,912 inpatient dermatology consultations over a period of 10 years at a tertiary care center, and identified six patients aged 22 months to 2 years (mean, 5.1 years) diagnosed with RMSF. The patients were evaluated in the months of April, May, and June, and three of the six patients infected with the vector-borne obligate intracellular bacterium, Rickettsia rickettsii, had died within 4 days of hospitalization, according to the authors.
Two of the fatal cases involved delayed anti-rickettsial therapy after the patients were misdiagnosed with group A Streptococcus. None of the six children were initially evaluated for R rickettsii; they averaged three encounters with their clinician before being admitted for acute inpatient care, where they received intravenous doxycycline after nearly a week of symptoms.
“All fatal cases were complicated by neurologic manifestations, including seizures, obtundation, and uncal herniation,” a finding that is consistent with the literature, the authors said.
Although the high-fatality rate might be the result of the small study size, Ms Tull and her coinvestigators concluded that the disease should be considered in all differential diagnoses for children who present with a fever and rash during the summer months in endemic areas, particularly since pediatric cases of the disease are associated with poorer outcomes than adult cases.
Given that RMSF often remains subclinical in its early stages, and typically presents with nonspecific symptoms of fever, rash, headache, and abdominal pain when it does emerge, physicians might be tempted to defer treatment until after serological and histological results are in, as is the standard method. Concerns over doxycycline’s tendency to stain teeth and cause enamel hypoplasia are also common. However, empirical administration could mean the difference between life and death, since treatment within the first 5 days following infection is associated with better outcomes—an algorithm complicated by the fact that symptoms caused by R rickettsii have been known to take as long as 21 days to appear.
In the study, Ms Tull and her colleagues found that the average time between exposure to the tick and the onset of symptoms was 6.6 days (range, 1-21 days).
Currently, there are no diagnostic tests “that reliably diagnose RMSF during the first 7 days of illness,” and most patients “do not develop detectable antibodies until the second week of illness,” the investigators reported. Even then, sensitivity of indirect fluorescent antibody serum testing after the second week of illness is only between 86% and 94%, they noted. Further, the sensitivity of immunohistochemical (IHC) tissue staining has been reported at 70%, and false-negative IHC results are common in acute disease when antibody response is harder to detect.
Ms Tull and her colleagues found that five of the six patients in their study had negative IHC testing; two of the six had positive serum antibody titers. For this reason, they concluded that RMSF diagnosis should be based on “clinical history, examination, and laboratory abnormalities” rather than laboratory testing, and urged that “prompt treatment should be instituted empirically.”
Tull R, Ahn C, Daniel A, Yosipovitch G, Strowd LC. Retrospective study of Rocky Mountain spotted fever in children. Pediatr Dermatol. 2016 Dec 19. doi:10.1111/pde.13053. [Epub ahead of print]
Vagus nerve stimulation shows stroke recovery promise
HOUSTON – Stroke patients with arm weakness had a clinically significant boost in arm function after about 19 weeks on a rehabilitation program that combined vagus nerve stimulation with rehabilitation training sessions in a multicenter, randomized, and sham-controlled proof-of-concept study with 17 patients.
This promising result follows a prior 21-patient study with a similar design and results (Stroke. 2016 Jan;47[1]:143-50), making the next step a pivotal trial with about 120 randomized patients that should start in 2017, Jesse Dawson, MD, said at the International Stroke Conference sponsored by the American Heart Association.
Results in the new study showed that eight poststroke patients with arm weakness who received a prolonged course of vagus nerve stimulation (VNS) and rehabilitation training had an average boost from baseline in their upper-extremity Fugl-Meyer score of 9.5 points measured 132 days after the start of the regimen, compared with an average 3.8-point rise among nine similar patients who underwent the same rehabilitation training but without VNS. A rise of 4-7 points on the upper-extremity Fugl-Meyer score is considered clinically significant for chronic stroke patients (J Physiotherapy. 2017 Jan;63[1]:53). The difference in mean scores between the VNS and control groups after 132 days was statistically significant for a secondary endpoint of the study.
The study’s primary endpoint, the difference between the control and VNS patients in mean upper-extremity Fugl-Meyer scores at the end of the initial phase of the study – a 6-week supervised training period – was 7.6 points in the VNS recipients and 5.3 points for the control patients, a difference that was not statistically significant.
The 9.5-point boost in average scores with more prolonged treatment and follow-up in the VNS patients is “highly likely to be clinically significant,” Dr. Dawson said. “We would like to see an effect earlier, with clinically important effects after 6 weeks of treatment. That would make the intervention easier to translate into clinical practice.”
The study ran at three U.S. centers and in Glasgow and enrolled patients who were 4 months to 5 years out from their index stroke and had moderate to severe arm weakness based on an upper-extremity Fugl-Meyer score of 20-50. The average age of the 17 patients in the study was 60 years. They were an average of 1.5 years removed from their index stroke.
All of the patients received an implanted device to produce VNS. The eight patients in the active arm received VNS during their 2-hour, thrice-weekly rehabilitation training sessions for the first 6 weeks of the study, with about 400 individual stimulations delivered during each training session. The nine controls received brief VNS to aid blinding, but had no meaningful VNS while they replicated the rehabilitation training regimen of the intervention group. At the end of 6 weeks, no training or VNS was done for 30 days. Then for the next 60 days, all patients did a daily program of unsupervised home rehabilitation exercises and patients in the intervention arm also self-administered 30 minutes of VNS daily.
The 17 patients who received a VNS device implant had three serious adverse events, Dr. Dawson reported: one infection, one episode of dyspnea, and one episode of vocal cord paralysis. None of the adverse events were judged definitely or likely linked to the stimulator, and all three effects were in control patients. In several patients in both arms, nonserious adverse effects occurred that are expected for the surgery used, including bruising, pain, swelling, and scarring. When the study ended, patients originally randomized to the sham group underwent active intervention with VNS and subsequently had an average 13-point increase on their upper extremity Fugl-Meyer score.
MicroTransponder, the company developing the vagus nerve stimulation device, funded the study. Dr. Dawson has received travel and meeting cost reimbursements from MicroTransponder, and several coauthors are employees of the company.
[email protected]
On Twitter @mitchelzoler
Arm weakness is a critical complication for patients after a stroke and is a great target for intervention. Patients with moderate to severe arm weakness such as those enrolled in this trial are seriously affected by their loss of arm function. It’s bad for patients when they cannot use an arm.
These new results are obviously exploratory, but they create a lot of hope.
Philip B. Gorelick, MD, is medical director of the Hauenstein Neuroscience Center of Saint Mary’s Health Care in Grand Rapids, Mich., and professor of translational science and molecular medicine at Michigan State University, Grand Rapids. He had no disclosures. He made these comments during a press conference.
Arm weakness is a critical complication for patients after a stroke and is a great target for intervention. Patients with moderate to severe arm weakness such as those enrolled in this trial are seriously affected by their loss of arm function. It’s bad for patients when they cannot use an arm.
These new results are obviously exploratory, but they create a lot of hope.
Philip B. Gorelick, MD, is medical director of the Hauenstein Neuroscience Center of Saint Mary’s Health Care in Grand Rapids, Mich., and professor of translational science and molecular medicine at Michigan State University, Grand Rapids. He had no disclosures. He made these comments during a press conference.
Arm weakness is a critical complication for patients after a stroke and is a great target for intervention. Patients with moderate to severe arm weakness such as those enrolled in this trial are seriously affected by their loss of arm function. It’s bad for patients when they cannot use an arm.
These new results are obviously exploratory, but they create a lot of hope.
Philip B. Gorelick, MD, is medical director of the Hauenstein Neuroscience Center of Saint Mary’s Health Care in Grand Rapids, Mich., and professor of translational science and molecular medicine at Michigan State University, Grand Rapids. He had no disclosures. He made these comments during a press conference.
HOUSTON – Stroke patients with arm weakness had a clinically significant boost in arm function after about 19 weeks on a rehabilitation program that combined vagus nerve stimulation with rehabilitation training sessions in a multicenter, randomized, and sham-controlled proof-of-concept study with 17 patients.
This promising result follows a prior 21-patient study with a similar design and results (Stroke. 2016 Jan;47[1]:143-50), making the next step a pivotal trial with about 120 randomized patients that should start in 2017, Jesse Dawson, MD, said at the International Stroke Conference sponsored by the American Heart Association.
Results in the new study showed that eight poststroke patients with arm weakness who received a prolonged course of vagus nerve stimulation (VNS) and rehabilitation training had an average boost from baseline in their upper-extremity Fugl-Meyer score of 9.5 points measured 132 days after the start of the regimen, compared with an average 3.8-point rise among nine similar patients who underwent the same rehabilitation training but without VNS. A rise of 4-7 points on the upper-extremity Fugl-Meyer score is considered clinically significant for chronic stroke patients (J Physiotherapy. 2017 Jan;63[1]:53). The difference in mean scores between the VNS and control groups after 132 days was statistically significant for a secondary endpoint of the study.
The study’s primary endpoint, the difference between the control and VNS patients in mean upper-extremity Fugl-Meyer scores at the end of the initial phase of the study – a 6-week supervised training period – was 7.6 points in the VNS recipients and 5.3 points for the control patients, a difference that was not statistically significant.
The 9.5-point boost in average scores with more prolonged treatment and follow-up in the VNS patients is “highly likely to be clinically significant,” Dr. Dawson said. “We would like to see an effect earlier, with clinically important effects after 6 weeks of treatment. That would make the intervention easier to translate into clinical practice.”
The study ran at three U.S. centers and in Glasgow and enrolled patients who were 4 months to 5 years out from their index stroke and had moderate to severe arm weakness based on an upper-extremity Fugl-Meyer score of 20-50. The average age of the 17 patients in the study was 60 years. They were an average of 1.5 years removed from their index stroke.
All of the patients received an implanted device to produce VNS. The eight patients in the active arm received VNS during their 2-hour, thrice-weekly rehabilitation training sessions for the first 6 weeks of the study, with about 400 individual stimulations delivered during each training session. The nine controls received brief VNS to aid blinding, but had no meaningful VNS while they replicated the rehabilitation training regimen of the intervention group. At the end of 6 weeks, no training or VNS was done for 30 days. Then for the next 60 days, all patients did a daily program of unsupervised home rehabilitation exercises and patients in the intervention arm also self-administered 30 minutes of VNS daily.
The 17 patients who received a VNS device implant had three serious adverse events, Dr. Dawson reported: one infection, one episode of dyspnea, and one episode of vocal cord paralysis. None of the adverse events were judged definitely or likely linked to the stimulator, and all three effects were in control patients. In several patients in both arms, nonserious adverse effects occurred that are expected for the surgery used, including bruising, pain, swelling, and scarring. When the study ended, patients originally randomized to the sham group underwent active intervention with VNS and subsequently had an average 13-point increase on their upper extremity Fugl-Meyer score.
MicroTransponder, the company developing the vagus nerve stimulation device, funded the study. Dr. Dawson has received travel and meeting cost reimbursements from MicroTransponder, and several coauthors are employees of the company.
[email protected]
On Twitter @mitchelzoler
HOUSTON – Stroke patients with arm weakness had a clinically significant boost in arm function after about 19 weeks on a rehabilitation program that combined vagus nerve stimulation with rehabilitation training sessions in a multicenter, randomized, and sham-controlled proof-of-concept study with 17 patients.
This promising result follows a prior 21-patient study with a similar design and results (Stroke. 2016 Jan;47[1]:143-50), making the next step a pivotal trial with about 120 randomized patients that should start in 2017, Jesse Dawson, MD, said at the International Stroke Conference sponsored by the American Heart Association.
Results in the new study showed that eight poststroke patients with arm weakness who received a prolonged course of vagus nerve stimulation (VNS) and rehabilitation training had an average boost from baseline in their upper-extremity Fugl-Meyer score of 9.5 points measured 132 days after the start of the regimen, compared with an average 3.8-point rise among nine similar patients who underwent the same rehabilitation training but without VNS. A rise of 4-7 points on the upper-extremity Fugl-Meyer score is considered clinically significant for chronic stroke patients (J Physiotherapy. 2017 Jan;63[1]:53). The difference in mean scores between the VNS and control groups after 132 days was statistically significant for a secondary endpoint of the study.
The study’s primary endpoint, the difference between the control and VNS patients in mean upper-extremity Fugl-Meyer scores at the end of the initial phase of the study – a 6-week supervised training period – was 7.6 points in the VNS recipients and 5.3 points for the control patients, a difference that was not statistically significant.
The 9.5-point boost in average scores with more prolonged treatment and follow-up in the VNS patients is “highly likely to be clinically significant,” Dr. Dawson said. “We would like to see an effect earlier, with clinically important effects after 6 weeks of treatment. That would make the intervention easier to translate into clinical practice.”
The study ran at three U.S. centers and in Glasgow and enrolled patients who were 4 months to 5 years out from their index stroke and had moderate to severe arm weakness based on an upper-extremity Fugl-Meyer score of 20-50. The average age of the 17 patients in the study was 60 years. They were an average of 1.5 years removed from their index stroke.
All of the patients received an implanted device to produce VNS. The eight patients in the active arm received VNS during their 2-hour, thrice-weekly rehabilitation training sessions for the first 6 weeks of the study, with about 400 individual stimulations delivered during each training session. The nine controls received brief VNS to aid blinding, but had no meaningful VNS while they replicated the rehabilitation training regimen of the intervention group. At the end of 6 weeks, no training or VNS was done for 30 days. Then for the next 60 days, all patients did a daily program of unsupervised home rehabilitation exercises and patients in the intervention arm also self-administered 30 minutes of VNS daily.
The 17 patients who received a VNS device implant had three serious adverse events, Dr. Dawson reported: one infection, one episode of dyspnea, and one episode of vocal cord paralysis. None of the adverse events were judged definitely or likely linked to the stimulator, and all three effects were in control patients. In several patients in both arms, nonserious adverse effects occurred that are expected for the surgery used, including bruising, pain, swelling, and scarring. When the study ended, patients originally randomized to the sham group underwent active intervention with VNS and subsequently had an average 13-point increase on their upper extremity Fugl-Meyer score.
MicroTransponder, the company developing the vagus nerve stimulation device, funded the study. Dr. Dawson has received travel and meeting cost reimbursements from MicroTransponder, and several coauthors are employees of the company.
[email protected]
On Twitter @mitchelzoler
AT THE INTERNATIONAL STROKE CONFERENCE
Key clinical point:
Major finding: Vagus nerve stimulation linked with a mean 9.5-point rise in upper-extremity Fugl-Meyer score at 132-day follow-up.
Data source: A multicenter, randomized, sham-controlled study with 17 chronic stroke patients.
Disclosures: MicroTransponder, the company developing the vagus nerve stimulation device, funded the study. Dr. Dawson has received travel and meeting cost reimbursements from MicroTransponder, and several coauthors are employees of the company.
Cancers in patients deemed lowest risk under Lung-RADS
A reporting system for lung cancer screening with low-dose computed tomography may underemphasize important abnormal findings other than nodules, researchers say, potentially leading to missed malignancies.
The American College of Radiology Lung Imaging Reporting and Data System, or Lung-RADS, was introduced in 2014 to standardize reporting for low-dose CT findings and also to reduce false-positive rates, by applying tighter criteria that was used in the National Lung Screening Trial.
Lung-RADS does not have specific reporting categories for patients with isolated hilar and mediastinal adenopathy or pleural effusion in the absence of lung nodules, even though these can indicate malignancy. It does allow for the inclusion of what is called an “S” code to indicate clinically significant findings other than nodules.
In the March 2017 issue of CHEST, Hiren Mehta, MD, and his colleagues at the University of Florida in Gainesville, report on four cases from their center in which patients with these pathologies had their scans read as Lung-RADS category 1, indicating a less than 1% likelihood of malignancy. No S codes were added to their reports. Subsequent testing in these patients revealed cancers (CHEST. 2017 March;151[3]:525-26).
The four cases were:
- A 56-year-old male with hilar and mediastinal adenopathy who was recommended for repeat screening at 12 months. The patient presented 6 months later with pneumonia; biopsy revealed large cell lung cancer.
- A 76-year-old male with paratracheal lymph nodes and a solitary subcarinal lymph node. A subsequent biopsy revealed adenocarcinoma.
- A 67-year-old male whose scan showed bulky hilar and mediastinal adenopathy. Subsequent testing revealed Hodgkin’s lymphoma.
- A 75-year-old female whose scan showed a small pleural effusion and no nodules. Repeat scanning at 1 year showed enlargement of the effusion and lung adenocarcinoma.
Dr. Mehta and colleagues noted in their analysis that Lung-RADS has not been studied prospectively in real practice settings and that the four cases – two of which involved delayed diagnosis – reveal “a significant limitation” of Lung-RADS.
“Based on our experience, we believe that particular caution should be exercised in reporting Lung-RADS 1 category for patients with adenopathy/pleural effusion with no lung nodules, as a majority of the lung cancer screening scans will be ordered by [primary care providers] ... [As] with any new system, an ongoing evaluation of the performance of Lung-RADS should be conducted so that the sensitivity and mortality benefit seen in the [National Lung Screening Trial] is not compromised.”
We strongly believe, based on our experience with these 4 cases that the new version of Lung-RADS 2.0 should [account for shortcomings of the current Lung-RADS] and have a separate category for findings that are highly suspicious for malignancy but do not have an accompanying lung nodule,” they wrote.
The investigators did not disclose outside funding or conflicts of interest related to their findings.
*This story was updated March 16, 2017, with the correct journal source.
The performance of lung cancer screening does not absolve the interpreter from pointing out clinically important findings whether or not they are related to lung cancer. Review of the entire examination for other potentially significant findings should be performed and reported in accordance with applicable standards, says The Joint American College of Radiology and Society of Thoracic Radiology practice parameter for the performance and reporting of lung cancer screening thoracic CT. In addition to adenopathy and pleural effusion, detection of abnormalities such as severe coronary artery calcifications, aortic aneurysms, severe emphysema and suspicious masses in the upper abdomen should be called out not just in the body of the report, but also in the final impression so that it is easily available to the reader of the report.
Lung-RADS recognizes the importance of incidental findings with an additional coding letter, the “S” code. The letter “S” should be attached any time there is an abnormality considered clinically important that is not a pulmonary nodule. For the cases presented in this study, the appropriate code for the subjects should have been Lung-RADS 1S with a specific recommendation for the management of the “S” findings. It is incumbent on individuals interpreting these examinations to appropriately account for and report all significant findings, not simply lung nodules, and to be familiar with and understand Lung-RADS. Judicious use of the Lung-RADS “S” code along with specific discussion of the report’s final impression is recommended as a means of improving communication.
James Ravenel, MD; Nichole Tanner, MD, MSCR, FCCP; and Gerard Silvestri, MD, MS, FCCP, are with the Medical University of South Carolina, Charleston. Dr. Tanner also is with the Ralph H. Johnson Veterans Affairs Hospital, Charleston.
These comments have been modified from an editorial accompanying Dr. Mehta and his colleagues’ study in CHEST (Chest. 2017 March;151[3]:539-43). The authors disclosed no conflicts of interest related to their editorial.
The performance of lung cancer screening does not absolve the interpreter from pointing out clinically important findings whether or not they are related to lung cancer. Review of the entire examination for other potentially significant findings should be performed and reported in accordance with applicable standards, says The Joint American College of Radiology and Society of Thoracic Radiology practice parameter for the performance and reporting of lung cancer screening thoracic CT. In addition to adenopathy and pleural effusion, detection of abnormalities such as severe coronary artery calcifications, aortic aneurysms, severe emphysema and suspicious masses in the upper abdomen should be called out not just in the body of the report, but also in the final impression so that it is easily available to the reader of the report.
Lung-RADS recognizes the importance of incidental findings with an additional coding letter, the “S” code. The letter “S” should be attached any time there is an abnormality considered clinically important that is not a pulmonary nodule. For the cases presented in this study, the appropriate code for the subjects should have been Lung-RADS 1S with a specific recommendation for the management of the “S” findings. It is incumbent on individuals interpreting these examinations to appropriately account for and report all significant findings, not simply lung nodules, and to be familiar with and understand Lung-RADS. Judicious use of the Lung-RADS “S” code along with specific discussion of the report’s final impression is recommended as a means of improving communication.
James Ravenel, MD; Nichole Tanner, MD, MSCR, FCCP; and Gerard Silvestri, MD, MS, FCCP, are with the Medical University of South Carolina, Charleston. Dr. Tanner also is with the Ralph H. Johnson Veterans Affairs Hospital, Charleston.
These comments have been modified from an editorial accompanying Dr. Mehta and his colleagues’ study in CHEST (Chest. 2017 March;151[3]:539-43). The authors disclosed no conflicts of interest related to their editorial.
The performance of lung cancer screening does not absolve the interpreter from pointing out clinically important findings whether or not they are related to lung cancer. Review of the entire examination for other potentially significant findings should be performed and reported in accordance with applicable standards, says The Joint American College of Radiology and Society of Thoracic Radiology practice parameter for the performance and reporting of lung cancer screening thoracic CT. In addition to adenopathy and pleural effusion, detection of abnormalities such as severe coronary artery calcifications, aortic aneurysms, severe emphysema and suspicious masses in the upper abdomen should be called out not just in the body of the report, but also in the final impression so that it is easily available to the reader of the report.
Lung-RADS recognizes the importance of incidental findings with an additional coding letter, the “S” code. The letter “S” should be attached any time there is an abnormality considered clinically important that is not a pulmonary nodule. For the cases presented in this study, the appropriate code for the subjects should have been Lung-RADS 1S with a specific recommendation for the management of the “S” findings. It is incumbent on individuals interpreting these examinations to appropriately account for and report all significant findings, not simply lung nodules, and to be familiar with and understand Lung-RADS. Judicious use of the Lung-RADS “S” code along with specific discussion of the report’s final impression is recommended as a means of improving communication.
James Ravenel, MD; Nichole Tanner, MD, MSCR, FCCP; and Gerard Silvestri, MD, MS, FCCP, are with the Medical University of South Carolina, Charleston. Dr. Tanner also is with the Ralph H. Johnson Veterans Affairs Hospital, Charleston.
These comments have been modified from an editorial accompanying Dr. Mehta and his colleagues’ study in CHEST (Chest. 2017 March;151[3]:539-43). The authors disclosed no conflicts of interest related to their editorial.
A reporting system for lung cancer screening with low-dose computed tomography may underemphasize important abnormal findings other than nodules, researchers say, potentially leading to missed malignancies.
The American College of Radiology Lung Imaging Reporting and Data System, or Lung-RADS, was introduced in 2014 to standardize reporting for low-dose CT findings and also to reduce false-positive rates, by applying tighter criteria that was used in the National Lung Screening Trial.
Lung-RADS does not have specific reporting categories for patients with isolated hilar and mediastinal adenopathy or pleural effusion in the absence of lung nodules, even though these can indicate malignancy. It does allow for the inclusion of what is called an “S” code to indicate clinically significant findings other than nodules.
In the March 2017 issue of CHEST, Hiren Mehta, MD, and his colleagues at the University of Florida in Gainesville, report on four cases from their center in which patients with these pathologies had their scans read as Lung-RADS category 1, indicating a less than 1% likelihood of malignancy. No S codes were added to their reports. Subsequent testing in these patients revealed cancers (CHEST. 2017 March;151[3]:525-26).
The four cases were:
- A 56-year-old male with hilar and mediastinal adenopathy who was recommended for repeat screening at 12 months. The patient presented 6 months later with pneumonia; biopsy revealed large cell lung cancer.
- A 76-year-old male with paratracheal lymph nodes and a solitary subcarinal lymph node. A subsequent biopsy revealed adenocarcinoma.
- A 67-year-old male whose scan showed bulky hilar and mediastinal adenopathy. Subsequent testing revealed Hodgkin’s lymphoma.
- A 75-year-old female whose scan showed a small pleural effusion and no nodules. Repeat scanning at 1 year showed enlargement of the effusion and lung adenocarcinoma.
Dr. Mehta and colleagues noted in their analysis that Lung-RADS has not been studied prospectively in real practice settings and that the four cases – two of which involved delayed diagnosis – reveal “a significant limitation” of Lung-RADS.
“Based on our experience, we believe that particular caution should be exercised in reporting Lung-RADS 1 category for patients with adenopathy/pleural effusion with no lung nodules, as a majority of the lung cancer screening scans will be ordered by [primary care providers] ... [As] with any new system, an ongoing evaluation of the performance of Lung-RADS should be conducted so that the sensitivity and mortality benefit seen in the [National Lung Screening Trial] is not compromised.”
We strongly believe, based on our experience with these 4 cases that the new version of Lung-RADS 2.0 should [account for shortcomings of the current Lung-RADS] and have a separate category for findings that are highly suspicious for malignancy but do not have an accompanying lung nodule,” they wrote.
The investigators did not disclose outside funding or conflicts of interest related to their findings.
*This story was updated March 16, 2017, with the correct journal source.
A reporting system for lung cancer screening with low-dose computed tomography may underemphasize important abnormal findings other than nodules, researchers say, potentially leading to missed malignancies.
The American College of Radiology Lung Imaging Reporting and Data System, or Lung-RADS, was introduced in 2014 to standardize reporting for low-dose CT findings and also to reduce false-positive rates, by applying tighter criteria that was used in the National Lung Screening Trial.
Lung-RADS does not have specific reporting categories for patients with isolated hilar and mediastinal adenopathy or pleural effusion in the absence of lung nodules, even though these can indicate malignancy. It does allow for the inclusion of what is called an “S” code to indicate clinically significant findings other than nodules.
In the March 2017 issue of CHEST, Hiren Mehta, MD, and his colleagues at the University of Florida in Gainesville, report on four cases from their center in which patients with these pathologies had their scans read as Lung-RADS category 1, indicating a less than 1% likelihood of malignancy. No S codes were added to their reports. Subsequent testing in these patients revealed cancers (CHEST. 2017 March;151[3]:525-26).
The four cases were:
- A 56-year-old male with hilar and mediastinal adenopathy who was recommended for repeat screening at 12 months. The patient presented 6 months later with pneumonia; biopsy revealed large cell lung cancer.
- A 76-year-old male with paratracheal lymph nodes and a solitary subcarinal lymph node. A subsequent biopsy revealed adenocarcinoma.
- A 67-year-old male whose scan showed bulky hilar and mediastinal adenopathy. Subsequent testing revealed Hodgkin’s lymphoma.
- A 75-year-old female whose scan showed a small pleural effusion and no nodules. Repeat scanning at 1 year showed enlargement of the effusion and lung adenocarcinoma.
Dr. Mehta and colleagues noted in their analysis that Lung-RADS has not been studied prospectively in real practice settings and that the four cases – two of which involved delayed diagnosis – reveal “a significant limitation” of Lung-RADS.
“Based on our experience, we believe that particular caution should be exercised in reporting Lung-RADS 1 category for patients with adenopathy/pleural effusion with no lung nodules, as a majority of the lung cancer screening scans will be ordered by [primary care providers] ... [As] with any new system, an ongoing evaluation of the performance of Lung-RADS should be conducted so that the sensitivity and mortality benefit seen in the [National Lung Screening Trial] is not compromised.”
We strongly believe, based on our experience with these 4 cases that the new version of Lung-RADS 2.0 should [account for shortcomings of the current Lung-RADS] and have a separate category for findings that are highly suspicious for malignancy but do not have an accompanying lung nodule,” they wrote.
The investigators did not disclose outside funding or conflicts of interest related to their findings.
*This story was updated March 16, 2017, with the correct journal source.
FROM CHEST*
Key clinical point: The current Lung-RADS system for classing low-dose CT results may not adequately capture cancer risk in patients with adenopathy or pleural effusion
Major finding: Four patients with adenopathy or pleural effusion in the absence of nodules were found to have lung cancer despite first scans classed as negative
Data source: Case reports from a university based center using Lung-RADS 1.0 in its lung cancer screening program.
Disclosures: The investigators did not disclose outside funding or conflicts of interest related to their findings.
Cervicovaginal microbiota correlates with preterm birth rate
LAS VEGAS – Certain cervicovaginal microbiota predispose women to spontaneous preterm birth, according to a new study, while other microbiota were found to be protective against preterm delivery.
The findings stand in contrast to previous clinical trials that “targeted uterine activity and/or uterine infection,” said Michal Elovitz, MD, the first author of a study presented at the annual Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine.
To answer the question, Dr. Elovitz and her colleagues conducted a large prospective cohort and validation study, testing the hypothesis that cervicovaginal microbial communities in women “destined to have a preterm birth” would differ from those of control patients.
The Motherhood and the Microbiome study enrolled 1,500 women aged 13-50 years with singleton pregnancies to constitute the prospective cohort. Cervicovaginal swabs were obtained at three time points: at gestational weeks 16-20, 20-24, and 24-28. Dr. Elovitz, professor of ob.gyn. at the University of Pennsylvania, Philadelphia, was the study adjudicator for determining preterm births.
Within the prospective cohort, Dr. Elovitz and her collaborators identified 83 cases of spontaneous preterm birth (SPTB), and frequency matched them by race to 336 patients who had term deliveries in a 4:1 ratio. The cervicovaginal microbiota of these patients was characterized by performing 165 rRNA gene analyses. Once the bacterial composition and structure had been identified, the investigators then calculated the effect of cervicovaginal bacterial composition on the risk of SPTB by using the log ratio between the mean relative abundance of a given phylotype for the SPTB, compared with the term birth samples.
A second prospective cohort of 616 women was formed for validation; cervicovaginal specimens in this cohort were collected between 22 and 32 weeks of gestation.
Taking both cohorts together, a total of 127 phylotypes were found in all samples. A total of 13 bacterial species were positively associated with an increased risk of spontaneous preterm birth in the primary cohort; 37 species were significantly associated with a decreased risk of spontaneous preterm birth.
“Bifidobacterium species were noted to be significantly protective against SPTB at all gestational time points,” wrote Dr. Elovitz and her collaborators in the abstract accompanying the presentation. On the other hand, they wrote, “BVAB2, BVAB3, and Mobiluncus were associated with a dramatic increase[d] risk of SPTB (all q-values less than 0.0001).”
Abundant Mobiluncus mulieris, in particular, was associated with significantly increased risk of SPTB at all time points during the study. The odds ratio for SPTB with a positive mobiluncus swab at visit one was 9.21.
Since the study examined both relative and absolute abundance of individual bacterial species, the investigators were able to determine that when Bifidobacterium breve was present, the incidence of BVAB3-associated preterm birth dropped from more than 30% to less than 10% (P = .006).
The notion that specific cervicovaginal bacterial species can be associated with increased rate of SPTB represents a different finding than most previous work in this field, said Dr. Elovitz, adding that much of the research on the vaginal microbiome during the reproductive years has focused on groupings of predominant bacteria, termed community state types (CSTs). “Classification of communities into CST, as performed in the nonpregnant woman, is not revealing for PTB,” Dr. Elovitz said.
Future research into cervicovaginal microbial communities and spontaneous preterm birth are likely to produce new methods to risk-stratify women and potential new therapeutics to reduce the rate of spontaneous preterm birth, she added.
The presentation won the conference’s March of Dimes award for best abstract in prematurity.
Dr. Elovitz reported having no relevant financial disclosures.
[email protected]
On Twitter @karioakes
LAS VEGAS – Certain cervicovaginal microbiota predispose women to spontaneous preterm birth, according to a new study, while other microbiota were found to be protective against preterm delivery.
The findings stand in contrast to previous clinical trials that “targeted uterine activity and/or uterine infection,” said Michal Elovitz, MD, the first author of a study presented at the annual Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine.
To answer the question, Dr. Elovitz and her colleagues conducted a large prospective cohort and validation study, testing the hypothesis that cervicovaginal microbial communities in women “destined to have a preterm birth” would differ from those of control patients.
The Motherhood and the Microbiome study enrolled 1,500 women aged 13-50 years with singleton pregnancies to constitute the prospective cohort. Cervicovaginal swabs were obtained at three time points: at gestational weeks 16-20, 20-24, and 24-28. Dr. Elovitz, professor of ob.gyn. at the University of Pennsylvania, Philadelphia, was the study adjudicator for determining preterm births.
Within the prospective cohort, Dr. Elovitz and her collaborators identified 83 cases of spontaneous preterm birth (SPTB), and frequency matched them by race to 336 patients who had term deliveries in a 4:1 ratio. The cervicovaginal microbiota of these patients was characterized by performing 165 rRNA gene analyses. Once the bacterial composition and structure had been identified, the investigators then calculated the effect of cervicovaginal bacterial composition on the risk of SPTB by using the log ratio between the mean relative abundance of a given phylotype for the SPTB, compared with the term birth samples.
A second prospective cohort of 616 women was formed for validation; cervicovaginal specimens in this cohort were collected between 22 and 32 weeks of gestation.
Taking both cohorts together, a total of 127 phylotypes were found in all samples. A total of 13 bacterial species were positively associated with an increased risk of spontaneous preterm birth in the primary cohort; 37 species were significantly associated with a decreased risk of spontaneous preterm birth.
“Bifidobacterium species were noted to be significantly protective against SPTB at all gestational time points,” wrote Dr. Elovitz and her collaborators in the abstract accompanying the presentation. On the other hand, they wrote, “BVAB2, BVAB3, and Mobiluncus were associated with a dramatic increase[d] risk of SPTB (all q-values less than 0.0001).”
Abundant Mobiluncus mulieris, in particular, was associated with significantly increased risk of SPTB at all time points during the study. The odds ratio for SPTB with a positive mobiluncus swab at visit one was 9.21.
Since the study examined both relative and absolute abundance of individual bacterial species, the investigators were able to determine that when Bifidobacterium breve was present, the incidence of BVAB3-associated preterm birth dropped from more than 30% to less than 10% (P = .006).
The notion that specific cervicovaginal bacterial species can be associated with increased rate of SPTB represents a different finding than most previous work in this field, said Dr. Elovitz, adding that much of the research on the vaginal microbiome during the reproductive years has focused on groupings of predominant bacteria, termed community state types (CSTs). “Classification of communities into CST, as performed in the nonpregnant woman, is not revealing for PTB,” Dr. Elovitz said.
Future research into cervicovaginal microbial communities and spontaneous preterm birth are likely to produce new methods to risk-stratify women and potential new therapeutics to reduce the rate of spontaneous preterm birth, she added.
The presentation won the conference’s March of Dimes award for best abstract in prematurity.
Dr. Elovitz reported having no relevant financial disclosures.
[email protected]
On Twitter @karioakes
LAS VEGAS – Certain cervicovaginal microbiota predispose women to spontaneous preterm birth, according to a new study, while other microbiota were found to be protective against preterm delivery.
The findings stand in contrast to previous clinical trials that “targeted uterine activity and/or uterine infection,” said Michal Elovitz, MD, the first author of a study presented at the annual Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine.
To answer the question, Dr. Elovitz and her colleagues conducted a large prospective cohort and validation study, testing the hypothesis that cervicovaginal microbial communities in women “destined to have a preterm birth” would differ from those of control patients.
The Motherhood and the Microbiome study enrolled 1,500 women aged 13-50 years with singleton pregnancies to constitute the prospective cohort. Cervicovaginal swabs were obtained at three time points: at gestational weeks 16-20, 20-24, and 24-28. Dr. Elovitz, professor of ob.gyn. at the University of Pennsylvania, Philadelphia, was the study adjudicator for determining preterm births.
Within the prospective cohort, Dr. Elovitz and her collaborators identified 83 cases of spontaneous preterm birth (SPTB), and frequency matched them by race to 336 patients who had term deliveries in a 4:1 ratio. The cervicovaginal microbiota of these patients was characterized by performing 165 rRNA gene analyses. Once the bacterial composition and structure had been identified, the investigators then calculated the effect of cervicovaginal bacterial composition on the risk of SPTB by using the log ratio between the mean relative abundance of a given phylotype for the SPTB, compared with the term birth samples.
A second prospective cohort of 616 women was formed for validation; cervicovaginal specimens in this cohort were collected between 22 and 32 weeks of gestation.
Taking both cohorts together, a total of 127 phylotypes were found in all samples. A total of 13 bacterial species were positively associated with an increased risk of spontaneous preterm birth in the primary cohort; 37 species were significantly associated with a decreased risk of spontaneous preterm birth.
“Bifidobacterium species were noted to be significantly protective against SPTB at all gestational time points,” wrote Dr. Elovitz and her collaborators in the abstract accompanying the presentation. On the other hand, they wrote, “BVAB2, BVAB3, and Mobiluncus were associated with a dramatic increase[d] risk of SPTB (all q-values less than 0.0001).”
Abundant Mobiluncus mulieris, in particular, was associated with significantly increased risk of SPTB at all time points during the study. The odds ratio for SPTB with a positive mobiluncus swab at visit one was 9.21.
Since the study examined both relative and absolute abundance of individual bacterial species, the investigators were able to determine that when Bifidobacterium breve was present, the incidence of BVAB3-associated preterm birth dropped from more than 30% to less than 10% (P = .006).
The notion that specific cervicovaginal bacterial species can be associated with increased rate of SPTB represents a different finding than most previous work in this field, said Dr. Elovitz, adding that much of the research on the vaginal microbiome during the reproductive years has focused on groupings of predominant bacteria, termed community state types (CSTs). “Classification of communities into CST, as performed in the nonpregnant woman, is not revealing for PTB,” Dr. Elovitz said.
Future research into cervicovaginal microbial communities and spontaneous preterm birth are likely to produce new methods to risk-stratify women and potential new therapeutics to reduce the rate of spontaneous preterm birth, she added.
The presentation won the conference’s March of Dimes award for best abstract in prematurity.
Dr. Elovitz reported having no relevant financial disclosures.
[email protected]
On Twitter @karioakes
AT THE PREGNANCY MEETING
Key clinical point:
Major finding: Mobiluncus mulieris in the cervicovaginal space was associated with an odds ratio of 9.21 for spontaneous preterm birth.
Data source: Nested case-control study of 83 cases of spontaneous preterm birth matched with 336 term deliveries, drawn from 1,500 patients participating in the National Institute of Nursing Research–sponsored Motherhood and Microbiome study.
Disclosures: Dr. Elovitz reported having no relevant financial disclosures.
Screening for Symptomatic Mefloquine Exposure Among Veterans With Chronic Psychiatric Symptoms
Mefloquine is an antimalarial drug that is associated with a significant risk of chronic neuropsychiatric adverse effects (AEs). The drug was licensed by the FDA in 1989 after development by scientists affiliated with Walter Reed Army Institute of Research (WRAIR). By the early 1990s, mefloquine had become the U.S. military’s drug of choice both for treatment of uncomplicated malaria and for antimalarial prophylaxis and was administered as a convenient weekly dose. Mefloquine was prescribed widely to U.S. military personnel beginning with operations in Somalia in 1992 and over the next 2 decades during certain deployments to Iraq and Afghanistan and to other malaria-endemic areas.1
In 2013, following a decline of U.S. military use, the FDA added a boxed warning to the mefloquine product documentation to caution that neuropsychiatric AEs from the drug could last years after use and even be permanent. The U.S. military subsequently deemed mefloquine to be a prophylactic “drug of last resort.”2 Recently, researchers at WRAIR have acknowledged that chronic neuropsychiatric AEs attributable to mefloquine, including nightmares, insomnia, anxiety, irritability, and cognitive dysfunction, may confound the diagnosis of posttraumatic stress disorder (PTSD).3 The VA has awarded at least 1 disability claim for service-connected psychiatric conditions that it attributed to mefloquine exposure, and it is likely that in the coming years such claims will increase.2
Susceptibility to Chronic Neuropsychiatric AEs
Why mefloquine seems to cause chronic neuropsychiatric AEs in only certain individuals is unclear, although genetic susceptibility to drug-induced toxic encephalopathy and neurotoxicity are suspected.1 There is no screening test for susceptibility to AEs before mefloquine use, so the current U.S. product documentation cautiously warns that when used for prophylaxis, mefloquine should be discontinued at the onset of any neurologic or psychiatric symptom, many of which are considered prodromal to more serious AEs that may occur with continued dosing.4
Although chronic neuropsychiatric AEs have been reported to develop after only a single weekly dose, most clinically significant chronic AEs seem to occur among those who developed at least 1 prodromal neuropsychiatric symptom during early use but who continued weekly use despite these symptoms in a manner contrary to current product documentation guidance.4 In contrast, when mefloquine is administered for the treatment of malaria, typically at 5 times the weekly prophylactic dose and commonly in split doses over 8 to 12 hours, dosing is often complete by the time prodromal symptoms develop. Consequently, when mefloquine is used for treatment of malaria, the risks of more serious AEs are significantly higher than when the drug is used as directed in prophylaxis.5
Screening for Symptomatic Mefloquine Exposure
As the boxed warning indicates, certain psychiatric symptoms that occur with mefloquine use may become chronic and may confound psychiatric diagnosis. Particularly among veterans, these symptoms risk being misattributed, potentially affecting treatment decisions.6 Clinicians caring for veterans with persistent psychiatric symptoms should therefore screen for prior symptomatic mefloquine exposure and consider the possible AEs of the drug when formulating a differential diagnosis and treatment plan.
For example, a veteran with a history of symptomatic mefloquine exposure who later is diagnosed with PTSD may experience 1 or more symptoms, such as insomnia or cognitive dysfunction, which may be primarily attributable to the chronic AEs of the drug. The origins of the symptoms may be distinct from exposure to trauma and may not respond as effectively to certain conventional therapies for PTSD, requiring consideration of alternate therapies.3 The confounding role of psychiatric symptoms attributable to mefloquine exposure may explain failed response to medications and psychotherapy. Multidisciplinary evaluation and management may be appropriate for such patients.
If symptomatic mefloquine exposure is suspected, a clinician must establish evidence of exposure to the drug and the veteran’s development of neuropsychiatric symptoms associated with such exposure. The following sections provide guidance to aid in screening both for exposure to the drug and for the development of specific neuropsychiatric symptoms during prophylaxis or following the treatment of malaria.
Mefloquine Exposure
Mefloquine was licensed in the U.S. as a branded medication (Lariam) from 1989 to 2011, and the drug also has been available in a variety of generic equivalents from 2003 to the present. All versions of mefloquine approved in the U.S. have been formulated as a white/slightly-off-white, smaller than dime-sized round tablet, containing 250 mg of mefloquine hydrochloride.
When used for prophylaxis in military settings, the drug was often dispensed informally without documentation, sometimes including directly observed therapy under command direction.1,2 Therefore, even in the absence of prescribing documentation, a veteran who endorses a consistent history of malaria prophylaxis with mefloquine should be considered as having evidence of exposure.2
Exposure to mefloquine is unlikely if the veteran reports taking a daily antimalarial medication—more likely it was doxycycline or atovaquone/proguanil (marketed as Malarone). In rare cases, the drug may have been erroneously prescribed or been mistakenly taken daily for prophylaxis or, in more common cases, a prophylactic “loading dose” (typically 1 tablet daily for 3 days prior to weekly dosing) was used.7,8
Exposure also was unlikely if the veteran reports taking an antimalarial that was dosed weekly with a tablet that was not of the appropriate color, shape, and size. More likely that drug was chloroquine. Although most prophylactic use of mefloquine among U.S. veterans followed its licensing by the FDA in 1989, the drug is known to have been administered to a small number of U.S. military personnel prior to its licensing during clinical trials, including personnel deployed on certain operations during the 1980s.1
For treatment of malaria, mefloquine was used widely until better-tolerated drugs became available, beginning in the early 2000s, although some use of mefloquine in the military continues to this day. In most cases, clinicians should rely on records of hospitalization to identify whether mefloquine was administered. In rare cases where documentation is unavailable, exposure should be assumed if the veteran reports a reliable history of taking about 5 tablets (corresponding to the usual treatment dose of 1,250 mg) of appropriate color, shape, and size in response to confirmed or suspected malaria infection, either in 1 dose, or in split doses over 8 to 12 hours.
Symptoms During Prophylaxis
If prophylactic exposure to the drug has been established, the clinician should confirm the presence of neuropsychiatric symptoms during the exposure. Particularly among veterans deploying to malaria-endemic combat areas, such symptoms may have occurred during a period of heightened stress coincident with their initial deployment, and the veterans may have misattributed these symptoms to nonmefloquine factors. The clinician should therefore take a careful history to identify specific symptoms listed in the mefloquine product documentation. Many AEs will commonly manifest following the first 3 doses, and the clinician may find that focusing on this period is useful.9
When mefloquine is used for prophylaxis, anxiety and depression each affect between 1% and 10% of users. Other AEs that may develop include panic attacks; severe mood swings; behavioral AEs, including agitation, aggression, restlessness, and mania; symptoms of psychosis, including paranoia, delusions, and hallucinations; dissociative symptoms, including depersonalization; suicidal ideation; and cognitive AEs, including confusion.
The common symptoms of insomnia and abnormal dreaming affect > 10% of users. Particularly if multiple symptoms occur or if any of these symptoms occur following or coincident with symptoms of disturbed sleep, these should be considered strong evidence of symptomatic exposure.4 Veterans who report a history of continued mefloquine use despite the onset of such symptoms may be at particularly increased risk of chronic AEs.
The clinician should consider as evidence of symptomatic exposure information provided by others, including reports of obvious signs of nightmares or psychosis affecting the veteran. Clinicians should be aware that confusion and other psychiatric AEs caused by mefloquine during prophylactic use may limit the validity of self-reported history. Similarly, a history of seizure with mefloquine use or of the development of specific neurologic symptoms, particularly visual disturbances, dizziness, vertigo, disequilibrium, and paresthesias, also should be considered strong evidence of symptomatic exposure and indication of an increased risk of chronic psychiatric AEs.4
Posttreatment Adverse Effects
Although chronic psychiatric AEs following malaria infection have long been attributed to cerebral involvement, recognition that mefloquine may independently cause chronic neuropsychiatric AEs may require that individual cases be reexamined to properly assign causation.10 Particularly in uncomplicated cases of malaria, neuropsychiatric symptoms that develop only after treatment with mefloquine should be considered plausibly to be due to the drug and as evidence of symptomatic exposure.
As with use of mefloquine in prophylaxis, these neuropsychiatric symptoms may evolve in the weeks to months following exposure. They also may contribute to lasting and significant changes in personality, mood, cognition, thought, sleep, and behavior.6
Conclusion
Chronic AEs from mefloquine may provide a parsimonious explanation for the onset and persistence of a veteran’s psychiatric symptoms, particularly in cases where these may have failed to respond to treatment. Clinicians evaluating veterans who are seeking care for lasting psychiatric symptoms should ensure that they screen for prior symptomatic mefloquine exposure. As recognition grows of the drug’s chronic AEs, symptomatic mefloquine exposure is likely to emerge as a significant known confounder in the diagnosis of psychiatric disorders, including PTSD, among the current generation of U.S. veterans.
1. Nevin RL. Mefloquine and posttraumatic stress disorder. In: Ritchie EC, ed. Textbook of Military Medicine. Forensic and Ethical Issues in Military Behavioral Health. Washington, DC: Borden Institute; 2015:277-296.
2. Nevin RL, Ritchie EC. FDA black box, VA red ink? A successful service-connected disability claim for chronic neuropsychiatric adverse effects from mefloquine. Fed Pract. 2016;33(10):20-24.
3. Livezey J, Oliver T, Cantilena L. Prolonged neuropsychiatric symptoms in a military service member exposed to mefloquine. Drug Saf Case Rep. 2016;3(1):7.
4. Nevin RL, Byrd AM. Neuropsychiatric adverse reactions to mefloquine: a systematic comparison of prescribing and patient safety guidance in the US, UK, Ireland, Australia, New Zealand, and Canada. Neurol Ther. 2016;5(1):69-83.
5. Rendi-Wagner P, Noedl H, Wernsdorfer WH, Wiedermann G, Mikolasek A, Kollaritsch H. Unexpected frequency, duration and spectrum of adverse events after therapeutic dose of mefloquine in healthy adults. Acta Trop. 2002;81(2):167-173.
6. Nevin RL, Ritchie E. The mefloquine intoxication syndrome: a significant potential confounder in the diagnosis and management of PTSD and other chronic deployment-related neuropsychiatric disorders. In: Ritchie EC, ed. Posttraumatic Stress Disorder and Related Diseases in Combat Veterans. Cham, Switzerland: Springer International Publishing; 2015:257-278.
7. Cohen MR, Smetzer JL. FDA advise-ERR: mefloquine—not the same as Malarone; zoster vaccine is not for the immunosuppressed; TXA mistaken as tenecteplase; guidelines for adult IV push medications. Hosp Pharm. 2015;50(11):961-964.
8. Boudreau E, Schuster B, Sanchez J, et al. Tolerability of prophylactic Lariam regimens. Trop Med Parasitol. 1993;44(3):257-265.
9. Stürchler D, Handschin J, Kaiser D, et al. Neuropsychiatric side effects of mefloquine. N Engl J Med. 1990;322(24):1752-1753.
10. Nevin RL, Croft AM. Psychiatric effects of malaria and anti-malarial drugs: historical and modern perspectives. Malar J. 2016;15:332.
Mefloquine is an antimalarial drug that is associated with a significant risk of chronic neuropsychiatric adverse effects (AEs). The drug was licensed by the FDA in 1989 after development by scientists affiliated with Walter Reed Army Institute of Research (WRAIR). By the early 1990s, mefloquine had become the U.S. military’s drug of choice both for treatment of uncomplicated malaria and for antimalarial prophylaxis and was administered as a convenient weekly dose. Mefloquine was prescribed widely to U.S. military personnel beginning with operations in Somalia in 1992 and over the next 2 decades during certain deployments to Iraq and Afghanistan and to other malaria-endemic areas.1
In 2013, following a decline of U.S. military use, the FDA added a boxed warning to the mefloquine product documentation to caution that neuropsychiatric AEs from the drug could last years after use and even be permanent. The U.S. military subsequently deemed mefloquine to be a prophylactic “drug of last resort.”2 Recently, researchers at WRAIR have acknowledged that chronic neuropsychiatric AEs attributable to mefloquine, including nightmares, insomnia, anxiety, irritability, and cognitive dysfunction, may confound the diagnosis of posttraumatic stress disorder (PTSD).3 The VA has awarded at least 1 disability claim for service-connected psychiatric conditions that it attributed to mefloquine exposure, and it is likely that in the coming years such claims will increase.2
Susceptibility to Chronic Neuropsychiatric AEs
Why mefloquine seems to cause chronic neuropsychiatric AEs in only certain individuals is unclear, although genetic susceptibility to drug-induced toxic encephalopathy and neurotoxicity are suspected.1 There is no screening test for susceptibility to AEs before mefloquine use, so the current U.S. product documentation cautiously warns that when used for prophylaxis, mefloquine should be discontinued at the onset of any neurologic or psychiatric symptom, many of which are considered prodromal to more serious AEs that may occur with continued dosing.4
Although chronic neuropsychiatric AEs have been reported to develop after only a single weekly dose, most clinically significant chronic AEs seem to occur among those who developed at least 1 prodromal neuropsychiatric symptom during early use but who continued weekly use despite these symptoms in a manner contrary to current product documentation guidance.4 In contrast, when mefloquine is administered for the treatment of malaria, typically at 5 times the weekly prophylactic dose and commonly in split doses over 8 to 12 hours, dosing is often complete by the time prodromal symptoms develop. Consequently, when mefloquine is used for treatment of malaria, the risks of more serious AEs are significantly higher than when the drug is used as directed in prophylaxis.5
Screening for Symptomatic Mefloquine Exposure
As the boxed warning indicates, certain psychiatric symptoms that occur with mefloquine use may become chronic and may confound psychiatric diagnosis. Particularly among veterans, these symptoms risk being misattributed, potentially affecting treatment decisions.6 Clinicians caring for veterans with persistent psychiatric symptoms should therefore screen for prior symptomatic mefloquine exposure and consider the possible AEs of the drug when formulating a differential diagnosis and treatment plan.
For example, a veteran with a history of symptomatic mefloquine exposure who later is diagnosed with PTSD may experience 1 or more symptoms, such as insomnia or cognitive dysfunction, which may be primarily attributable to the chronic AEs of the drug. The origins of the symptoms may be distinct from exposure to trauma and may not respond as effectively to certain conventional therapies for PTSD, requiring consideration of alternate therapies.3 The confounding role of psychiatric symptoms attributable to mefloquine exposure may explain failed response to medications and psychotherapy. Multidisciplinary evaluation and management may be appropriate for such patients.
If symptomatic mefloquine exposure is suspected, a clinician must establish evidence of exposure to the drug and the veteran’s development of neuropsychiatric symptoms associated with such exposure. The following sections provide guidance to aid in screening both for exposure to the drug and for the development of specific neuropsychiatric symptoms during prophylaxis or following the treatment of malaria.
Mefloquine Exposure
Mefloquine was licensed in the U.S. as a branded medication (Lariam) from 1989 to 2011, and the drug also has been available in a variety of generic equivalents from 2003 to the present. All versions of mefloquine approved in the U.S. have been formulated as a white/slightly-off-white, smaller than dime-sized round tablet, containing 250 mg of mefloquine hydrochloride.
When used for prophylaxis in military settings, the drug was often dispensed informally without documentation, sometimes including directly observed therapy under command direction.1,2 Therefore, even in the absence of prescribing documentation, a veteran who endorses a consistent history of malaria prophylaxis with mefloquine should be considered as having evidence of exposure.2
Exposure to mefloquine is unlikely if the veteran reports taking a daily antimalarial medication—more likely it was doxycycline or atovaquone/proguanil (marketed as Malarone). In rare cases, the drug may have been erroneously prescribed or been mistakenly taken daily for prophylaxis or, in more common cases, a prophylactic “loading dose” (typically 1 tablet daily for 3 days prior to weekly dosing) was used.7,8
Exposure also was unlikely if the veteran reports taking an antimalarial that was dosed weekly with a tablet that was not of the appropriate color, shape, and size. More likely that drug was chloroquine. Although most prophylactic use of mefloquine among U.S. veterans followed its licensing by the FDA in 1989, the drug is known to have been administered to a small number of U.S. military personnel prior to its licensing during clinical trials, including personnel deployed on certain operations during the 1980s.1
For treatment of malaria, mefloquine was used widely until better-tolerated drugs became available, beginning in the early 2000s, although some use of mefloquine in the military continues to this day. In most cases, clinicians should rely on records of hospitalization to identify whether mefloquine was administered. In rare cases where documentation is unavailable, exposure should be assumed if the veteran reports a reliable history of taking about 5 tablets (corresponding to the usual treatment dose of 1,250 mg) of appropriate color, shape, and size in response to confirmed or suspected malaria infection, either in 1 dose, or in split doses over 8 to 12 hours.
Symptoms During Prophylaxis
If prophylactic exposure to the drug has been established, the clinician should confirm the presence of neuropsychiatric symptoms during the exposure. Particularly among veterans deploying to malaria-endemic combat areas, such symptoms may have occurred during a period of heightened stress coincident with their initial deployment, and the veterans may have misattributed these symptoms to nonmefloquine factors. The clinician should therefore take a careful history to identify specific symptoms listed in the mefloquine product documentation. Many AEs will commonly manifest following the first 3 doses, and the clinician may find that focusing on this period is useful.9
When mefloquine is used for prophylaxis, anxiety and depression each affect between 1% and 10% of users. Other AEs that may develop include panic attacks; severe mood swings; behavioral AEs, including agitation, aggression, restlessness, and mania; symptoms of psychosis, including paranoia, delusions, and hallucinations; dissociative symptoms, including depersonalization; suicidal ideation; and cognitive AEs, including confusion.
The common symptoms of insomnia and abnormal dreaming affect > 10% of users. Particularly if multiple symptoms occur or if any of these symptoms occur following or coincident with symptoms of disturbed sleep, these should be considered strong evidence of symptomatic exposure.4 Veterans who report a history of continued mefloquine use despite the onset of such symptoms may be at particularly increased risk of chronic AEs.
The clinician should consider as evidence of symptomatic exposure information provided by others, including reports of obvious signs of nightmares or psychosis affecting the veteran. Clinicians should be aware that confusion and other psychiatric AEs caused by mefloquine during prophylactic use may limit the validity of self-reported history. Similarly, a history of seizure with mefloquine use or of the development of specific neurologic symptoms, particularly visual disturbances, dizziness, vertigo, disequilibrium, and paresthesias, also should be considered strong evidence of symptomatic exposure and indication of an increased risk of chronic psychiatric AEs.4
Posttreatment Adverse Effects
Although chronic psychiatric AEs following malaria infection have long been attributed to cerebral involvement, recognition that mefloquine may independently cause chronic neuropsychiatric AEs may require that individual cases be reexamined to properly assign causation.10 Particularly in uncomplicated cases of malaria, neuropsychiatric symptoms that develop only after treatment with mefloquine should be considered plausibly to be due to the drug and as evidence of symptomatic exposure.
As with use of mefloquine in prophylaxis, these neuropsychiatric symptoms may evolve in the weeks to months following exposure. They also may contribute to lasting and significant changes in personality, mood, cognition, thought, sleep, and behavior.6
Conclusion
Chronic AEs from mefloquine may provide a parsimonious explanation for the onset and persistence of a veteran’s psychiatric symptoms, particularly in cases where these may have failed to respond to treatment. Clinicians evaluating veterans who are seeking care for lasting psychiatric symptoms should ensure that they screen for prior symptomatic mefloquine exposure. As recognition grows of the drug’s chronic AEs, symptomatic mefloquine exposure is likely to emerge as a significant known confounder in the diagnosis of psychiatric disorders, including PTSD, among the current generation of U.S. veterans.
Mefloquine is an antimalarial drug that is associated with a significant risk of chronic neuropsychiatric adverse effects (AEs). The drug was licensed by the FDA in 1989 after development by scientists affiliated with Walter Reed Army Institute of Research (WRAIR). By the early 1990s, mefloquine had become the U.S. military’s drug of choice both for treatment of uncomplicated malaria and for antimalarial prophylaxis and was administered as a convenient weekly dose. Mefloquine was prescribed widely to U.S. military personnel beginning with operations in Somalia in 1992 and over the next 2 decades during certain deployments to Iraq and Afghanistan and to other malaria-endemic areas.1
In 2013, following a decline of U.S. military use, the FDA added a boxed warning to the mefloquine product documentation to caution that neuropsychiatric AEs from the drug could last years after use and even be permanent. The U.S. military subsequently deemed mefloquine to be a prophylactic “drug of last resort.”2 Recently, researchers at WRAIR have acknowledged that chronic neuropsychiatric AEs attributable to mefloquine, including nightmares, insomnia, anxiety, irritability, and cognitive dysfunction, may confound the diagnosis of posttraumatic stress disorder (PTSD).3 The VA has awarded at least 1 disability claim for service-connected psychiatric conditions that it attributed to mefloquine exposure, and it is likely that in the coming years such claims will increase.2
Susceptibility to Chronic Neuropsychiatric AEs
Why mefloquine seems to cause chronic neuropsychiatric AEs in only certain individuals is unclear, although genetic susceptibility to drug-induced toxic encephalopathy and neurotoxicity are suspected.1 There is no screening test for susceptibility to AEs before mefloquine use, so the current U.S. product documentation cautiously warns that when used for prophylaxis, mefloquine should be discontinued at the onset of any neurologic or psychiatric symptom, many of which are considered prodromal to more serious AEs that may occur with continued dosing.4
Although chronic neuropsychiatric AEs have been reported to develop after only a single weekly dose, most clinically significant chronic AEs seem to occur among those who developed at least 1 prodromal neuropsychiatric symptom during early use but who continued weekly use despite these symptoms in a manner contrary to current product documentation guidance.4 In contrast, when mefloquine is administered for the treatment of malaria, typically at 5 times the weekly prophylactic dose and commonly in split doses over 8 to 12 hours, dosing is often complete by the time prodromal symptoms develop. Consequently, when mefloquine is used for treatment of malaria, the risks of more serious AEs are significantly higher than when the drug is used as directed in prophylaxis.5
Screening for Symptomatic Mefloquine Exposure
As the boxed warning indicates, certain psychiatric symptoms that occur with mefloquine use may become chronic and may confound psychiatric diagnosis. Particularly among veterans, these symptoms risk being misattributed, potentially affecting treatment decisions.6 Clinicians caring for veterans with persistent psychiatric symptoms should therefore screen for prior symptomatic mefloquine exposure and consider the possible AEs of the drug when formulating a differential diagnosis and treatment plan.
For example, a veteran with a history of symptomatic mefloquine exposure who later is diagnosed with PTSD may experience 1 or more symptoms, such as insomnia or cognitive dysfunction, which may be primarily attributable to the chronic AEs of the drug. The origins of the symptoms may be distinct from exposure to trauma and may not respond as effectively to certain conventional therapies for PTSD, requiring consideration of alternate therapies.3 The confounding role of psychiatric symptoms attributable to mefloquine exposure may explain failed response to medications and psychotherapy. Multidisciplinary evaluation and management may be appropriate for such patients.
If symptomatic mefloquine exposure is suspected, a clinician must establish evidence of exposure to the drug and the veteran’s development of neuropsychiatric symptoms associated with such exposure. The following sections provide guidance to aid in screening both for exposure to the drug and for the development of specific neuropsychiatric symptoms during prophylaxis or following the treatment of malaria.
Mefloquine Exposure
Mefloquine was licensed in the U.S. as a branded medication (Lariam) from 1989 to 2011, and the drug also has been available in a variety of generic equivalents from 2003 to the present. All versions of mefloquine approved in the U.S. have been formulated as a white/slightly-off-white, smaller than dime-sized round tablet, containing 250 mg of mefloquine hydrochloride.
When used for prophylaxis in military settings, the drug was often dispensed informally without documentation, sometimes including directly observed therapy under command direction.1,2 Therefore, even in the absence of prescribing documentation, a veteran who endorses a consistent history of malaria prophylaxis with mefloquine should be considered as having evidence of exposure.2
Exposure to mefloquine is unlikely if the veteran reports taking a daily antimalarial medication—more likely it was doxycycline or atovaquone/proguanil (marketed as Malarone). In rare cases, the drug may have been erroneously prescribed or been mistakenly taken daily for prophylaxis or, in more common cases, a prophylactic “loading dose” (typically 1 tablet daily for 3 days prior to weekly dosing) was used.7,8
Exposure also was unlikely if the veteran reports taking an antimalarial that was dosed weekly with a tablet that was not of the appropriate color, shape, and size. More likely that drug was chloroquine. Although most prophylactic use of mefloquine among U.S. veterans followed its licensing by the FDA in 1989, the drug is known to have been administered to a small number of U.S. military personnel prior to its licensing during clinical trials, including personnel deployed on certain operations during the 1980s.1
For treatment of malaria, mefloquine was used widely until better-tolerated drugs became available, beginning in the early 2000s, although some use of mefloquine in the military continues to this day. In most cases, clinicians should rely on records of hospitalization to identify whether mefloquine was administered. In rare cases where documentation is unavailable, exposure should be assumed if the veteran reports a reliable history of taking about 5 tablets (corresponding to the usual treatment dose of 1,250 mg) of appropriate color, shape, and size in response to confirmed or suspected malaria infection, either in 1 dose, or in split doses over 8 to 12 hours.
Symptoms During Prophylaxis
If prophylactic exposure to the drug has been established, the clinician should confirm the presence of neuropsychiatric symptoms during the exposure. Particularly among veterans deploying to malaria-endemic combat areas, such symptoms may have occurred during a period of heightened stress coincident with their initial deployment, and the veterans may have misattributed these symptoms to nonmefloquine factors. The clinician should therefore take a careful history to identify specific symptoms listed in the mefloquine product documentation. Many AEs will commonly manifest following the first 3 doses, and the clinician may find that focusing on this period is useful.9
When mefloquine is used for prophylaxis, anxiety and depression each affect between 1% and 10% of users. Other AEs that may develop include panic attacks; severe mood swings; behavioral AEs, including agitation, aggression, restlessness, and mania; symptoms of psychosis, including paranoia, delusions, and hallucinations; dissociative symptoms, including depersonalization; suicidal ideation; and cognitive AEs, including confusion.
The common symptoms of insomnia and abnormal dreaming affect > 10% of users. Particularly if multiple symptoms occur or if any of these symptoms occur following or coincident with symptoms of disturbed sleep, these should be considered strong evidence of symptomatic exposure.4 Veterans who report a history of continued mefloquine use despite the onset of such symptoms may be at particularly increased risk of chronic AEs.
The clinician should consider as evidence of symptomatic exposure information provided by others, including reports of obvious signs of nightmares or psychosis affecting the veteran. Clinicians should be aware that confusion and other psychiatric AEs caused by mefloquine during prophylactic use may limit the validity of self-reported history. Similarly, a history of seizure with mefloquine use or of the development of specific neurologic symptoms, particularly visual disturbances, dizziness, vertigo, disequilibrium, and paresthesias, also should be considered strong evidence of symptomatic exposure and indication of an increased risk of chronic psychiatric AEs.4
Posttreatment Adverse Effects
Although chronic psychiatric AEs following malaria infection have long been attributed to cerebral involvement, recognition that mefloquine may independently cause chronic neuropsychiatric AEs may require that individual cases be reexamined to properly assign causation.10 Particularly in uncomplicated cases of malaria, neuropsychiatric symptoms that develop only after treatment with mefloquine should be considered plausibly to be due to the drug and as evidence of symptomatic exposure.
As with use of mefloquine in prophylaxis, these neuropsychiatric symptoms may evolve in the weeks to months following exposure. They also may contribute to lasting and significant changes in personality, mood, cognition, thought, sleep, and behavior.6
Conclusion
Chronic AEs from mefloquine may provide a parsimonious explanation for the onset and persistence of a veteran’s psychiatric symptoms, particularly in cases where these may have failed to respond to treatment. Clinicians evaluating veterans who are seeking care for lasting psychiatric symptoms should ensure that they screen for prior symptomatic mefloquine exposure. As recognition grows of the drug’s chronic AEs, symptomatic mefloquine exposure is likely to emerge as a significant known confounder in the diagnosis of psychiatric disorders, including PTSD, among the current generation of U.S. veterans.
1. Nevin RL. Mefloquine and posttraumatic stress disorder. In: Ritchie EC, ed. Textbook of Military Medicine. Forensic and Ethical Issues in Military Behavioral Health. Washington, DC: Borden Institute; 2015:277-296.
2. Nevin RL, Ritchie EC. FDA black box, VA red ink? A successful service-connected disability claim for chronic neuropsychiatric adverse effects from mefloquine. Fed Pract. 2016;33(10):20-24.
3. Livezey J, Oliver T, Cantilena L. Prolonged neuropsychiatric symptoms in a military service member exposed to mefloquine. Drug Saf Case Rep. 2016;3(1):7.
4. Nevin RL, Byrd AM. Neuropsychiatric adverse reactions to mefloquine: a systematic comparison of prescribing and patient safety guidance in the US, UK, Ireland, Australia, New Zealand, and Canada. Neurol Ther. 2016;5(1):69-83.
5. Rendi-Wagner P, Noedl H, Wernsdorfer WH, Wiedermann G, Mikolasek A, Kollaritsch H. Unexpected frequency, duration and spectrum of adverse events after therapeutic dose of mefloquine in healthy adults. Acta Trop. 2002;81(2):167-173.
6. Nevin RL, Ritchie E. The mefloquine intoxication syndrome: a significant potential confounder in the diagnosis and management of PTSD and other chronic deployment-related neuropsychiatric disorders. In: Ritchie EC, ed. Posttraumatic Stress Disorder and Related Diseases in Combat Veterans. Cham, Switzerland: Springer International Publishing; 2015:257-278.
7. Cohen MR, Smetzer JL. FDA advise-ERR: mefloquine—not the same as Malarone; zoster vaccine is not for the immunosuppressed; TXA mistaken as tenecteplase; guidelines for adult IV push medications. Hosp Pharm. 2015;50(11):961-964.
8. Boudreau E, Schuster B, Sanchez J, et al. Tolerability of prophylactic Lariam regimens. Trop Med Parasitol. 1993;44(3):257-265.
9. Stürchler D, Handschin J, Kaiser D, et al. Neuropsychiatric side effects of mefloquine. N Engl J Med. 1990;322(24):1752-1753.
10. Nevin RL, Croft AM. Psychiatric effects of malaria and anti-malarial drugs: historical and modern perspectives. Malar J. 2016;15:332.
1. Nevin RL. Mefloquine and posttraumatic stress disorder. In: Ritchie EC, ed. Textbook of Military Medicine. Forensic and Ethical Issues in Military Behavioral Health. Washington, DC: Borden Institute; 2015:277-296.
2. Nevin RL, Ritchie EC. FDA black box, VA red ink? A successful service-connected disability claim for chronic neuropsychiatric adverse effects from mefloquine. Fed Pract. 2016;33(10):20-24.
3. Livezey J, Oliver T, Cantilena L. Prolonged neuropsychiatric symptoms in a military service member exposed to mefloquine. Drug Saf Case Rep. 2016;3(1):7.
4. Nevin RL, Byrd AM. Neuropsychiatric adverse reactions to mefloquine: a systematic comparison of prescribing and patient safety guidance in the US, UK, Ireland, Australia, New Zealand, and Canada. Neurol Ther. 2016;5(1):69-83.
5. Rendi-Wagner P, Noedl H, Wernsdorfer WH, Wiedermann G, Mikolasek A, Kollaritsch H. Unexpected frequency, duration and spectrum of adverse events after therapeutic dose of mefloquine in healthy adults. Acta Trop. 2002;81(2):167-173.
6. Nevin RL, Ritchie E. The mefloquine intoxication syndrome: a significant potential confounder in the diagnosis and management of PTSD and other chronic deployment-related neuropsychiatric disorders. In: Ritchie EC, ed. Posttraumatic Stress Disorder and Related Diseases in Combat Veterans. Cham, Switzerland: Springer International Publishing; 2015:257-278.
7. Cohen MR, Smetzer JL. FDA advise-ERR: mefloquine—not the same as Malarone; zoster vaccine is not for the immunosuppressed; TXA mistaken as tenecteplase; guidelines for adult IV push medications. Hosp Pharm. 2015;50(11):961-964.
8. Boudreau E, Schuster B, Sanchez J, et al. Tolerability of prophylactic Lariam regimens. Trop Med Parasitol. 1993;44(3):257-265.
9. Stürchler D, Handschin J, Kaiser D, et al. Neuropsychiatric side effects of mefloquine. N Engl J Med. 1990;322(24):1752-1753.
10. Nevin RL, Croft AM. Psychiatric effects of malaria and anti-malarial drugs: historical and modern perspectives. Malar J. 2016;15:332.
The Link Between Low-Density Lipoproteins and Chronic Lymphocytic Leukemia
Researchers from the University of Toronto had found in earlier studies that low-density lipoprotein (LDL) levels are elevated in up to 75% of patients with chronic lymphocytic leukemia (CLL). They also found that statins delayed the need for chemotherapy in those patients by nearly 3 years. They furthered their research using data on 2,124 patients with CLL and 7,935 controls in a population-based, case-control study. The researchers found a significantly higher incidence of hypercholesterolemia before CLL was diagnosed and a survival benefit of 3.7 years for patients taking statins.
In a new study to understand why hypercholesterolemia is apparently a tumor promoter for CLL, researchers first used an in vitro model of the “microenvironments” called pseudofollicles, where CLL cells proliferate. The researchers purified CLL cells from patients and activated them in lipid-poor conditions with interleukin-2 and resiquimod to represent stimulatory signals in pseudofollicles.
Related: New Treatments for Chronic Lymphocytic Leukemia
Adding LDLs increased viable cell numbers and signal transduction in molecules that mediate growth and proliferation of CLL cells.
To determine whether the effects were unique to CLL, the researchers conducted a similar experiment using peripheral blood mononuclear cells from donors without CLL. Their results suggested that normal blood cells handled cholesterol from LDLs in a different way than did CLL cells.
In another experiment, the researchers used circulating CLL cells from an additional cohort of 30 patients, including 11 who had been taking statins for at least 6 months. Cholesterol content of circulating CLL cells correlated directly with blood LDL levels, suggesting that LDLs may enhance proliferative responses of CLL cells to inflammatory signals. Statin use was associated with lower cholesterol in CLL cells, fewer circulating leukemia cells, and longer doubling times in vivo.
Researchers from the University of Toronto had found in earlier studies that low-density lipoprotein (LDL) levels are elevated in up to 75% of patients with chronic lymphocytic leukemia (CLL). They also found that statins delayed the need for chemotherapy in those patients by nearly 3 years. They furthered their research using data on 2,124 patients with CLL and 7,935 controls in a population-based, case-control study. The researchers found a significantly higher incidence of hypercholesterolemia before CLL was diagnosed and a survival benefit of 3.7 years for patients taking statins.
In a new study to understand why hypercholesterolemia is apparently a tumor promoter for CLL, researchers first used an in vitro model of the “microenvironments” called pseudofollicles, where CLL cells proliferate. The researchers purified CLL cells from patients and activated them in lipid-poor conditions with interleukin-2 and resiquimod to represent stimulatory signals in pseudofollicles.
Related: New Treatments for Chronic Lymphocytic Leukemia
Adding LDLs increased viable cell numbers and signal transduction in molecules that mediate growth and proliferation of CLL cells.
To determine whether the effects were unique to CLL, the researchers conducted a similar experiment using peripheral blood mononuclear cells from donors without CLL. Their results suggested that normal blood cells handled cholesterol from LDLs in a different way than did CLL cells.
In another experiment, the researchers used circulating CLL cells from an additional cohort of 30 patients, including 11 who had been taking statins for at least 6 months. Cholesterol content of circulating CLL cells correlated directly with blood LDL levels, suggesting that LDLs may enhance proliferative responses of CLL cells to inflammatory signals. Statin use was associated with lower cholesterol in CLL cells, fewer circulating leukemia cells, and longer doubling times in vivo.
Researchers from the University of Toronto had found in earlier studies that low-density lipoprotein (LDL) levels are elevated in up to 75% of patients with chronic lymphocytic leukemia (CLL). They also found that statins delayed the need for chemotherapy in those patients by nearly 3 years. They furthered their research using data on 2,124 patients with CLL and 7,935 controls in a population-based, case-control study. The researchers found a significantly higher incidence of hypercholesterolemia before CLL was diagnosed and a survival benefit of 3.7 years for patients taking statins.
In a new study to understand why hypercholesterolemia is apparently a tumor promoter for CLL, researchers first used an in vitro model of the “microenvironments” called pseudofollicles, where CLL cells proliferate. The researchers purified CLL cells from patients and activated them in lipid-poor conditions with interleukin-2 and resiquimod to represent stimulatory signals in pseudofollicles.
Related: New Treatments for Chronic Lymphocytic Leukemia
Adding LDLs increased viable cell numbers and signal transduction in molecules that mediate growth and proliferation of CLL cells.
To determine whether the effects were unique to CLL, the researchers conducted a similar experiment using peripheral blood mononuclear cells from donors without CLL. Their results suggested that normal blood cells handled cholesterol from LDLs in a different way than did CLL cells.
In another experiment, the researchers used circulating CLL cells from an additional cohort of 30 patients, including 11 who had been taking statins for at least 6 months. Cholesterol content of circulating CLL cells correlated directly with blood LDL levels, suggesting that LDLs may enhance proliferative responses of CLL cells to inflammatory signals. Statin use was associated with lower cholesterol in CLL cells, fewer circulating leukemia cells, and longer doubling times in vivo.
Applying a Time-Out and Standardized Report Form in Anesthesia Handoffs
Improving health care safety is one of the top priorities of the U.S. health care system. A key element for health care safety is the elimination of sentinel events—unexpected occurrences involving death or serious physical or psychological injury, such as loss of limb or function—or even the risk.1 Problems in communication, continuity of care, and planning have been identified as the root cause in more than 80% of documented sentinel events.2 As a direct result, The Joint Commission (JC) added National Patient Safety Goal 2E, which instructs each organization to implement a standardized approach to patient handoff.1 According to the JC, the objective of a handoff is to “provide accurate information about a patient’s care, treatment, and services, current condition, and any recent or anticipated changesand must include open communication and opportunities for questions.”1,3 The JC identified the patient handoff from anesthesia providers to the Surgical Intensive Care Unit (SICU) and Postanesthesia Care Unit (PACU) an opportunity for an improvement.1,3
At the Memphis VAMC in Tennessee, there was no established protocol for patient handoff from anesthesia providers to the SICU and PACU. The Anesthesia and SICU staffs were frustrated by inconsistent and incomplete postsurgical handoffs. Issues identified by the anesthesia team included difficulty contacting SICU staff to give a report and inconsistent availability of staff on first arrival to SICU. The SICU staff felt communication was rushed and there were inconsistencies in length and quality of the reports, resulting in incomplete postsurgical handoffs.
A baseline survey showed only 75% of staff felt the handoff report was thorough, and 67% “felt like a team.” In response, a multidisciplinary safe patient handoff committee (SPHOC) was formed by representatives from the involved units to discuss issues and offer solutions. The SPHOC efforts were aided by the VA National Center for Patient Safety (NCPS).
This quality improvement project was implemented as part of the U.S. Army Graduate Program in Anesthesia Nursing (USAGPAN) and the Northeastern University doctorate of nursing practice curriculum. The goal was to develop a simple, reliable, easily trainable handoff protocol for implemententation. This goal aligned with the priorites of the Memphis VAMC, USAGPAN, and VA to establish a culture based on patient safety and continuity of care.4
Methods
Standardization of handoffs began with JC National Patient Safety Goal 2E. There has been a wealth of medical literature on the need for standardization of handoffs and the implementation of specific handoff protocols in the postoperative setting. The SPHOC completed a review of the literature supporting standardization of handoff protocols. After completion, a second literature search was completed to identify the concepts for the implementation phase of the project. A critical appraisal of the evidence was completed using the method described by Melnyk and Fineout-Overholt.5 Literature from January 2005 through March 2015 was obtained via the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Google Scholar. The search methods included the keywords handover, handoff, transfer, and safety combined with anesthesia, PACU, surgery, operating room, and intensive care. Articles about handoffs not originating in the operating room (OR) were excluded.
The 13 articles found in the literature review established an overall need for standardization of handoffs outside the OR. Four articles identified a correlation between adverse events and poor or incomplete handoffs.3,6-8 Multiple articles discussed the need to develop a standardized handoff protocol in order to increase team work and quality of care.3,6,7,9,10 Petrovic and colleagues reported a 10% decrease in missed information and a boost in staff satisfaction from 61% to 81% with a standardized handoff.9 Additionally, a decrease in handoff time by > 1 minute was noted.8 Two articles identified an increase in quality of care after the implementation of a standardized handoff protocol.8,10
The second phase of the literature review examined relevant handoff information, best practices for participation in the handoff, and established staff buy-in for the process. Segall and colleagues created a table with handoff strategies consistently identified in the literature.10 The most relevant of these were using a structured written checklist to guide communication, using protocols to standardize the process, and providing formal team training.10
Six articles identified a written checklist and standardized handoff process as successful strategies used to improve patient safety.11-16 Zavalkoff and colleagues discussed the use of a template sheet filled out by the anesthesia provider prior to the handoff for consistency and accuracy of report.16 Catchpole and colleagues drew correlations between a Formula 1 pit stop and anesthesia handoffs and discussed the teamwork portion of the handoff protocol relating to staff buy-in.14 After delegating roles and making a set protocol for the handoff process, the study group was able to meet their objectives of efficient and safe handoff.14
With the information provided from the literature review, the SPHOC established a standardized handoff for the postsurgical patient. The committee created a handoff sheet for the anesthesia provider to use for report. This also included standardizing the handoff process and delineating specific roles for each provider.
After completing a NCPS training workshop, goals were identified at a SPHOC meeting. The SPHOC discussed current barriers to safe patient transfer and suggestions to overcome the barriers. Initial interventions planned by SPHOC focused on the problems of unsafe handoffs and delays in transfer. First, SICU identified the best phone number to call, which was distributed to the anesthesia and OR staffs. Additionally, the committee began tracking the number of attempted calls to reach SICU and availability of the nurse to take the report.
Implementation
A standardized handoff form was created by SPHOC, and anesthesia providers began to call time-out after the patient was deemed stable. After time-out was called, the SICU nurse provided his or her undivided attention and received the report. When SPHOC deemed the process successful, it was implemented in PACU as well. The entire OR, PACU, and anesthesia staffs were updated regarding the progress of the SPHOC on a monthly basis.
The implementation phase involved SPHOC tracking compliance of handoff sheets and time-outs. Compliance was tracked by counting the number of handoff sheets collected at the end of the day vs the total number of cases on the OR schedule. Tracking compliance with SICU transfers was monitored by the SICU members of the SPHOC through a tracking form. Initially a high level of SICU weekly compliance (93%) was noted.
Building on this success, SPHOC extended use of the handoff sheets and time-out to the PACU. Student registered nurse anesthetists (SRNAs) were tasked with education of the anesthesia and PACU staffs. Education continued via individual teaching, presentation at staff meetings, and e-mail reminders. To prevent confusion, no additional changes were made to the handoff sheet for an extended trial.
Despite these interventions, PACU compliance began to lag, averaging 33% over 3 weeks. Encouraging staff buy-in and a change in culture were identified as strategies to improve compliance. The third month of the trial started with 71% compliance. Interventions regarding staff buy-in emphasized individual accountability. Names were attached to handoff sheets, and those found with < 80% of sheets completed were provided with additional education. Those participants with ≥ 80% compliance were praised for their efforts.
Fostering a culture change proved to be more challenging. Interviews and discussions with anesthesia staff identified forgetting to fill out the sheet as the most common reason for noncompliance. Laminated copies of the handoff sheet were affixed to all anesthesia machines as a visual reminder. A sign denoting where to place the completed handoff sheets was placed in the PACU as a visual cue. The SPHOC stocked each anesthesia machine with handoff sheets on a daily basis.
To strengthen the culture of change, the PACU and SICU RNs were encouraged to ask for a time-out from the anesthesia provider. Handoff sheets were printed on yellow card stock to encourage anesthesia staff to “slow down for patient safety.” With these interventions, compliance increased to 98% by the end of the month.
Survey
An anonymous and voluntary survey was created and distributed to all staff involved in the handoff process. The 5-question survey was based on a 5-point Likert scale from 1 for strongly disagree to 5 for strongly disagree. The survey included the following questions: The new surgery report is very thorough; I feel more comfortable when assuming care of the postoperative patient; staff is more attentive when listening to the surgery report when a time-out is called; I feel the new surgery report is more effective and efficient; I feel I am more of a team with the OR with our changes in handoff of care process.
The survey was used as a baseline and to evaluate further changes in the process. Medical literature has shown that improper handoff communication was the leading cause of adverse events in the postsurgical patient.3,6
Results
Surgery to SICU transfers using the Handoff card increased from 33% in the first month to an average of 98% after interventions. In the 10-month intervention period,
After compliance initially increased, SPHOC focused on the more complex aspects of the handoff process—staff satisfaction, which was chosen based on an area of weakness identified in the initial survey results. Overall, staff was satisfied with the handoff sheets; however, only 67% of SICU staff reported that they felt part of the team with the OR as a result of the handoff of care process.
To address this issue, the team delineated roles for providers when a new surgical patient arrived in the SICU. This was dubbed the ABCs of safe handoff with roles for the anesthesia provider or respiratory therapist, the circulating nurse and SICU nurse, and the anesthesia provider. A graphic representation explains the mnemonic, the roles created, and laminated copies were distributed throughout the OR and SICU (Figure). Subsequent surveys showed 80% of staff felt more like a team with the new process.
Conclusion
The overall impact of the project has been to further promote a culture of patient safety at the Memphis VAMC and establish continuity of care as an institutional priority. The existing handoff sheet, time-out, and cross-check have been adapted to all hospital-wide transfers. With the SPHOC guidance and expertise, PACU began using a handoff sheet and time-out when transferring patients to the medical/surgical floors. The handoff sheet has also been adapted to fit the needs of transfers from the emergency department to the medical/surgical floors.
The framework of a standardized handoff is adaptable for other units to customize and has been adopted hospital-wide. The project is sustainable as it requires almost no money to create and sustain. The primary weakness of the process is the requirement of sustained staff participation and buy-in. Each unit and hospital invariably comes with a different culture and priorities; therefore, the process developed at Memphis VAMC may not meet the needs of other facilities. ˜
Acknowledgments
Special thanks to Susan Baldwin, RN; Bianca Mathews, MSN, RN; Wendy Regel, RN; Armance White, CRNA; Reginald Witt, MD; Odie Powell, RN; Alma Farris, RN; Clarisa Reed, RN; Susan Baily, RN; Linda Sueing, RN; Teresa Nguyen, RN; and John Craig, DNP, CRNA.
1. The Joint Commission. Topic library item: sentinel event policy and procedures.. http://www .jointcommission.org/Sentinel_Event_Policy _and_Procedures. Updated October 14, 2016. Accessed February 14, 2017.
2. Streitenberger K, Breen-Reid K, Harris C. Handoffs in care—can we make them safer? Pediatr Clin N Am. 2006;53(6):1185-1195.
3. Petrovic MA, Aboumatar H, Baumgartner WA, et al. Pilot implementation of a perioperative protocol to guide operating room-to-intensive care unit patient handoffs. J Cardiothorac Vasc Anesth. 2012;26(1):11-16.
4. U.S. Department of Veteran Affairs. VA national center for patient safety. http://www.patientsafety .va.gov/about/index.asp . Updated June 3, 2015. Accessed February 14, 2017.
5. Melnyk BM, Fineout-Overholt E. Evidence-Based Practice in Nursing & Healthcare: A Guide to Best Practice. Philadelphia, PA: Lippincott Williams & Wilkins; 2011.
6. Hudson CC, McDonald B, Hudson JK, Tran D, Boodhwani M. Impact of anesthetic handover on mortality and morbidity in cardiac surgery: a cohort study. J Cardiothorac Vasc Anesth. 2015;29(1):11-16.
7. Lane-Fall MB, Beidas RS, Pascual JL, et al. Handoffs and transitions in critical care (HATRICC): protocol for a mixed methods study of operating room to intensive care unit handoffs. BMC Surg. 2012;14:96.
8. Nagpal K, Arora S, Abboudi M, et al. Postoperative handover: problems, pitfalls, and prevention of error. Ann Surg. 2010;252(1):171-176.
9. Petrovic MA, Martinez EA, Aboumatar H. Implementing a perioperative handoff tool to improve postprocedural patient transfers. Jt Comm J Qual Patient Saf. 2012;38(3):135-142.
10. Segall N, Bonifacio AS, Schroeder RA, et al; Durham VA Patient Safety Center of Inquiry. Can we make postoperative patient handovers safer? A systematic review of the literature. Anesth Analg. 2012;115(1):102-115.
11. Riesenberg LA, Leitzsch J, Little BW. Systematic review of handoff mnemonics literature. Am J Med Qual. 2009;24(3):196-204.
12. Arora V, Johnson J. A model for building a standardized hand-off protocol. Jt Comm J Qual Patient Saf. 206;32(11):646-655.
13. Riesenberg LA, Leitzsch J, Cunningham JM. Nursing handoffs: a systematic review of the literature. Am J Nurse. 2010;110(4):24-34.
14. Catchpole KR, de Leval MR, McEwan A, et al. Patient handover from surgery to intensive care: using Formula 1 pit‐stop and aviation models to improve safety and quality. Paediatr Anesth. 2007;17(5):470-478.
15. Wahr JA, Prager RL, Abernathy JH III, et al; American Heart Association Council on Cardiovascular Surgery and Anesthesia, Council on Cardiovascular and Stroke Nursing, and Council on Quality of Care and Outcomes Research. Patient safety in the cardiac operating room: human factors and teamwork: a scientific statement from the American Heart Association. Circulation. 2013;128(10):1139-1169.
16. Zavalkoff SR, Razack SI, Lavoie J, Dancea AB. Handover after pediatric heart surgery: a simple tool improves information exchange. Pediatr Crit Care Med. 2011;12(3):309-313.
Improving health care safety is one of the top priorities of the U.S. health care system. A key element for health care safety is the elimination of sentinel events—unexpected occurrences involving death or serious physical or psychological injury, such as loss of limb or function—or even the risk.1 Problems in communication, continuity of care, and planning have been identified as the root cause in more than 80% of documented sentinel events.2 As a direct result, The Joint Commission (JC) added National Patient Safety Goal 2E, which instructs each organization to implement a standardized approach to patient handoff.1 According to the JC, the objective of a handoff is to “provide accurate information about a patient’s care, treatment, and services, current condition, and any recent or anticipated changesand must include open communication and opportunities for questions.”1,3 The JC identified the patient handoff from anesthesia providers to the Surgical Intensive Care Unit (SICU) and Postanesthesia Care Unit (PACU) an opportunity for an improvement.1,3
At the Memphis VAMC in Tennessee, there was no established protocol for patient handoff from anesthesia providers to the SICU and PACU. The Anesthesia and SICU staffs were frustrated by inconsistent and incomplete postsurgical handoffs. Issues identified by the anesthesia team included difficulty contacting SICU staff to give a report and inconsistent availability of staff on first arrival to SICU. The SICU staff felt communication was rushed and there were inconsistencies in length and quality of the reports, resulting in incomplete postsurgical handoffs.
A baseline survey showed only 75% of staff felt the handoff report was thorough, and 67% “felt like a team.” In response, a multidisciplinary safe patient handoff committee (SPHOC) was formed by representatives from the involved units to discuss issues and offer solutions. The SPHOC efforts were aided by the VA National Center for Patient Safety (NCPS).
This quality improvement project was implemented as part of the U.S. Army Graduate Program in Anesthesia Nursing (USAGPAN) and the Northeastern University doctorate of nursing practice curriculum. The goal was to develop a simple, reliable, easily trainable handoff protocol for implemententation. This goal aligned with the priorites of the Memphis VAMC, USAGPAN, and VA to establish a culture based on patient safety and continuity of care.4
Methods
Standardization of handoffs began with JC National Patient Safety Goal 2E. There has been a wealth of medical literature on the need for standardization of handoffs and the implementation of specific handoff protocols in the postoperative setting. The SPHOC completed a review of the literature supporting standardization of handoff protocols. After completion, a second literature search was completed to identify the concepts for the implementation phase of the project. A critical appraisal of the evidence was completed using the method described by Melnyk and Fineout-Overholt.5 Literature from January 2005 through March 2015 was obtained via the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Google Scholar. The search methods included the keywords handover, handoff, transfer, and safety combined with anesthesia, PACU, surgery, operating room, and intensive care. Articles about handoffs not originating in the operating room (OR) were excluded.
The 13 articles found in the literature review established an overall need for standardization of handoffs outside the OR. Four articles identified a correlation between adverse events and poor or incomplete handoffs.3,6-8 Multiple articles discussed the need to develop a standardized handoff protocol in order to increase team work and quality of care.3,6,7,9,10 Petrovic and colleagues reported a 10% decrease in missed information and a boost in staff satisfaction from 61% to 81% with a standardized handoff.9 Additionally, a decrease in handoff time by > 1 minute was noted.8 Two articles identified an increase in quality of care after the implementation of a standardized handoff protocol.8,10
The second phase of the literature review examined relevant handoff information, best practices for participation in the handoff, and established staff buy-in for the process. Segall and colleagues created a table with handoff strategies consistently identified in the literature.10 The most relevant of these were using a structured written checklist to guide communication, using protocols to standardize the process, and providing formal team training.10
Six articles identified a written checklist and standardized handoff process as successful strategies used to improve patient safety.11-16 Zavalkoff and colleagues discussed the use of a template sheet filled out by the anesthesia provider prior to the handoff for consistency and accuracy of report.16 Catchpole and colleagues drew correlations between a Formula 1 pit stop and anesthesia handoffs and discussed the teamwork portion of the handoff protocol relating to staff buy-in.14 After delegating roles and making a set protocol for the handoff process, the study group was able to meet their objectives of efficient and safe handoff.14
With the information provided from the literature review, the SPHOC established a standardized handoff for the postsurgical patient. The committee created a handoff sheet for the anesthesia provider to use for report. This also included standardizing the handoff process and delineating specific roles for each provider.
After completing a NCPS training workshop, goals were identified at a SPHOC meeting. The SPHOC discussed current barriers to safe patient transfer and suggestions to overcome the barriers. Initial interventions planned by SPHOC focused on the problems of unsafe handoffs and delays in transfer. First, SICU identified the best phone number to call, which was distributed to the anesthesia and OR staffs. Additionally, the committee began tracking the number of attempted calls to reach SICU and availability of the nurse to take the report.
Implementation
A standardized handoff form was created by SPHOC, and anesthesia providers began to call time-out after the patient was deemed stable. After time-out was called, the SICU nurse provided his or her undivided attention and received the report. When SPHOC deemed the process successful, it was implemented in PACU as well. The entire OR, PACU, and anesthesia staffs were updated regarding the progress of the SPHOC on a monthly basis.
The implementation phase involved SPHOC tracking compliance of handoff sheets and time-outs. Compliance was tracked by counting the number of handoff sheets collected at the end of the day vs the total number of cases on the OR schedule. Tracking compliance with SICU transfers was monitored by the SICU members of the SPHOC through a tracking form. Initially a high level of SICU weekly compliance (93%) was noted.
Building on this success, SPHOC extended use of the handoff sheets and time-out to the PACU. Student registered nurse anesthetists (SRNAs) were tasked with education of the anesthesia and PACU staffs. Education continued via individual teaching, presentation at staff meetings, and e-mail reminders. To prevent confusion, no additional changes were made to the handoff sheet for an extended trial.
Despite these interventions, PACU compliance began to lag, averaging 33% over 3 weeks. Encouraging staff buy-in and a change in culture were identified as strategies to improve compliance. The third month of the trial started with 71% compliance. Interventions regarding staff buy-in emphasized individual accountability. Names were attached to handoff sheets, and those found with < 80% of sheets completed were provided with additional education. Those participants with ≥ 80% compliance were praised for their efforts.
Fostering a culture change proved to be more challenging. Interviews and discussions with anesthesia staff identified forgetting to fill out the sheet as the most common reason for noncompliance. Laminated copies of the handoff sheet were affixed to all anesthesia machines as a visual reminder. A sign denoting where to place the completed handoff sheets was placed in the PACU as a visual cue. The SPHOC stocked each anesthesia machine with handoff sheets on a daily basis.
To strengthen the culture of change, the PACU and SICU RNs were encouraged to ask for a time-out from the anesthesia provider. Handoff sheets were printed on yellow card stock to encourage anesthesia staff to “slow down for patient safety.” With these interventions, compliance increased to 98% by the end of the month.
Survey
An anonymous and voluntary survey was created and distributed to all staff involved in the handoff process. The 5-question survey was based on a 5-point Likert scale from 1 for strongly disagree to 5 for strongly disagree. The survey included the following questions: The new surgery report is very thorough; I feel more comfortable when assuming care of the postoperative patient; staff is more attentive when listening to the surgery report when a time-out is called; I feel the new surgery report is more effective and efficient; I feel I am more of a team with the OR with our changes in handoff of care process.
The survey was used as a baseline and to evaluate further changes in the process. Medical literature has shown that improper handoff communication was the leading cause of adverse events in the postsurgical patient.3,6
Results
Surgery to SICU transfers using the Handoff card increased from 33% in the first month to an average of 98% after interventions. In the 10-month intervention period,
After compliance initially increased, SPHOC focused on the more complex aspects of the handoff process—staff satisfaction, which was chosen based on an area of weakness identified in the initial survey results. Overall, staff was satisfied with the handoff sheets; however, only 67% of SICU staff reported that they felt part of the team with the OR as a result of the handoff of care process.
To address this issue, the team delineated roles for providers when a new surgical patient arrived in the SICU. This was dubbed the ABCs of safe handoff with roles for the anesthesia provider or respiratory therapist, the circulating nurse and SICU nurse, and the anesthesia provider. A graphic representation explains the mnemonic, the roles created, and laminated copies were distributed throughout the OR and SICU (Figure). Subsequent surveys showed 80% of staff felt more like a team with the new process.
Conclusion
The overall impact of the project has been to further promote a culture of patient safety at the Memphis VAMC and establish continuity of care as an institutional priority. The existing handoff sheet, time-out, and cross-check have been adapted to all hospital-wide transfers. With the SPHOC guidance and expertise, PACU began using a handoff sheet and time-out when transferring patients to the medical/surgical floors. The handoff sheet has also been adapted to fit the needs of transfers from the emergency department to the medical/surgical floors.
The framework of a standardized handoff is adaptable for other units to customize and has been adopted hospital-wide. The project is sustainable as it requires almost no money to create and sustain. The primary weakness of the process is the requirement of sustained staff participation and buy-in. Each unit and hospital invariably comes with a different culture and priorities; therefore, the process developed at Memphis VAMC may not meet the needs of other facilities. ˜
Acknowledgments
Special thanks to Susan Baldwin, RN; Bianca Mathews, MSN, RN; Wendy Regel, RN; Armance White, CRNA; Reginald Witt, MD; Odie Powell, RN; Alma Farris, RN; Clarisa Reed, RN; Susan Baily, RN; Linda Sueing, RN; Teresa Nguyen, RN; and John Craig, DNP, CRNA.
Improving health care safety is one of the top priorities of the U.S. health care system. A key element for health care safety is the elimination of sentinel events—unexpected occurrences involving death or serious physical or psychological injury, such as loss of limb or function—or even the risk.1 Problems in communication, continuity of care, and planning have been identified as the root cause in more than 80% of documented sentinel events.2 As a direct result, The Joint Commission (JC) added National Patient Safety Goal 2E, which instructs each organization to implement a standardized approach to patient handoff.1 According to the JC, the objective of a handoff is to “provide accurate information about a patient’s care, treatment, and services, current condition, and any recent or anticipated changesand must include open communication and opportunities for questions.”1,3 The JC identified the patient handoff from anesthesia providers to the Surgical Intensive Care Unit (SICU) and Postanesthesia Care Unit (PACU) an opportunity for an improvement.1,3
At the Memphis VAMC in Tennessee, there was no established protocol for patient handoff from anesthesia providers to the SICU and PACU. The Anesthesia and SICU staffs were frustrated by inconsistent and incomplete postsurgical handoffs. Issues identified by the anesthesia team included difficulty contacting SICU staff to give a report and inconsistent availability of staff on first arrival to SICU. The SICU staff felt communication was rushed and there were inconsistencies in length and quality of the reports, resulting in incomplete postsurgical handoffs.
A baseline survey showed only 75% of staff felt the handoff report was thorough, and 67% “felt like a team.” In response, a multidisciplinary safe patient handoff committee (SPHOC) was formed by representatives from the involved units to discuss issues and offer solutions. The SPHOC efforts were aided by the VA National Center for Patient Safety (NCPS).
This quality improvement project was implemented as part of the U.S. Army Graduate Program in Anesthesia Nursing (USAGPAN) and the Northeastern University doctorate of nursing practice curriculum. The goal was to develop a simple, reliable, easily trainable handoff protocol for implemententation. This goal aligned with the priorites of the Memphis VAMC, USAGPAN, and VA to establish a culture based on patient safety and continuity of care.4
Methods
Standardization of handoffs began with JC National Patient Safety Goal 2E. There has been a wealth of medical literature on the need for standardization of handoffs and the implementation of specific handoff protocols in the postoperative setting. The SPHOC completed a review of the literature supporting standardization of handoff protocols. After completion, a second literature search was completed to identify the concepts for the implementation phase of the project. A critical appraisal of the evidence was completed using the method described by Melnyk and Fineout-Overholt.5 Literature from January 2005 through March 2015 was obtained via the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Google Scholar. The search methods included the keywords handover, handoff, transfer, and safety combined with anesthesia, PACU, surgery, operating room, and intensive care. Articles about handoffs not originating in the operating room (OR) were excluded.
The 13 articles found in the literature review established an overall need for standardization of handoffs outside the OR. Four articles identified a correlation between adverse events and poor or incomplete handoffs.3,6-8 Multiple articles discussed the need to develop a standardized handoff protocol in order to increase team work and quality of care.3,6,7,9,10 Petrovic and colleagues reported a 10% decrease in missed information and a boost in staff satisfaction from 61% to 81% with a standardized handoff.9 Additionally, a decrease in handoff time by > 1 minute was noted.8 Two articles identified an increase in quality of care after the implementation of a standardized handoff protocol.8,10
The second phase of the literature review examined relevant handoff information, best practices for participation in the handoff, and established staff buy-in for the process. Segall and colleagues created a table with handoff strategies consistently identified in the literature.10 The most relevant of these were using a structured written checklist to guide communication, using protocols to standardize the process, and providing formal team training.10
Six articles identified a written checklist and standardized handoff process as successful strategies used to improve patient safety.11-16 Zavalkoff and colleagues discussed the use of a template sheet filled out by the anesthesia provider prior to the handoff for consistency and accuracy of report.16 Catchpole and colleagues drew correlations between a Formula 1 pit stop and anesthesia handoffs and discussed the teamwork portion of the handoff protocol relating to staff buy-in.14 After delegating roles and making a set protocol for the handoff process, the study group was able to meet their objectives of efficient and safe handoff.14
With the information provided from the literature review, the SPHOC established a standardized handoff for the postsurgical patient. The committee created a handoff sheet for the anesthesia provider to use for report. This also included standardizing the handoff process and delineating specific roles for each provider.
After completing a NCPS training workshop, goals were identified at a SPHOC meeting. The SPHOC discussed current barriers to safe patient transfer and suggestions to overcome the barriers. Initial interventions planned by SPHOC focused on the problems of unsafe handoffs and delays in transfer. First, SICU identified the best phone number to call, which was distributed to the anesthesia and OR staffs. Additionally, the committee began tracking the number of attempted calls to reach SICU and availability of the nurse to take the report.
Implementation
A standardized handoff form was created by SPHOC, and anesthesia providers began to call time-out after the patient was deemed stable. After time-out was called, the SICU nurse provided his or her undivided attention and received the report. When SPHOC deemed the process successful, it was implemented in PACU as well. The entire OR, PACU, and anesthesia staffs were updated regarding the progress of the SPHOC on a monthly basis.
The implementation phase involved SPHOC tracking compliance of handoff sheets and time-outs. Compliance was tracked by counting the number of handoff sheets collected at the end of the day vs the total number of cases on the OR schedule. Tracking compliance with SICU transfers was monitored by the SICU members of the SPHOC through a tracking form. Initially a high level of SICU weekly compliance (93%) was noted.
Building on this success, SPHOC extended use of the handoff sheets and time-out to the PACU. Student registered nurse anesthetists (SRNAs) were tasked with education of the anesthesia and PACU staffs. Education continued via individual teaching, presentation at staff meetings, and e-mail reminders. To prevent confusion, no additional changes were made to the handoff sheet for an extended trial.
Despite these interventions, PACU compliance began to lag, averaging 33% over 3 weeks. Encouraging staff buy-in and a change in culture were identified as strategies to improve compliance. The third month of the trial started with 71% compliance. Interventions regarding staff buy-in emphasized individual accountability. Names were attached to handoff sheets, and those found with < 80% of sheets completed were provided with additional education. Those participants with ≥ 80% compliance were praised for their efforts.
Fostering a culture change proved to be more challenging. Interviews and discussions with anesthesia staff identified forgetting to fill out the sheet as the most common reason for noncompliance. Laminated copies of the handoff sheet were affixed to all anesthesia machines as a visual reminder. A sign denoting where to place the completed handoff sheets was placed in the PACU as a visual cue. The SPHOC stocked each anesthesia machine with handoff sheets on a daily basis.
To strengthen the culture of change, the PACU and SICU RNs were encouraged to ask for a time-out from the anesthesia provider. Handoff sheets were printed on yellow card stock to encourage anesthesia staff to “slow down for patient safety.” With these interventions, compliance increased to 98% by the end of the month.
Survey
An anonymous and voluntary survey was created and distributed to all staff involved in the handoff process. The 5-question survey was based on a 5-point Likert scale from 1 for strongly disagree to 5 for strongly disagree. The survey included the following questions: The new surgery report is very thorough; I feel more comfortable when assuming care of the postoperative patient; staff is more attentive when listening to the surgery report when a time-out is called; I feel the new surgery report is more effective and efficient; I feel I am more of a team with the OR with our changes in handoff of care process.
The survey was used as a baseline and to evaluate further changes in the process. Medical literature has shown that improper handoff communication was the leading cause of adverse events in the postsurgical patient.3,6
Results
Surgery to SICU transfers using the Handoff card increased from 33% in the first month to an average of 98% after interventions. In the 10-month intervention period,
After compliance initially increased, SPHOC focused on the more complex aspects of the handoff process—staff satisfaction, which was chosen based on an area of weakness identified in the initial survey results. Overall, staff was satisfied with the handoff sheets; however, only 67% of SICU staff reported that they felt part of the team with the OR as a result of the handoff of care process.
To address this issue, the team delineated roles for providers when a new surgical patient arrived in the SICU. This was dubbed the ABCs of safe handoff with roles for the anesthesia provider or respiratory therapist, the circulating nurse and SICU nurse, and the anesthesia provider. A graphic representation explains the mnemonic, the roles created, and laminated copies were distributed throughout the OR and SICU (Figure). Subsequent surveys showed 80% of staff felt more like a team with the new process.
Conclusion
The overall impact of the project has been to further promote a culture of patient safety at the Memphis VAMC and establish continuity of care as an institutional priority. The existing handoff sheet, time-out, and cross-check have been adapted to all hospital-wide transfers. With the SPHOC guidance and expertise, PACU began using a handoff sheet and time-out when transferring patients to the medical/surgical floors. The handoff sheet has also been adapted to fit the needs of transfers from the emergency department to the medical/surgical floors.
The framework of a standardized handoff is adaptable for other units to customize and has been adopted hospital-wide. The project is sustainable as it requires almost no money to create and sustain. The primary weakness of the process is the requirement of sustained staff participation and buy-in. Each unit and hospital invariably comes with a different culture and priorities; therefore, the process developed at Memphis VAMC may not meet the needs of other facilities. ˜
Acknowledgments
Special thanks to Susan Baldwin, RN; Bianca Mathews, MSN, RN; Wendy Regel, RN; Armance White, CRNA; Reginald Witt, MD; Odie Powell, RN; Alma Farris, RN; Clarisa Reed, RN; Susan Baily, RN; Linda Sueing, RN; Teresa Nguyen, RN; and John Craig, DNP, CRNA.
1. The Joint Commission. Topic library item: sentinel event policy and procedures.. http://www .jointcommission.org/Sentinel_Event_Policy _and_Procedures. Updated October 14, 2016. Accessed February 14, 2017.
2. Streitenberger K, Breen-Reid K, Harris C. Handoffs in care—can we make them safer? Pediatr Clin N Am. 2006;53(6):1185-1195.
3. Petrovic MA, Aboumatar H, Baumgartner WA, et al. Pilot implementation of a perioperative protocol to guide operating room-to-intensive care unit patient handoffs. J Cardiothorac Vasc Anesth. 2012;26(1):11-16.
4. U.S. Department of Veteran Affairs. VA national center for patient safety. http://www.patientsafety .va.gov/about/index.asp . Updated June 3, 2015. Accessed February 14, 2017.
5. Melnyk BM, Fineout-Overholt E. Evidence-Based Practice in Nursing & Healthcare: A Guide to Best Practice. Philadelphia, PA: Lippincott Williams & Wilkins; 2011.
6. Hudson CC, McDonald B, Hudson JK, Tran D, Boodhwani M. Impact of anesthetic handover on mortality and morbidity in cardiac surgery: a cohort study. J Cardiothorac Vasc Anesth. 2015;29(1):11-16.
7. Lane-Fall MB, Beidas RS, Pascual JL, et al. Handoffs and transitions in critical care (HATRICC): protocol for a mixed methods study of operating room to intensive care unit handoffs. BMC Surg. 2012;14:96.
8. Nagpal K, Arora S, Abboudi M, et al. Postoperative handover: problems, pitfalls, and prevention of error. Ann Surg. 2010;252(1):171-176.
9. Petrovic MA, Martinez EA, Aboumatar H. Implementing a perioperative handoff tool to improve postprocedural patient transfers. Jt Comm J Qual Patient Saf. 2012;38(3):135-142.
10. Segall N, Bonifacio AS, Schroeder RA, et al; Durham VA Patient Safety Center of Inquiry. Can we make postoperative patient handovers safer? A systematic review of the literature. Anesth Analg. 2012;115(1):102-115.
11. Riesenberg LA, Leitzsch J, Little BW. Systematic review of handoff mnemonics literature. Am J Med Qual. 2009;24(3):196-204.
12. Arora V, Johnson J. A model for building a standardized hand-off protocol. Jt Comm J Qual Patient Saf. 206;32(11):646-655.
13. Riesenberg LA, Leitzsch J, Cunningham JM. Nursing handoffs: a systematic review of the literature. Am J Nurse. 2010;110(4):24-34.
14. Catchpole KR, de Leval MR, McEwan A, et al. Patient handover from surgery to intensive care: using Formula 1 pit‐stop and aviation models to improve safety and quality. Paediatr Anesth. 2007;17(5):470-478.
15. Wahr JA, Prager RL, Abernathy JH III, et al; American Heart Association Council on Cardiovascular Surgery and Anesthesia, Council on Cardiovascular and Stroke Nursing, and Council on Quality of Care and Outcomes Research. Patient safety in the cardiac operating room: human factors and teamwork: a scientific statement from the American Heart Association. Circulation. 2013;128(10):1139-1169.
16. Zavalkoff SR, Razack SI, Lavoie J, Dancea AB. Handover after pediatric heart surgery: a simple tool improves information exchange. Pediatr Crit Care Med. 2011;12(3):309-313.
1. The Joint Commission. Topic library item: sentinel event policy and procedures.. http://www .jointcommission.org/Sentinel_Event_Policy _and_Procedures. Updated October 14, 2016. Accessed February 14, 2017.
2. Streitenberger K, Breen-Reid K, Harris C. Handoffs in care—can we make them safer? Pediatr Clin N Am. 2006;53(6):1185-1195.
3. Petrovic MA, Aboumatar H, Baumgartner WA, et al. Pilot implementation of a perioperative protocol to guide operating room-to-intensive care unit patient handoffs. J Cardiothorac Vasc Anesth. 2012;26(1):11-16.
4. U.S. Department of Veteran Affairs. VA national center for patient safety. http://www.patientsafety .va.gov/about/index.asp . Updated June 3, 2015. Accessed February 14, 2017.
5. Melnyk BM, Fineout-Overholt E. Evidence-Based Practice in Nursing & Healthcare: A Guide to Best Practice. Philadelphia, PA: Lippincott Williams & Wilkins; 2011.
6. Hudson CC, McDonald B, Hudson JK, Tran D, Boodhwani M. Impact of anesthetic handover on mortality and morbidity in cardiac surgery: a cohort study. J Cardiothorac Vasc Anesth. 2015;29(1):11-16.
7. Lane-Fall MB, Beidas RS, Pascual JL, et al. Handoffs and transitions in critical care (HATRICC): protocol for a mixed methods study of operating room to intensive care unit handoffs. BMC Surg. 2012;14:96.
8. Nagpal K, Arora S, Abboudi M, et al. Postoperative handover: problems, pitfalls, and prevention of error. Ann Surg. 2010;252(1):171-176.
9. Petrovic MA, Martinez EA, Aboumatar H. Implementing a perioperative handoff tool to improve postprocedural patient transfers. Jt Comm J Qual Patient Saf. 2012;38(3):135-142.
10. Segall N, Bonifacio AS, Schroeder RA, et al; Durham VA Patient Safety Center of Inquiry. Can we make postoperative patient handovers safer? A systematic review of the literature. Anesth Analg. 2012;115(1):102-115.
11. Riesenberg LA, Leitzsch J, Little BW. Systematic review of handoff mnemonics literature. Am J Med Qual. 2009;24(3):196-204.
12. Arora V, Johnson J. A model for building a standardized hand-off protocol. Jt Comm J Qual Patient Saf. 206;32(11):646-655.
13. Riesenberg LA, Leitzsch J, Cunningham JM. Nursing handoffs: a systematic review of the literature. Am J Nurse. 2010;110(4):24-34.
14. Catchpole KR, de Leval MR, McEwan A, et al. Patient handover from surgery to intensive care: using Formula 1 pit‐stop and aviation models to improve safety and quality. Paediatr Anesth. 2007;17(5):470-478.
15. Wahr JA, Prager RL, Abernathy JH III, et al; American Heart Association Council on Cardiovascular Surgery and Anesthesia, Council on Cardiovascular and Stroke Nursing, and Council on Quality of Care and Outcomes Research. Patient safety in the cardiac operating room: human factors and teamwork: a scientific statement from the American Heart Association. Circulation. 2013;128(10):1139-1169.
16. Zavalkoff SR, Razack SI, Lavoie J, Dancea AB. Handover after pediatric heart surgery: a simple tool improves information exchange. Pediatr Crit Care Med. 2011;12(3):309-313.
Pathogenesis of breast-implant-associated ALCL
SAN FRANCISCO—A small study suggests an abnormal immune response characterized by the production of interleukin-13 (IL-13) underlies the pathogenesis of breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).
The immune response appears to be directed toward bacterial antigens on the surface of the breast implants.
Marshall E. Kadin, MD, of Roger Williams Medical Center in Providence, Rhode Island, presented these findings at the 9th Annual T-cell Lymphoma Forum.
Dr Kadin noted that BIA-ALCL is a rare type of CD30+ T-cell ALCL that has been reported in more than 200 women worldwide.
Although a cause-and-effect relationship between breast implants and BIA-ALCL has been suggested, the underlying pathogenesis of this malignancy is unclear.
A bacterial biofilm containing gram-negative bacilli has been detected in breast implants from patients with BIA-ALCL.
Therefore, Dr Kadin and his colleagues hypothesized that an immune response toward the bacterial antigens may mediate the pathogenesis of BIA-ALCL.
The researchers studied 13 clinical samples of breast implant capsules and regional lymph nodes from 4 patients with BIA-ALCL, 7 patients with systemic ALCL, and 1 patient with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS).
Immunohistochemistry was used to determine the presence of IL-13, IL-4, GATA3, and immunoglobulin E (IgE) in these samples.
All clinical samples of anaplastic cells from breast implant capsules tested positive for the presence of IL-13 (13/13). GATA3 was expressed in most anaplastic cell samples (12/13), and IL-4 expression was found in some anaplastic cell samples (6/13). IL-13 and GATA3 expression were observed in some intra-capsular small lymphocytes.
While IL-13 was also detected in BIA-ALCL cell lines, it was not found in 4 of the 7 systemic ALCL cases or the PTCL-NOS case.
Dr Kadin said the lack of IL-13 receptor expression in BIA-ALCL cell lines suggests that IL-13 is not an autocrine growth factor for BIA-ALCL, and its expression is most likely associated with an allergic immune response.
IL-13 is known to induce immunoglobulin class switching in plasma cells to produce IgE. H&E and Giemsa staining of the BIA-ALCL tumor tissue and involved regional lymph nodes revealed IgE and eosinophils on the surface of mast cells and follicular dendritic cells.
Taken together, these data point to an allergic reaction in breast implant capsules of BIA-ALCL.
Dr Kadin was hopeful that these findings could be extrapolated to prevent BIA-ALCL by identifying individuals at higher risk for developing the disease.
The next step for this research is to decipher the role of bacterial antigens in mediating the immune response and whether women who develop BIA-ALCL have a significant increase in other atopic conditions. 
SAN FRANCISCO—A small study suggests an abnormal immune response characterized by the production of interleukin-13 (IL-13) underlies the pathogenesis of breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).
The immune response appears to be directed toward bacterial antigens on the surface of the breast implants.
Marshall E. Kadin, MD, of Roger Williams Medical Center in Providence, Rhode Island, presented these findings at the 9th Annual T-cell Lymphoma Forum.
Dr Kadin noted that BIA-ALCL is a rare type of CD30+ T-cell ALCL that has been reported in more than 200 women worldwide.
Although a cause-and-effect relationship between breast implants and BIA-ALCL has been suggested, the underlying pathogenesis of this malignancy is unclear.
A bacterial biofilm containing gram-negative bacilli has been detected in breast implants from patients with BIA-ALCL.
Therefore, Dr Kadin and his colleagues hypothesized that an immune response toward the bacterial antigens may mediate the pathogenesis of BIA-ALCL.
The researchers studied 13 clinical samples of breast implant capsules and regional lymph nodes from 4 patients with BIA-ALCL, 7 patients with systemic ALCL, and 1 patient with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS).
Immunohistochemistry was used to determine the presence of IL-13, IL-4, GATA3, and immunoglobulin E (IgE) in these samples.
All clinical samples of anaplastic cells from breast implant capsules tested positive for the presence of IL-13 (13/13). GATA3 was expressed in most anaplastic cell samples (12/13), and IL-4 expression was found in some anaplastic cell samples (6/13). IL-13 and GATA3 expression were observed in some intra-capsular small lymphocytes.
While IL-13 was also detected in BIA-ALCL cell lines, it was not found in 4 of the 7 systemic ALCL cases or the PTCL-NOS case.
Dr Kadin said the lack of IL-13 receptor expression in BIA-ALCL cell lines suggests that IL-13 is not an autocrine growth factor for BIA-ALCL, and its expression is most likely associated with an allergic immune response.
IL-13 is known to induce immunoglobulin class switching in plasma cells to produce IgE. H&E and Giemsa staining of the BIA-ALCL tumor tissue and involved regional lymph nodes revealed IgE and eosinophils on the surface of mast cells and follicular dendritic cells.
Taken together, these data point to an allergic reaction in breast implant capsules of BIA-ALCL.
Dr Kadin was hopeful that these findings could be extrapolated to prevent BIA-ALCL by identifying individuals at higher risk for developing the disease.
The next step for this research is to decipher the role of bacterial antigens in mediating the immune response and whether women who develop BIA-ALCL have a significant increase in other atopic conditions.
SAN FRANCISCO—A small study suggests an abnormal immune response characterized by the production of interleukin-13 (IL-13) underlies the pathogenesis of breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).
The immune response appears to be directed toward bacterial antigens on the surface of the breast implants.
Marshall E. Kadin, MD, of Roger Williams Medical Center in Providence, Rhode Island, presented these findings at the 9th Annual T-cell Lymphoma Forum.
Dr Kadin noted that BIA-ALCL is a rare type of CD30+ T-cell ALCL that has been reported in more than 200 women worldwide.
Although a cause-and-effect relationship between breast implants and BIA-ALCL has been suggested, the underlying pathogenesis of this malignancy is unclear.
A bacterial biofilm containing gram-negative bacilli has been detected in breast implants from patients with BIA-ALCL.
Therefore, Dr Kadin and his colleagues hypothesized that an immune response toward the bacterial antigens may mediate the pathogenesis of BIA-ALCL.
The researchers studied 13 clinical samples of breast implant capsules and regional lymph nodes from 4 patients with BIA-ALCL, 7 patients with systemic ALCL, and 1 patient with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS).
Immunohistochemistry was used to determine the presence of IL-13, IL-4, GATA3, and immunoglobulin E (IgE) in these samples.
All clinical samples of anaplastic cells from breast implant capsules tested positive for the presence of IL-13 (13/13). GATA3 was expressed in most anaplastic cell samples (12/13), and IL-4 expression was found in some anaplastic cell samples (6/13). IL-13 and GATA3 expression were observed in some intra-capsular small lymphocytes.
While IL-13 was also detected in BIA-ALCL cell lines, it was not found in 4 of the 7 systemic ALCL cases or the PTCL-NOS case.
Dr Kadin said the lack of IL-13 receptor expression in BIA-ALCL cell lines suggests that IL-13 is not an autocrine growth factor for BIA-ALCL, and its expression is most likely associated with an allergic immune response.
IL-13 is known to induce immunoglobulin class switching in plasma cells to produce IgE. H&E and Giemsa staining of the BIA-ALCL tumor tissue and involved regional lymph nodes revealed IgE and eosinophils on the surface of mast cells and follicular dendritic cells.
Taken together, these data point to an allergic reaction in breast implant capsules of BIA-ALCL.
Dr Kadin was hopeful that these findings could be extrapolated to prevent BIA-ALCL by identifying individuals at higher risk for developing the disease.
The next step for this research is to decipher the role of bacterial antigens in mediating the immune response and whether women who develop BIA-ALCL have a significant increase in other atopic conditions.
Study reveals higher rate of early death in kids with cancer
New research suggests that, in the US, early deaths from childhood cancer may be more common than clinical trials suggest.
Researchers found the rate of death within 1 month of diagnosis was higher among patients included in a large national database than among patients enrolled in phase 3 trials.
The data also indicated that early death is more likely in cancer patients under the age of 1 and those belonging to minority racial and ethnic groups.
Adam Green, MD, of the University of Colorado Anschutz Medical Campus in Aurora, and his colleagues conducted this research and reported the results in the Journal of Clinical Oncology.
The researchers analyzed data from the Surveillance, Epidemiology and End Results (SEER) database, which collects about 15% of all cancer outcomes across the US (representing a geographic and socioeconomic cross-section).
The team identified 36,337 patients with pediatric cancer (ages 0 to 19) diagnosed between 1992 and 2011. Of these patients, 555 (1.5%) died within 1 month of diagnosis.
Young age
Overall, the strongest predictor of early death was age below 1 year. The odds ratio (OR) was 4.36 for these patients (P<0.001), 0.75 for patients age 1 to 4, 0.78 for patients age 5 to 9, 1.00 (reference) for those age 10 to 14, and 1.69 for those age 15 to 19.
For hematologic malignancies, the adjusted OR (adjusted by poverty, unemployment, education, and year of diagnosis) was 4.32 for patients younger than 1 (P<0.001), 0.76 for patients age 1 to 4, 0.79 for patients age 5 to 9, 1.00 for those age 10 to 14, and 1.76 for those age 15 to 19 (P=0.002).
“In general, babies are just challenging, clinically, because they can’t tell you what they’re feeling,” Dr Green noted. “Parents and physicians have to pick the ones with cancer from the ones with a cold, without the patient being able to tell you about symptoms that could be diagnostic.”
“Babies tend to get aggressive cancers, it’s hard to tell when they’re getting sick, and some are even born with cancers that have already progressed. These factors combine to make very young age the strongest predictor of early death in our study.”
Race/ethnicity
Black race and Hispanic ethnicity also predicted early death. The OR was 1.48 for black race, 1.00 for white race (reference), and 1.09 for “other” races (P=0.102). The OR was 1.39 for Hispanic patients and 1.00 (reference) for non-Hispanic patients (P=0.007).
For hematologic malignancies, the adjusted OR was 1.68 for black patients (P=0.01) and 1.44 for patients of other, non-white races. The adjusted OR was 1.48 for Hispanic patients (P=0.009).
Dr Green said he hopes future studies will be able to determine the factors responsible for these disparities.
Higher death rates
Dr Green and his colleagues also found the rate of early death due to pediatric cancers is higher than reported in clinical trials, and this was true for all cancer subtypes assessed.
“Most of what we know about outcomes for cancer patients come from clinical trials, which have much more thorough reporting rules than cancer treated outside trials,” Dr Green said. “However, these kids in our study aren’t surviving long enough to join clinical trials.”
The researchers looked at a phase 3 trial (COG AAML0531) of pediatric patients with acute myeloid leukemia (AML) who were studied from August 2006 to June 2010. The early death rate in this trial was 1.6% (16/1022).
In contrast, the SEER database showed an early death rate for pediatric AML patients of 5.9% (15/256) during the same period as the trial and 6.2% (106/1698) for the period from 1992 to 2011. This is almost 4 times as high as the death rate in the trial.
The same effect was observed for acute lymphoblastic leukemia (ALL).
The early death rate for non-infant ALL was 0.7% (13/1790) in a trial (POG 9900) conducted from April 2000 to April 2005, 1.6% (30/1823) in the SEER data covering the same time period, and 1.3% (94/7353) in the SEER data from 1992 to 2011.
For infant ALL, the rates were 2.0% (3/149) in a trial (COG AALL0631) conducted from January 2008 to June 2014, 5.0% (2/40) in the SEER data during the trial period, and 5.4% (12/223) in the SEER data from 1992 to 2011.
“I had a hunch this was a bigger problem than we thought,” Dr Green said. “Now we see that is indeed the case.”
New research suggests that, in the US, early deaths from childhood cancer may be more common than clinical trials suggest.
Researchers found the rate of death within 1 month of diagnosis was higher among patients included in a large national database than among patients enrolled in phase 3 trials.
The data also indicated that early death is more likely in cancer patients under the age of 1 and those belonging to minority racial and ethnic groups.
Adam Green, MD, of the University of Colorado Anschutz Medical Campus in Aurora, and his colleagues conducted this research and reported the results in the Journal of Clinical Oncology.
The researchers analyzed data from the Surveillance, Epidemiology and End Results (SEER) database, which collects about 15% of all cancer outcomes across the US (representing a geographic and socioeconomic cross-section).
The team identified 36,337 patients with pediatric cancer (ages 0 to 19) diagnosed between 1992 and 2011. Of these patients, 555 (1.5%) died within 1 month of diagnosis.
Young age
Overall, the strongest predictor of early death was age below 1 year. The odds ratio (OR) was 4.36 for these patients (P<0.001), 0.75 for patients age 1 to 4, 0.78 for patients age 5 to 9, 1.00 (reference) for those age 10 to 14, and 1.69 for those age 15 to 19.
For hematologic malignancies, the adjusted OR (adjusted by poverty, unemployment, education, and year of diagnosis) was 4.32 for patients younger than 1 (P<0.001), 0.76 for patients age 1 to 4, 0.79 for patients age 5 to 9, 1.00 for those age 10 to 14, and 1.76 for those age 15 to 19 (P=0.002).
“In general, babies are just challenging, clinically, because they can’t tell you what they’re feeling,” Dr Green noted. “Parents and physicians have to pick the ones with cancer from the ones with a cold, without the patient being able to tell you about symptoms that could be diagnostic.”
“Babies tend to get aggressive cancers, it’s hard to tell when they’re getting sick, and some are even born with cancers that have already progressed. These factors combine to make very young age the strongest predictor of early death in our study.”
Race/ethnicity
Black race and Hispanic ethnicity also predicted early death. The OR was 1.48 for black race, 1.00 for white race (reference), and 1.09 for “other” races (P=0.102). The OR was 1.39 for Hispanic patients and 1.00 (reference) for non-Hispanic patients (P=0.007).
For hematologic malignancies, the adjusted OR was 1.68 for black patients (P=0.01) and 1.44 for patients of other, non-white races. The adjusted OR was 1.48 for Hispanic patients (P=0.009).
Dr Green said he hopes future studies will be able to determine the factors responsible for these disparities.
Higher death rates
Dr Green and his colleagues also found the rate of early death due to pediatric cancers is higher than reported in clinical trials, and this was true for all cancer subtypes assessed.
“Most of what we know about outcomes for cancer patients come from clinical trials, which have much more thorough reporting rules than cancer treated outside trials,” Dr Green said. “However, these kids in our study aren’t surviving long enough to join clinical trials.”
The researchers looked at a phase 3 trial (COG AAML0531) of pediatric patients with acute myeloid leukemia (AML) who were studied from August 2006 to June 2010. The early death rate in this trial was 1.6% (16/1022).
In contrast, the SEER database showed an early death rate for pediatric AML patients of 5.9% (15/256) during the same period as the trial and 6.2% (106/1698) for the period from 1992 to 2011. This is almost 4 times as high as the death rate in the trial.
The same effect was observed for acute lymphoblastic leukemia (ALL).
The early death rate for non-infant ALL was 0.7% (13/1790) in a trial (POG 9900) conducted from April 2000 to April 2005, 1.6% (30/1823) in the SEER data covering the same time period, and 1.3% (94/7353) in the SEER data from 1992 to 2011.
For infant ALL, the rates were 2.0% (3/149) in a trial (COG AALL0631) conducted from January 2008 to June 2014, 5.0% (2/40) in the SEER data during the trial period, and 5.4% (12/223) in the SEER data from 1992 to 2011.
“I had a hunch this was a bigger problem than we thought,” Dr Green said. “Now we see that is indeed the case.”
New research suggests that, in the US, early deaths from childhood cancer may be more common than clinical trials suggest.
Researchers found the rate of death within 1 month of diagnosis was higher among patients included in a large national database than among patients enrolled in phase 3 trials.
The data also indicated that early death is more likely in cancer patients under the age of 1 and those belonging to minority racial and ethnic groups.
Adam Green, MD, of the University of Colorado Anschutz Medical Campus in Aurora, and his colleagues conducted this research and reported the results in the Journal of Clinical Oncology.
The researchers analyzed data from the Surveillance, Epidemiology and End Results (SEER) database, which collects about 15% of all cancer outcomes across the US (representing a geographic and socioeconomic cross-section).
The team identified 36,337 patients with pediatric cancer (ages 0 to 19) diagnosed between 1992 and 2011. Of these patients, 555 (1.5%) died within 1 month of diagnosis.
Young age
Overall, the strongest predictor of early death was age below 1 year. The odds ratio (OR) was 4.36 for these patients (P<0.001), 0.75 for patients age 1 to 4, 0.78 for patients age 5 to 9, 1.00 (reference) for those age 10 to 14, and 1.69 for those age 15 to 19.
For hematologic malignancies, the adjusted OR (adjusted by poverty, unemployment, education, and year of diagnosis) was 4.32 for patients younger than 1 (P<0.001), 0.76 for patients age 1 to 4, 0.79 for patients age 5 to 9, 1.00 for those age 10 to 14, and 1.76 for those age 15 to 19 (P=0.002).
“In general, babies are just challenging, clinically, because they can’t tell you what they’re feeling,” Dr Green noted. “Parents and physicians have to pick the ones with cancer from the ones with a cold, without the patient being able to tell you about symptoms that could be diagnostic.”
“Babies tend to get aggressive cancers, it’s hard to tell when they’re getting sick, and some are even born with cancers that have already progressed. These factors combine to make very young age the strongest predictor of early death in our study.”
Race/ethnicity
Black race and Hispanic ethnicity also predicted early death. The OR was 1.48 for black race, 1.00 for white race (reference), and 1.09 for “other” races (P=0.102). The OR was 1.39 for Hispanic patients and 1.00 (reference) for non-Hispanic patients (P=0.007).
For hematologic malignancies, the adjusted OR was 1.68 for black patients (P=0.01) and 1.44 for patients of other, non-white races. The adjusted OR was 1.48 for Hispanic patients (P=0.009).
Dr Green said he hopes future studies will be able to determine the factors responsible for these disparities.
Higher death rates
Dr Green and his colleagues also found the rate of early death due to pediatric cancers is higher than reported in clinical trials, and this was true for all cancer subtypes assessed.
“Most of what we know about outcomes for cancer patients come from clinical trials, which have much more thorough reporting rules than cancer treated outside trials,” Dr Green said. “However, these kids in our study aren’t surviving long enough to join clinical trials.”
The researchers looked at a phase 3 trial (COG AAML0531) of pediatric patients with acute myeloid leukemia (AML) who were studied from August 2006 to June 2010. The early death rate in this trial was 1.6% (16/1022).
In contrast, the SEER database showed an early death rate for pediatric AML patients of 5.9% (15/256) during the same period as the trial and 6.2% (106/1698) for the period from 1992 to 2011. This is almost 4 times as high as the death rate in the trial.
The same effect was observed for acute lymphoblastic leukemia (ALL).
The early death rate for non-infant ALL was 0.7% (13/1790) in a trial (POG 9900) conducted from April 2000 to April 2005, 1.6% (30/1823) in the SEER data covering the same time period, and 1.3% (94/7353) in the SEER data from 1992 to 2011.
For infant ALL, the rates were 2.0% (3/149) in a trial (COG AALL0631) conducted from January 2008 to June 2014, 5.0% (2/40) in the SEER data during the trial period, and 5.4% (12/223) in the SEER data from 1992 to 2011.
“I had a hunch this was a bigger problem than we thought,” Dr Green said. “Now we see that is indeed the case.”
Gene therapy proves effective in SCD patient
Researchers have reported a favorable outcome in the first patient with severe sickle cell disease (SCD) to receive gene therapy in the HGB-205 study.
The subject, known as Patient 1204, was treated with LentiGlobin BB305, a product consisting of his own manipulated hematopoietic stem cells (HSCs).
A functional human β-globin gene was inserted into the patient’s HSCs ex vivo, and the cells were returned to him via transplant.
Fifteen months after receiving this treatment, Patient 1204 had high levels of anti-sickling hemoglobin (HbAT87Q), and there were no adverse events thought to be related to LentiGlobin BB305.
These results were published in NEJM. The research was supported by bluebird bio, the company developing LentiGlobin BB305.
Patient 1204 is a male with βS/βS genotype. In May 2014, at 13 years of age, the patient was enrolled in the HGB-205 study at Hôpital Necker-Enfants Malades in Paris, France.
The patient had received hydroxyurea from age 2 to 9 and had both a cholecystectomy and a splenectomy. He received regular transfusions (plus iron chelation with deferasirox) for 4 years prior to this study.
The patient had an average of 1.6 SCD-related events annually in the 9 years prior to starting transfusions. His complications from SCD included vaso-occlusive crises, acute-chest syndrome, bilateral hip osteonecrosis, and cerebral vasculopathy.
The patient underwent 2 bone marrow harvests to collect HSCs for gene transfer and back-up (6.2×108 and 5.4×108 total nucleated cells/kg harvested).
CD34+ cells were enriched from the harvested marrow and then transduced with LentiGlobin BB305 lentiviral vector.
The patient underwent myeloablation with intravenous busulfan (2.3 to 4.8 mg/kg per day for 4 days) with daily pharmacokinetic studies and dose adjustment. Total busulfan area under the curve was 19,363 μmol/min.
After a 2-day washout, the patient received LentiGlobin BB305 in October 2014 at a post-thaw total dose of 5.6×106 CD34+ cells/kg. Neutrophil and platelet engraftment were achieved on day 38 and day 91 post-transplant, respectively.
Red blood cell transfusions were to be continued after transplant until a sufficient proportion of HbAT87Q (25% to 30% of total hemoglobin) was detected. Transfusions were discontinued after day 88 post-transplant.
HbAT87Q reached 5.5 g/dL (46% of total hemoglobin) at month 9 and continued to increase to 5.7 g/dL at month 15 (48%). Hemoglobin S levels were 5.5 g/dL (46%) at month 9 and 5.8 g/dL (49%) at month 15.
Total hemoglobin levels were stable, between 10.6 and 12.0 g/dL, from months 6 to 15. Fetal hemoglobin levels remained below 1.0 g/dL.
No adverse events related to LentiGlobin BB305 were reported. There were, however, adverse events related to busulfan conditioning (grade 3 anemia, thrombocytopenia, and infection; grade 4 neutropenia).
During 15 months of follow-up, there were no SCD-related clinical events or hospitalizations. The patient was able to stop all medications, including pain medication.
The patient resumed regular school attendance and reported full participation in normal physical activities.
“We have managed this patient at Necker for more than 10 years, and standard treatments were not able to control his SCD symptoms,” said Marina Cavazzana, MD, PhD, of Hôpital Necker-Enfants Malades.
“He had to receive blood transfusions every month to prevent severe pain crises. Since receiving the autologous stem cell transplant with LentiGlobin, he has been free from severe symptoms and has resumed normal activities, without the need for further transfusions.”
Researchers have reported a favorable outcome in the first patient with severe sickle cell disease (SCD) to receive gene therapy in the HGB-205 study.
The subject, known as Patient 1204, was treated with LentiGlobin BB305, a product consisting of his own manipulated hematopoietic stem cells (HSCs).
A functional human β-globin gene was inserted into the patient’s HSCs ex vivo, and the cells were returned to him via transplant.
Fifteen months after receiving this treatment, Patient 1204 had high levels of anti-sickling hemoglobin (HbAT87Q), and there were no adverse events thought to be related to LentiGlobin BB305.
These results were published in NEJM. The research was supported by bluebird bio, the company developing LentiGlobin BB305.
Patient 1204 is a male with βS/βS genotype. In May 2014, at 13 years of age, the patient was enrolled in the HGB-205 study at Hôpital Necker-Enfants Malades in Paris, France.
The patient had received hydroxyurea from age 2 to 9 and had both a cholecystectomy and a splenectomy. He received regular transfusions (plus iron chelation with deferasirox) for 4 years prior to this study.
The patient had an average of 1.6 SCD-related events annually in the 9 years prior to starting transfusions. His complications from SCD included vaso-occlusive crises, acute-chest syndrome, bilateral hip osteonecrosis, and cerebral vasculopathy.
The patient underwent 2 bone marrow harvests to collect HSCs for gene transfer and back-up (6.2×108 and 5.4×108 total nucleated cells/kg harvested).
CD34+ cells were enriched from the harvested marrow and then transduced with LentiGlobin BB305 lentiviral vector.
The patient underwent myeloablation with intravenous busulfan (2.3 to 4.8 mg/kg per day for 4 days) with daily pharmacokinetic studies and dose adjustment. Total busulfan area under the curve was 19,363 μmol/min.
After a 2-day washout, the patient received LentiGlobin BB305 in October 2014 at a post-thaw total dose of 5.6×106 CD34+ cells/kg. Neutrophil and platelet engraftment were achieved on day 38 and day 91 post-transplant, respectively.
Red blood cell transfusions were to be continued after transplant until a sufficient proportion of HbAT87Q (25% to 30% of total hemoglobin) was detected. Transfusions were discontinued after day 88 post-transplant.
HbAT87Q reached 5.5 g/dL (46% of total hemoglobin) at month 9 and continued to increase to 5.7 g/dL at month 15 (48%). Hemoglobin S levels were 5.5 g/dL (46%) at month 9 and 5.8 g/dL (49%) at month 15.
Total hemoglobin levels were stable, between 10.6 and 12.0 g/dL, from months 6 to 15. Fetal hemoglobin levels remained below 1.0 g/dL.
No adverse events related to LentiGlobin BB305 were reported. There were, however, adverse events related to busulfan conditioning (grade 3 anemia, thrombocytopenia, and infection; grade 4 neutropenia).
During 15 months of follow-up, there were no SCD-related clinical events or hospitalizations. The patient was able to stop all medications, including pain medication.
The patient resumed regular school attendance and reported full participation in normal physical activities.
“We have managed this patient at Necker for more than 10 years, and standard treatments were not able to control his SCD symptoms,” said Marina Cavazzana, MD, PhD, of Hôpital Necker-Enfants Malades.
“He had to receive blood transfusions every month to prevent severe pain crises. Since receiving the autologous stem cell transplant with LentiGlobin, he has been free from severe symptoms and has resumed normal activities, without the need for further transfusions.”
Researchers have reported a favorable outcome in the first patient with severe sickle cell disease (SCD) to receive gene therapy in the HGB-205 study.
The subject, known as Patient 1204, was treated with LentiGlobin BB305, a product consisting of his own manipulated hematopoietic stem cells (HSCs).
A functional human β-globin gene was inserted into the patient’s HSCs ex vivo, and the cells were returned to him via transplant.
Fifteen months after receiving this treatment, Patient 1204 had high levels of anti-sickling hemoglobin (HbAT87Q), and there were no adverse events thought to be related to LentiGlobin BB305.
These results were published in NEJM. The research was supported by bluebird bio, the company developing LentiGlobin BB305.
Patient 1204 is a male with βS/βS genotype. In May 2014, at 13 years of age, the patient was enrolled in the HGB-205 study at Hôpital Necker-Enfants Malades in Paris, France.
The patient had received hydroxyurea from age 2 to 9 and had both a cholecystectomy and a splenectomy. He received regular transfusions (plus iron chelation with deferasirox) for 4 years prior to this study.
The patient had an average of 1.6 SCD-related events annually in the 9 years prior to starting transfusions. His complications from SCD included vaso-occlusive crises, acute-chest syndrome, bilateral hip osteonecrosis, and cerebral vasculopathy.
The patient underwent 2 bone marrow harvests to collect HSCs for gene transfer and back-up (6.2×108 and 5.4×108 total nucleated cells/kg harvested).
CD34+ cells were enriched from the harvested marrow and then transduced with LentiGlobin BB305 lentiviral vector.
The patient underwent myeloablation with intravenous busulfan (2.3 to 4.8 mg/kg per day for 4 days) with daily pharmacokinetic studies and dose adjustment. Total busulfan area under the curve was 19,363 μmol/min.
After a 2-day washout, the patient received LentiGlobin BB305 in October 2014 at a post-thaw total dose of 5.6×106 CD34+ cells/kg. Neutrophil and platelet engraftment were achieved on day 38 and day 91 post-transplant, respectively.
Red blood cell transfusions were to be continued after transplant until a sufficient proportion of HbAT87Q (25% to 30% of total hemoglobin) was detected. Transfusions were discontinued after day 88 post-transplant.
HbAT87Q reached 5.5 g/dL (46% of total hemoglobin) at month 9 and continued to increase to 5.7 g/dL at month 15 (48%). Hemoglobin S levels were 5.5 g/dL (46%) at month 9 and 5.8 g/dL (49%) at month 15.
Total hemoglobin levels were stable, between 10.6 and 12.0 g/dL, from months 6 to 15. Fetal hemoglobin levels remained below 1.0 g/dL.
No adverse events related to LentiGlobin BB305 were reported. There were, however, adverse events related to busulfan conditioning (grade 3 anemia, thrombocytopenia, and infection; grade 4 neutropenia).
During 15 months of follow-up, there were no SCD-related clinical events or hospitalizations. The patient was able to stop all medications, including pain medication.
The patient resumed regular school attendance and reported full participation in normal physical activities.
“We have managed this patient at Necker for more than 10 years, and standard treatments were not able to control his SCD symptoms,” said Marina Cavazzana, MD, PhD, of Hôpital Necker-Enfants Malades.
“He had to receive blood transfusions every month to prevent severe pain crises. Since receiving the autologous stem cell transplant with LentiGlobin, he has been free from severe symptoms and has resumed normal activities, without the need for further transfusions.”