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Routine screening for AAA in older men may harm more than help
Deaths from abdominal aortic aneurysm among Swedish men are going down – but not because they’re being screened for the potentially fatal condition.
Although the death rate has decreased by 70% since the early 2000s, screening only saved 2 lives per 10,000 men screened. It did, however, increase by 59% the risk of unnecessary surgery, Minna Johansson, MD, and colleagues wrote in the June 16 issue of the Lancet.
“Screening had only a minor effect on AAA mortality,” wrote Dr. Johansson of the University of Gothenburg (Sweden). “In absolute numbers, only 7% of the benefit estimated in the largest trial of AAA screening was observed. The observed large reductions in AAA mortality were present in both the screened and nonscreened cohorts and were thus mainly caused by other factors – probably reduced smoking. … Our results call the continued justification of AAA screening into question.”
In Sweden, all men aged 65 years are invited to a one-time ultrasound abdominal aorta screening. Most participate. Anyone with an aneurysm is followed up at a vascular surgery clinic, with surgery considered if the aortic diameter is 55 mm or larger.
Dr. Johansson and her colleagues plumbed national health records to estimate the risks and benefits of this routine screening. The study comprised 25,265 men invited to join the AAA screening program in Sweden from 2006 to 2009. Mortality data were compared with those from a contemporaneous cohort of 106,087 men of similar age who were not invited to screen. Finally, the mortality data were compared with national trends in AAA mortality in all Swedish men aged 40-99 years from 1987 to 2015.
A multivariate analysis adjusted for cohort year, marital status, educational level, income, and whether the patient already had an AAA diagnosis at baseline.
From the early 2000s to 2015, AAA mortality among men aged 65-74 years declined from 36 to10 deaths per 100,000. This 70% reduction was similar in both screened and unscreened populations; in fact, the decline began about a decade before population-based screening was introduced and continued to decrease at a steady rate afterward.
After 6 years of screening, there was a 30% reduction of AAA mortality in the screened population, compared with the unscreened, translating to an absolute mortality reduction of two deaths per 10,000 men offered screening.
Screening increased by 52% the number of AAAs detected. The absolute difference in incidence after 6 years of screening translated to an additional 49 overdiagnoses per 10,000 screened men.
Looking back into the mid-1990s, the investigators saw the numbers of elective AAA surgeries rise steadily. In the adjusted model, screened men were 59% more likely to have this procedure than unscreened. The increased risk didn’t come with an equally increased benefit, though. There was a 10% decrease in AAA ruptures, “rendering a risk of overtreatment of 19%, or 19 potentially avoidable elective surgeries per 10,000 men,” the team noted. “Sixty-three percent of all additional elective surgeries for AAA might therefore have constituted overtreat.”
The findings are at odds with large published studies that found a consistent benefit to screening.
“Compared with results at 7-year follow-up of the largest trial of screening for abdominal aortic aneurysm [Multicentre Aneurysm Screening Study (MASS)], we found about half of the benefit in terms of a relative effect and 7% of the estimated benefit in terms of absolute numbers [2 vs. 27 avoided deaths from AAA per 10,000 invited men]. Compared with previous estimates of overdiagnosis and overtreatment, we found a lower absolute number of over-diagnosed cases [49 vs.176 per 10,000 invited men] and fewer overtreated cases [19 vs. 37 per 10,000 invited men]. However, since the harms of screening decreased less than the benefit, the balance between benefits and harms seems much less appealing in today’s setting.”
None of the authors had any financial disclosures.
The study by Johansson et al. indicates a significant risk of overdiagnosis associated with routine screening for abdominal aortic aneurysm: Those risks may not be as clinically harmful as might be assumed, Stefan Acosta, MD, wrote in an accompanying editorial (Lancet 2018; 391: 2394-95).
“Although I agree that having a small AAA that needs long-term follow-up might be associated with negative psychological consequences, there could also be a window of opportunity [eg. with statins, antiplatelet therapy, and blood pressure reduction], for individuals with increased burden of cardiovascular disease. Indeed, screening for AAA, peripheral artery disease, and hypertension, with the initiation of relevant pharmacotherapy, if positive, reduces all-cause mortality and some evidence suggests that this approach of multifaceted vascular screening instead of isolated AAA screening should be considered.”
When performed according to the established criteria for elective AAA surgery, the procedure is associated with less than 1% postoperative mortality, “mainly because of wide implementation of endovascular aneurysm repair, a minimally invasive method.”
The 6-year follow-up time, as the authors noted, is relatively short. A 2016 review of the Swedish Nationwide Abdominal Aortic Aneurysm Screening Program determined that significant mortality benefit could take 10 years to materialize(Circ 2016;134:1141-8).
The full impact of Sweden’s remarkable decrease in smoking is almost certainly making itself known in these outcomes – smoking is implicated in 75% of AAA cases.
“The decreased prevalence of smoking in Sweden, from 44% of the population in 1970 to 15% in 2010, should be viewed as the main cause of the decreasing incidence and mortality of AAA. Every percent drop in the prevalence of smoking will have a huge effect on smoking-related diseases, such as cancer and AAA.”
Dr. Stefan is a vascular disease researcher at Lund (Sweden) University. He had no financial disclosures.
The study by Johansson et al. indicates a significant risk of overdiagnosis associated with routine screening for abdominal aortic aneurysm: Those risks may not be as clinically harmful as might be assumed, Stefan Acosta, MD, wrote in an accompanying editorial (Lancet 2018; 391: 2394-95).
“Although I agree that having a small AAA that needs long-term follow-up might be associated with negative psychological consequences, there could also be a window of opportunity [eg. with statins, antiplatelet therapy, and blood pressure reduction], for individuals with increased burden of cardiovascular disease. Indeed, screening for AAA, peripheral artery disease, and hypertension, with the initiation of relevant pharmacotherapy, if positive, reduces all-cause mortality and some evidence suggests that this approach of multifaceted vascular screening instead of isolated AAA screening should be considered.”
When performed according to the established criteria for elective AAA surgery, the procedure is associated with less than 1% postoperative mortality, “mainly because of wide implementation of endovascular aneurysm repair, a minimally invasive method.”
The 6-year follow-up time, as the authors noted, is relatively short. A 2016 review of the Swedish Nationwide Abdominal Aortic Aneurysm Screening Program determined that significant mortality benefit could take 10 years to materialize(Circ 2016;134:1141-8).
The full impact of Sweden’s remarkable decrease in smoking is almost certainly making itself known in these outcomes – smoking is implicated in 75% of AAA cases.
“The decreased prevalence of smoking in Sweden, from 44% of the population in 1970 to 15% in 2010, should be viewed as the main cause of the decreasing incidence and mortality of AAA. Every percent drop in the prevalence of smoking will have a huge effect on smoking-related diseases, such as cancer and AAA.”
Dr. Stefan is a vascular disease researcher at Lund (Sweden) University. He had no financial disclosures.
The study by Johansson et al. indicates a significant risk of overdiagnosis associated with routine screening for abdominal aortic aneurysm: Those risks may not be as clinically harmful as might be assumed, Stefan Acosta, MD, wrote in an accompanying editorial (Lancet 2018; 391: 2394-95).
“Although I agree that having a small AAA that needs long-term follow-up might be associated with negative psychological consequences, there could also be a window of opportunity [eg. with statins, antiplatelet therapy, and blood pressure reduction], for individuals with increased burden of cardiovascular disease. Indeed, screening for AAA, peripheral artery disease, and hypertension, with the initiation of relevant pharmacotherapy, if positive, reduces all-cause mortality and some evidence suggests that this approach of multifaceted vascular screening instead of isolated AAA screening should be considered.”
When performed according to the established criteria for elective AAA surgery, the procedure is associated with less than 1% postoperative mortality, “mainly because of wide implementation of endovascular aneurysm repair, a minimally invasive method.”
The 6-year follow-up time, as the authors noted, is relatively short. A 2016 review of the Swedish Nationwide Abdominal Aortic Aneurysm Screening Program determined that significant mortality benefit could take 10 years to materialize(Circ 2016;134:1141-8).
The full impact of Sweden’s remarkable decrease in smoking is almost certainly making itself known in these outcomes – smoking is implicated in 75% of AAA cases.
“The decreased prevalence of smoking in Sweden, from 44% of the population in 1970 to 15% in 2010, should be viewed as the main cause of the decreasing incidence and mortality of AAA. Every percent drop in the prevalence of smoking will have a huge effect on smoking-related diseases, such as cancer and AAA.”
Dr. Stefan is a vascular disease researcher at Lund (Sweden) University. He had no financial disclosures.
Deaths from abdominal aortic aneurysm among Swedish men are going down – but not because they’re being screened for the potentially fatal condition.
Although the death rate has decreased by 70% since the early 2000s, screening only saved 2 lives per 10,000 men screened. It did, however, increase by 59% the risk of unnecessary surgery, Minna Johansson, MD, and colleagues wrote in the June 16 issue of the Lancet.
“Screening had only a minor effect on AAA mortality,” wrote Dr. Johansson of the University of Gothenburg (Sweden). “In absolute numbers, only 7% of the benefit estimated in the largest trial of AAA screening was observed. The observed large reductions in AAA mortality were present in both the screened and nonscreened cohorts and were thus mainly caused by other factors – probably reduced smoking. … Our results call the continued justification of AAA screening into question.”
In Sweden, all men aged 65 years are invited to a one-time ultrasound abdominal aorta screening. Most participate. Anyone with an aneurysm is followed up at a vascular surgery clinic, with surgery considered if the aortic diameter is 55 mm or larger.
Dr. Johansson and her colleagues plumbed national health records to estimate the risks and benefits of this routine screening. The study comprised 25,265 men invited to join the AAA screening program in Sweden from 2006 to 2009. Mortality data were compared with those from a contemporaneous cohort of 106,087 men of similar age who were not invited to screen. Finally, the mortality data were compared with national trends in AAA mortality in all Swedish men aged 40-99 years from 1987 to 2015.
A multivariate analysis adjusted for cohort year, marital status, educational level, income, and whether the patient already had an AAA diagnosis at baseline.
From the early 2000s to 2015, AAA mortality among men aged 65-74 years declined from 36 to10 deaths per 100,000. This 70% reduction was similar in both screened and unscreened populations; in fact, the decline began about a decade before population-based screening was introduced and continued to decrease at a steady rate afterward.
After 6 years of screening, there was a 30% reduction of AAA mortality in the screened population, compared with the unscreened, translating to an absolute mortality reduction of two deaths per 10,000 men offered screening.
Screening increased by 52% the number of AAAs detected. The absolute difference in incidence after 6 years of screening translated to an additional 49 overdiagnoses per 10,000 screened men.
Looking back into the mid-1990s, the investigators saw the numbers of elective AAA surgeries rise steadily. In the adjusted model, screened men were 59% more likely to have this procedure than unscreened. The increased risk didn’t come with an equally increased benefit, though. There was a 10% decrease in AAA ruptures, “rendering a risk of overtreatment of 19%, or 19 potentially avoidable elective surgeries per 10,000 men,” the team noted. “Sixty-three percent of all additional elective surgeries for AAA might therefore have constituted overtreat.”
The findings are at odds with large published studies that found a consistent benefit to screening.
“Compared with results at 7-year follow-up of the largest trial of screening for abdominal aortic aneurysm [Multicentre Aneurysm Screening Study (MASS)], we found about half of the benefit in terms of a relative effect and 7% of the estimated benefit in terms of absolute numbers [2 vs. 27 avoided deaths from AAA per 10,000 invited men]. Compared with previous estimates of overdiagnosis and overtreatment, we found a lower absolute number of over-diagnosed cases [49 vs.176 per 10,000 invited men] and fewer overtreated cases [19 vs. 37 per 10,000 invited men]. However, since the harms of screening decreased less than the benefit, the balance between benefits and harms seems much less appealing in today’s setting.”
None of the authors had any financial disclosures.
Deaths from abdominal aortic aneurysm among Swedish men are going down – but not because they’re being screened for the potentially fatal condition.
Although the death rate has decreased by 70% since the early 2000s, screening only saved 2 lives per 10,000 men screened. It did, however, increase by 59% the risk of unnecessary surgery, Minna Johansson, MD, and colleagues wrote in the June 16 issue of the Lancet.
“Screening had only a minor effect on AAA mortality,” wrote Dr. Johansson of the University of Gothenburg (Sweden). “In absolute numbers, only 7% of the benefit estimated in the largest trial of AAA screening was observed. The observed large reductions in AAA mortality were present in both the screened and nonscreened cohorts and were thus mainly caused by other factors – probably reduced smoking. … Our results call the continued justification of AAA screening into question.”
In Sweden, all men aged 65 years are invited to a one-time ultrasound abdominal aorta screening. Most participate. Anyone with an aneurysm is followed up at a vascular surgery clinic, with surgery considered if the aortic diameter is 55 mm or larger.
Dr. Johansson and her colleagues plumbed national health records to estimate the risks and benefits of this routine screening. The study comprised 25,265 men invited to join the AAA screening program in Sweden from 2006 to 2009. Mortality data were compared with those from a contemporaneous cohort of 106,087 men of similar age who were not invited to screen. Finally, the mortality data were compared with national trends in AAA mortality in all Swedish men aged 40-99 years from 1987 to 2015.
A multivariate analysis adjusted for cohort year, marital status, educational level, income, and whether the patient already had an AAA diagnosis at baseline.
From the early 2000s to 2015, AAA mortality among men aged 65-74 years declined from 36 to10 deaths per 100,000. This 70% reduction was similar in both screened and unscreened populations; in fact, the decline began about a decade before population-based screening was introduced and continued to decrease at a steady rate afterward.
After 6 years of screening, there was a 30% reduction of AAA mortality in the screened population, compared with the unscreened, translating to an absolute mortality reduction of two deaths per 10,000 men offered screening.
Screening increased by 52% the number of AAAs detected. The absolute difference in incidence after 6 years of screening translated to an additional 49 overdiagnoses per 10,000 screened men.
Looking back into the mid-1990s, the investigators saw the numbers of elective AAA surgeries rise steadily. In the adjusted model, screened men were 59% more likely to have this procedure than unscreened. The increased risk didn’t come with an equally increased benefit, though. There was a 10% decrease in AAA ruptures, “rendering a risk of overtreatment of 19%, or 19 potentially avoidable elective surgeries per 10,000 men,” the team noted. “Sixty-three percent of all additional elective surgeries for AAA might therefore have constituted overtreat.”
The findings are at odds with large published studies that found a consistent benefit to screening.
“Compared with results at 7-year follow-up of the largest trial of screening for abdominal aortic aneurysm [Multicentre Aneurysm Screening Study (MASS)], we found about half of the benefit in terms of a relative effect and 7% of the estimated benefit in terms of absolute numbers [2 vs. 27 avoided deaths from AAA per 10,000 invited men]. Compared with previous estimates of overdiagnosis and overtreatment, we found a lower absolute number of over-diagnosed cases [49 vs.176 per 10,000 invited men] and fewer overtreated cases [19 vs. 37 per 10,000 invited men]. However, since the harms of screening decreased less than the benefit, the balance between benefits and harms seems much less appealing in today’s setting.”
None of the authors had any financial disclosures.
FROM THE LANCET
Key clinical point: Screening for abdominal aortic aneurysms in men saved few lives, but significantly increased the risk of overdiagnosis and unnecessary surgery.
Major finding: Screening saved two lives per 10,000 men, but showed an increased risk of overtreatment of 19%.
Study details: The population-based longitudinal cohort study comprised 131,352 men.
Disclosures: The authors had no financial disclosures.
Source: Johansson et al. Lancet 2018;391:2441-7.
Breastfeeding with the FDA’s novel drugs approved in 2017, and others
The use of only one 2017 novel drug (Benznidazole) during breastfeeding has been reported. No reports describing the use of the other drugs while breastfeeding have been located. Nevertheless, exposure of a nursing infant should be considered if the mother is taking any of these drugs.
During the first 2 days after birth, nearly all drugs will be excreted into milk, but the amounts are very small and will probably have no effect on the nursing infant. After the second day, drugs with molecular weights of less than 1,000 g/mol will be excreted into milk. Some drugs with high molecular weights may also be excreted, but they may be digested in the infant’s gut. If a mother is receiving one of the drugs below and is breastfeeding, her infant should be monitored for the most common adverse effects, shown below, that were observed in nonpregnant adults.
Anti-infectives
Benznidazole (MW 260 g/mol). Abdominal pain, rash, decreased weight, headache, nausea, vomiting, neutropenia, urticaria, pruritus, eosinophilia, decreased appetite.
Delafloxacin (Baxdela) (MW 441 g/mol). Nausea, diarrhea, headache, transaminase elevations, vomiting.
Glecaprevir / Pibrentasvir (Mavyret) (MWs 839, 1,113 g/mol). Headache, fatigue.
Letermovir (Prevymis) (MW 573 g/mol). Nausea, vomiting, diarrhea, peripheral edema, cough, headache, fatigue, abdominal pain.
Meropenem / vaborbactam (Vabomere) (MWs 438, 297 g/mol). Headache, diarrhea.
Ozenoxacin cream (Xepi) (MW 363 g/mol). No relevant adverse reactions.
Sofosbuvir / Velpatasvir / Voxilaprevir (Vosevi) (MWs 529, 883, 869 g/mol). Headache, fatigue, diarrhea, nausea.
Secnidazole (Solosec) (MW 185 g/mol). Headache, nausea, dysgeusia, vomiting, diarrhea, abdominal pain. Manufacturer recommends discontinuing breastfeeding for 96 hours after administration of the drug.
Antineoplastics
[Note: All of the drugs in this category are best avoided, if possible, when breastfeeding.]
Abemaciclib (Verzenio) (MW 507 g/mol). Diarrhea, neutropenia, nausea, vomiting, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, headache, alopecia, thrombocytopenia.
Acalabrutinib (Calquence) (MW 466 g/mol). Anemia, thrombocytopenia, headache, neutropenia, diarrhea, myalgia, bruising.
Avelumab (Bavencio) (MW 147 kg/mol). Fatigue, musculoskeletal pain, diarrhea, nausea, rash, decreased appetite, peripheral edema, urinary tract infection.
Brigatinib (Alunbrig) (MW 584 g/mol). Nausea, fatigue, cough, headache.
Copanlisib (Aliqopa) (MW 480 g/mol). Hyperglycemia, diarrhea, decreased strength and energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory infections, thrombocytopenia.
Durvalumab (Imfinzi) (MW 146 kg/mol). Fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, urinary tract infections, cough, upper respiratory tract infections, dyspnea, rash.
Enasidenib mesylate (Idhifa) (MW 569 g/mol). Nausea, vomiting, diarrhea, elevated bilirubin, decreased appetite.
Inotuzumab ozogamicin (Besponsa) (MW 160 kg/mol). Thrombocytopenia, neutropenia, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, increased gamma-glutamyltransferase, and hyperbilirubinemia.
Midostaurin (Rydapt) (MW 571 g/mol). Febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, hyperglycemia, vomiting, diarrhea, edema, pyrexia, dyspnea.
Neratinib (Nerlynx) (MW 557 g/mol). Diarrhea, nausea, vomiting, abdominal pain, fatigue, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, nail disorder, dry skin, abdominal distention, decreased weight, urinary tract infection.
Niraparib (Zejula) (MW 511 g/mol). Thrombocytopenia, anemia, neutropenia, leukopenia, palpitations, nausea, vomiting, constipation, abdominal pain/distention, mucositis/stomatitis, diarrhea, dry mouth, fatigue/asthenia, decreased appetite, urinary tract infection, myalgia, back pain, arthralgia, headache, dizziness, dysgeusia, insomnia, anxiety, nasopharyngitis, dyspnea, cough, rash, hypertension.
Ribociclib (Kisqali) (MW 553 g/mol). Neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, back pain.
Cardiovascular
Angiotensin II (Giapreza) (MW 1,046 g/mol). Thromboembolic events.
Central nervous system
Deutetrabenazine (Austedo) (MW 324 g/mol). Somnolence, diarrhea, dry mouth, fatigue, nasopharyngitis.
Edaravone (Radicava) (MW 174 g/mol). Confusion, gait disturbance, headache.
Naldemedine (Symproic) (MW 743 g/mol). Abdominal pain, diarrhea, nausea, gastroenteritis.
Ocrelizumab (Ocrevus) (MW 145 kg/mol). Upper and lower respiratory tract infections.
Safinamide (Xadago) (MW 399 g/mol). Dyskinesia, fall, nausea, insomnia.
Valbenazine (Ingrezza) (MW 419 g/mol). Somnolence.
Dermatologic
Brodalumab (Siliq) (MW 144 kg/mol). Arthralgia, headache, fatigue, diarrhea, oropharyngeal pain, nausea, myalgia, influenza, neutropenia, tinea infections.
Dupilumab (Dupixent) (MW 146.9 kg/mol). Conjunctivitis, blepharitis, oral herpes, keratitis, eye pruritus, other herpes simplex virus infection, dry eye.
Guselkumab (Tremfya) (MW 143.6 kg/mol). Upper respiratory infections, headache, arthralgia, diarrhea, gastroenteritis, tinea infections, herpes simplex infections.
Endocrine / metabolic
Deflazacort (Emflaza) (MW 442 g/mol). Cushingoid appearance, weight increased, increased appetite, upper respiratory tract infection, cough, pollakiuria, hirsutism, central obesity, nasopharyngitis.
Ertugliflozin (Steglatro) (MW 566 g/mol). Female genital mycotic infections.
Etelcalcetide (Parsabiv) (MW 1,048 g/mol). Blood calcium decreased, muscle spasms, diarrhea, nausea, vomiting, headache, hypocalcemia, paresthesia.
Macimorelin (Macrilen) (MW 535 g/mol). Dysgeusia, dizziness, headache, fatigue, nausea, hunger, diarrhea, upper respiratory tract infection, feeling hot, hyperhidrosis, nasopharyngitis, sinus bradycardia.
Semaglutide (Ozempic) (MW 4,114 g/mol). Nausea, vomiting, diarrhea, abdominal pain, constipation.
Vestronidase alfa (Mepsevii) (MW 72.5 kg/mol). Diarrhea, rash, anaphylaxis, pruritus.
Gastrointestinal
Plecanatide (Trulance) (MW 1.7 kg/mol). Diarrhea.
Telotristat (Xermelo) (MW 574 g/mol). Nausea, headache, increased gamma-glutamyltransferase, depression, flatulence, decreased appetite, peripheral edema, pyrexia.
Hematologic
Betrixaban (Bevyxxa) (MW 568 g/mol). Bleeding.
Emicizumab (Hemlibra) (MW 145.6 kg/mol). Headache, arthralgia.
Immunologic
Sarilumab (Kevzara) (MW 150 kg/mol). Neutropenia, increased ALT, upper respiratory infections, urinary tract infections.
Ophthalmic
Latanoprostene bunod (Vyzulta) (MW 508 g/mol). All related to the eye.
Netarsudil (Rhopressa) (MW 454 g/mol). All related to the eye.
Parathyroid hormone
Abaloparatide (Tymlos) (MW 3.9 kg/mol). Hypercalciuria, dizziness, nausea, headache, palpitations, fatigue, upper abdominal pain, vertigo.
Respiratory
Benralizumab (Fasenra) (MW 150 kg/mol). Headache, pharyngitis.
The use of only one 2017 novel drug (Benznidazole) during breastfeeding has been reported. No reports describing the use of the other drugs while breastfeeding have been located. Nevertheless, exposure of a nursing infant should be considered if the mother is taking any of these drugs.
During the first 2 days after birth, nearly all drugs will be excreted into milk, but the amounts are very small and will probably have no effect on the nursing infant. After the second day, drugs with molecular weights of less than 1,000 g/mol will be excreted into milk. Some drugs with high molecular weights may also be excreted, but they may be digested in the infant’s gut. If a mother is receiving one of the drugs below and is breastfeeding, her infant should be monitored for the most common adverse effects, shown below, that were observed in nonpregnant adults.
Anti-infectives
Benznidazole (MW 260 g/mol). Abdominal pain, rash, decreased weight, headache, nausea, vomiting, neutropenia, urticaria, pruritus, eosinophilia, decreased appetite.
Delafloxacin (Baxdela) (MW 441 g/mol). Nausea, diarrhea, headache, transaminase elevations, vomiting.
Glecaprevir / Pibrentasvir (Mavyret) (MWs 839, 1,113 g/mol). Headache, fatigue.
Letermovir (Prevymis) (MW 573 g/mol). Nausea, vomiting, diarrhea, peripheral edema, cough, headache, fatigue, abdominal pain.
Meropenem / vaborbactam (Vabomere) (MWs 438, 297 g/mol). Headache, diarrhea.
Ozenoxacin cream (Xepi) (MW 363 g/mol). No relevant adverse reactions.
Sofosbuvir / Velpatasvir / Voxilaprevir (Vosevi) (MWs 529, 883, 869 g/mol). Headache, fatigue, diarrhea, nausea.
Secnidazole (Solosec) (MW 185 g/mol). Headache, nausea, dysgeusia, vomiting, diarrhea, abdominal pain. Manufacturer recommends discontinuing breastfeeding for 96 hours after administration of the drug.
Antineoplastics
[Note: All of the drugs in this category are best avoided, if possible, when breastfeeding.]
Abemaciclib (Verzenio) (MW 507 g/mol). Diarrhea, neutropenia, nausea, vomiting, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, headache, alopecia, thrombocytopenia.
Acalabrutinib (Calquence) (MW 466 g/mol). Anemia, thrombocytopenia, headache, neutropenia, diarrhea, myalgia, bruising.
Avelumab (Bavencio) (MW 147 kg/mol). Fatigue, musculoskeletal pain, diarrhea, nausea, rash, decreased appetite, peripheral edema, urinary tract infection.
Brigatinib (Alunbrig) (MW 584 g/mol). Nausea, fatigue, cough, headache.
Copanlisib (Aliqopa) (MW 480 g/mol). Hyperglycemia, diarrhea, decreased strength and energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory infections, thrombocytopenia.
Durvalumab (Imfinzi) (MW 146 kg/mol). Fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, urinary tract infections, cough, upper respiratory tract infections, dyspnea, rash.
Enasidenib mesylate (Idhifa) (MW 569 g/mol). Nausea, vomiting, diarrhea, elevated bilirubin, decreased appetite.
Inotuzumab ozogamicin (Besponsa) (MW 160 kg/mol). Thrombocytopenia, neutropenia, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, increased gamma-glutamyltransferase, and hyperbilirubinemia.
Midostaurin (Rydapt) (MW 571 g/mol). Febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, hyperglycemia, vomiting, diarrhea, edema, pyrexia, dyspnea.
Neratinib (Nerlynx) (MW 557 g/mol). Diarrhea, nausea, vomiting, abdominal pain, fatigue, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, nail disorder, dry skin, abdominal distention, decreased weight, urinary tract infection.
Niraparib (Zejula) (MW 511 g/mol). Thrombocytopenia, anemia, neutropenia, leukopenia, palpitations, nausea, vomiting, constipation, abdominal pain/distention, mucositis/stomatitis, diarrhea, dry mouth, fatigue/asthenia, decreased appetite, urinary tract infection, myalgia, back pain, arthralgia, headache, dizziness, dysgeusia, insomnia, anxiety, nasopharyngitis, dyspnea, cough, rash, hypertension.
Ribociclib (Kisqali) (MW 553 g/mol). Neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, back pain.
Cardiovascular
Angiotensin II (Giapreza) (MW 1,046 g/mol). Thromboembolic events.
Central nervous system
Deutetrabenazine (Austedo) (MW 324 g/mol). Somnolence, diarrhea, dry mouth, fatigue, nasopharyngitis.
Edaravone (Radicava) (MW 174 g/mol). Confusion, gait disturbance, headache.
Naldemedine (Symproic) (MW 743 g/mol). Abdominal pain, diarrhea, nausea, gastroenteritis.
Ocrelizumab (Ocrevus) (MW 145 kg/mol). Upper and lower respiratory tract infections.
Safinamide (Xadago) (MW 399 g/mol). Dyskinesia, fall, nausea, insomnia.
Valbenazine (Ingrezza) (MW 419 g/mol). Somnolence.
Dermatologic
Brodalumab (Siliq) (MW 144 kg/mol). Arthralgia, headache, fatigue, diarrhea, oropharyngeal pain, nausea, myalgia, influenza, neutropenia, tinea infections.
Dupilumab (Dupixent) (MW 146.9 kg/mol). Conjunctivitis, blepharitis, oral herpes, keratitis, eye pruritus, other herpes simplex virus infection, dry eye.
Guselkumab (Tremfya) (MW 143.6 kg/mol). Upper respiratory infections, headache, arthralgia, diarrhea, gastroenteritis, tinea infections, herpes simplex infections.
Endocrine / metabolic
Deflazacort (Emflaza) (MW 442 g/mol). Cushingoid appearance, weight increased, increased appetite, upper respiratory tract infection, cough, pollakiuria, hirsutism, central obesity, nasopharyngitis.
Ertugliflozin (Steglatro) (MW 566 g/mol). Female genital mycotic infections.
Etelcalcetide (Parsabiv) (MW 1,048 g/mol). Blood calcium decreased, muscle spasms, diarrhea, nausea, vomiting, headache, hypocalcemia, paresthesia.
Macimorelin (Macrilen) (MW 535 g/mol). Dysgeusia, dizziness, headache, fatigue, nausea, hunger, diarrhea, upper respiratory tract infection, feeling hot, hyperhidrosis, nasopharyngitis, sinus bradycardia.
Semaglutide (Ozempic) (MW 4,114 g/mol). Nausea, vomiting, diarrhea, abdominal pain, constipation.
Vestronidase alfa (Mepsevii) (MW 72.5 kg/mol). Diarrhea, rash, anaphylaxis, pruritus.
Gastrointestinal
Plecanatide (Trulance) (MW 1.7 kg/mol). Diarrhea.
Telotristat (Xermelo) (MW 574 g/mol). Nausea, headache, increased gamma-glutamyltransferase, depression, flatulence, decreased appetite, peripheral edema, pyrexia.
Hematologic
Betrixaban (Bevyxxa) (MW 568 g/mol). Bleeding.
Emicizumab (Hemlibra) (MW 145.6 kg/mol). Headache, arthralgia.
Immunologic
Sarilumab (Kevzara) (MW 150 kg/mol). Neutropenia, increased ALT, upper respiratory infections, urinary tract infections.
Ophthalmic
Latanoprostene bunod (Vyzulta) (MW 508 g/mol). All related to the eye.
Netarsudil (Rhopressa) (MW 454 g/mol). All related to the eye.
Parathyroid hormone
Abaloparatide (Tymlos) (MW 3.9 kg/mol). Hypercalciuria, dizziness, nausea, headache, palpitations, fatigue, upper abdominal pain, vertigo.
Respiratory
Benralizumab (Fasenra) (MW 150 kg/mol). Headache, pharyngitis.
The use of only one 2017 novel drug (Benznidazole) during breastfeeding has been reported. No reports describing the use of the other drugs while breastfeeding have been located. Nevertheless, exposure of a nursing infant should be considered if the mother is taking any of these drugs.
During the first 2 days after birth, nearly all drugs will be excreted into milk, but the amounts are very small and will probably have no effect on the nursing infant. After the second day, drugs with molecular weights of less than 1,000 g/mol will be excreted into milk. Some drugs with high molecular weights may also be excreted, but they may be digested in the infant’s gut. If a mother is receiving one of the drugs below and is breastfeeding, her infant should be monitored for the most common adverse effects, shown below, that were observed in nonpregnant adults.
Anti-infectives
Benznidazole (MW 260 g/mol). Abdominal pain, rash, decreased weight, headache, nausea, vomiting, neutropenia, urticaria, pruritus, eosinophilia, decreased appetite.
Delafloxacin (Baxdela) (MW 441 g/mol). Nausea, diarrhea, headache, transaminase elevations, vomiting.
Glecaprevir / Pibrentasvir (Mavyret) (MWs 839, 1,113 g/mol). Headache, fatigue.
Letermovir (Prevymis) (MW 573 g/mol). Nausea, vomiting, diarrhea, peripheral edema, cough, headache, fatigue, abdominal pain.
Meropenem / vaborbactam (Vabomere) (MWs 438, 297 g/mol). Headache, diarrhea.
Ozenoxacin cream (Xepi) (MW 363 g/mol). No relevant adverse reactions.
Sofosbuvir / Velpatasvir / Voxilaprevir (Vosevi) (MWs 529, 883, 869 g/mol). Headache, fatigue, diarrhea, nausea.
Secnidazole (Solosec) (MW 185 g/mol). Headache, nausea, dysgeusia, vomiting, diarrhea, abdominal pain. Manufacturer recommends discontinuing breastfeeding for 96 hours after administration of the drug.
Antineoplastics
[Note: All of the drugs in this category are best avoided, if possible, when breastfeeding.]
Abemaciclib (Verzenio) (MW 507 g/mol). Diarrhea, neutropenia, nausea, vomiting, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, headache, alopecia, thrombocytopenia.
Acalabrutinib (Calquence) (MW 466 g/mol). Anemia, thrombocytopenia, headache, neutropenia, diarrhea, myalgia, bruising.
Avelumab (Bavencio) (MW 147 kg/mol). Fatigue, musculoskeletal pain, diarrhea, nausea, rash, decreased appetite, peripheral edema, urinary tract infection.
Brigatinib (Alunbrig) (MW 584 g/mol). Nausea, fatigue, cough, headache.
Copanlisib (Aliqopa) (MW 480 g/mol). Hyperglycemia, diarrhea, decreased strength and energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory infections, thrombocytopenia.
Durvalumab (Imfinzi) (MW 146 kg/mol). Fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, urinary tract infections, cough, upper respiratory tract infections, dyspnea, rash.
Enasidenib mesylate (Idhifa) (MW 569 g/mol). Nausea, vomiting, diarrhea, elevated bilirubin, decreased appetite.
Inotuzumab ozogamicin (Besponsa) (MW 160 kg/mol). Thrombocytopenia, neutropenia, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, increased gamma-glutamyltransferase, and hyperbilirubinemia.
Midostaurin (Rydapt) (MW 571 g/mol). Febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, hyperglycemia, vomiting, diarrhea, edema, pyrexia, dyspnea.
Neratinib (Nerlynx) (MW 557 g/mol). Diarrhea, nausea, vomiting, abdominal pain, fatigue, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, nail disorder, dry skin, abdominal distention, decreased weight, urinary tract infection.
Niraparib (Zejula) (MW 511 g/mol). Thrombocytopenia, anemia, neutropenia, leukopenia, palpitations, nausea, vomiting, constipation, abdominal pain/distention, mucositis/stomatitis, diarrhea, dry mouth, fatigue/asthenia, decreased appetite, urinary tract infection, myalgia, back pain, arthralgia, headache, dizziness, dysgeusia, insomnia, anxiety, nasopharyngitis, dyspnea, cough, rash, hypertension.
Ribociclib (Kisqali) (MW 553 g/mol). Neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, back pain.
Cardiovascular
Angiotensin II (Giapreza) (MW 1,046 g/mol). Thromboembolic events.
Central nervous system
Deutetrabenazine (Austedo) (MW 324 g/mol). Somnolence, diarrhea, dry mouth, fatigue, nasopharyngitis.
Edaravone (Radicava) (MW 174 g/mol). Confusion, gait disturbance, headache.
Naldemedine (Symproic) (MW 743 g/mol). Abdominal pain, diarrhea, nausea, gastroenteritis.
Ocrelizumab (Ocrevus) (MW 145 kg/mol). Upper and lower respiratory tract infections.
Safinamide (Xadago) (MW 399 g/mol). Dyskinesia, fall, nausea, insomnia.
Valbenazine (Ingrezza) (MW 419 g/mol). Somnolence.
Dermatologic
Brodalumab (Siliq) (MW 144 kg/mol). Arthralgia, headache, fatigue, diarrhea, oropharyngeal pain, nausea, myalgia, influenza, neutropenia, tinea infections.
Dupilumab (Dupixent) (MW 146.9 kg/mol). Conjunctivitis, blepharitis, oral herpes, keratitis, eye pruritus, other herpes simplex virus infection, dry eye.
Guselkumab (Tremfya) (MW 143.6 kg/mol). Upper respiratory infections, headache, arthralgia, diarrhea, gastroenteritis, tinea infections, herpes simplex infections.
Endocrine / metabolic
Deflazacort (Emflaza) (MW 442 g/mol). Cushingoid appearance, weight increased, increased appetite, upper respiratory tract infection, cough, pollakiuria, hirsutism, central obesity, nasopharyngitis.
Ertugliflozin (Steglatro) (MW 566 g/mol). Female genital mycotic infections.
Etelcalcetide (Parsabiv) (MW 1,048 g/mol). Blood calcium decreased, muscle spasms, diarrhea, nausea, vomiting, headache, hypocalcemia, paresthesia.
Macimorelin (Macrilen) (MW 535 g/mol). Dysgeusia, dizziness, headache, fatigue, nausea, hunger, diarrhea, upper respiratory tract infection, feeling hot, hyperhidrosis, nasopharyngitis, sinus bradycardia.
Semaglutide (Ozempic) (MW 4,114 g/mol). Nausea, vomiting, diarrhea, abdominal pain, constipation.
Vestronidase alfa (Mepsevii) (MW 72.5 kg/mol). Diarrhea, rash, anaphylaxis, pruritus.
Gastrointestinal
Plecanatide (Trulance) (MW 1.7 kg/mol). Diarrhea.
Telotristat (Xermelo) (MW 574 g/mol). Nausea, headache, increased gamma-glutamyltransferase, depression, flatulence, decreased appetite, peripheral edema, pyrexia.
Hematologic
Betrixaban (Bevyxxa) (MW 568 g/mol). Bleeding.
Emicizumab (Hemlibra) (MW 145.6 kg/mol). Headache, arthralgia.
Immunologic
Sarilumab (Kevzara) (MW 150 kg/mol). Neutropenia, increased ALT, upper respiratory infections, urinary tract infections.
Ophthalmic
Latanoprostene bunod (Vyzulta) (MW 508 g/mol). All related to the eye.
Netarsudil (Rhopressa) (MW 454 g/mol). All related to the eye.
Parathyroid hormone
Abaloparatide (Tymlos) (MW 3.9 kg/mol). Hypercalciuria, dizziness, nausea, headache, palpitations, fatigue, upper abdominal pain, vertigo.
Respiratory
Benralizumab (Fasenra) (MW 150 kg/mol). Headache, pharyngitis.
‘Captain of the ship’ doctrine
Question: The “Captain of the Ship” doctrine:
A. Is a legal principle used mostly in maritime law.
B. Is applicable only to surgeons in the operating room.
C. Is good law in all jurisdictions.
D. May be used by plaintiffs in emergency department triage litigation.
E. Originated when hospitals lost their charitable immunity.
Answer: D. Historically, the Captain of the Ship doctrine imputes liability to the surgeon who has the authority and right to control the actions of his assistants in the operating room.
Pennsylvania famously saw the use of the phrase in a 1949 case: “In the course of an operation in the operating room of a hospital, and until the surgeon leaves that room at the conclusion of the operation … he is in the same complete charge of those who are present and assisting him as is the captain of a ship over all on board.”1
Public hospitals in the 1940s were immune from liability because they were charitable organizations, so the Captain of the Ship doctrine emerged as a means for injured patients to recover damages against the surgeon instead. Courts have used various legal theories to justify this doctrine, which is basically grounded in vicarious liability, e.g., master-servant relationship (respondeat superior), borrowed servant, a nondelegable duty, or more broadly, principles of agency.
Use of the doctrine to shift liability to the surgeon in the operating room is well exemplified in litigation over retained sponges, left-behind instruments, burns in the operating room, administration of the wrong blood type, and allergic reaction to penicillin. Actual control of the surgeon’s assistants is not essential, but the right to merely supervise is insufficient. What is dispositive is the right and authority to determine an assistant’s actions.
However, what constitutes an “operating room” has been in dispute. It may simply mean a circumscribed and controlled area for medical procedures and/or treatment. Thus, the term has been extended to a room where only local anesthesia was used for esophageal dilation. Reasoning by analogy, the modern-day heart catheterization lab or interventional radiology suite would arguably count as “operating rooms” where the procedurist-doctor, usually a nonsurgeon, may be deemed to function as the captain of the ship.
Another place where a nonsurgeon may be involved is the hospital ED. It has been stated that emergency physicians have been held liable for adverse outcomes resulting from the patients under triage, based on the Captain of the Ship doctrine.2 Once a patient arrives in the ED, a legal duty to provide care arises, even if the physician has yet to see the patient. The federal Emergency Medical Treatment and Labor Act, which regulates much of what happens in the nation’s emergency departments, covers “any individual ... [who] comes to the emergency department and a request is made on the individual’s behalf for examination or treatment for a medical condition.”
Still, the doctrine is less likely to be invoked in a more spread-out area such as a general medical ward, where a physician’s control cannot be reasonably expected.
For example, courts have held that ward nurses giving injections into the buttock causing permanent neuropathy to a patient’s leg were not the agents of the prescribing physician, but just of the hospital employing them. The doctrine also was rejected in Collins v. Hand by the Pennsylvania Supreme Court, which reversed a judgment against a psychiatrist defendant.3 In the Collins case, notwithstanding the fact that the psychiatrist, Dr. Hand, had personally arranged for the patient’s transfer to another hospital and wrote orders for electroconvulsive therapy (which was complicated by fractures), Dr. Hand did not choose the doctor who was to administer the therapy, nor did he hire, compensate, or control any of the team members.
In the 1960s, hospitals began losing their charitable immunity status and assumed direct as well as vicarious liability for injuries to patients from the negligent acts of their employees, such as nurses. The key policy reason for having the Captain of the Ship doctrine then no longer existed. Besides, operating rooms became increasingly complex, and the senior surgeon was thought to be incapable of being in charge of all activities there.
Wisconsin is typical: A retained sponge following a laparoscopic cholecystectomy led to complications, and the patient sued the hospital and surgeon, claiming each was responsible for the nurses’ sponge-count error. The lower court had found that “as a matter of law [the surgeon] is in fact responsible and liable for the actions of the parties that were in the operating room with him and working under his supervision ... [the] doctor is the captain of the ship. That doctor is responsible for everything.”
Upon appeal, the Wisconsin Supreme Court reversed the decision of the lower court by rejecting the doctrine altogether, finding that it failed to reflect the emergence of hospitals as modern health care facilities.5
Still, the doctrine is by no means obsolete. In a Colorado case, the court wrote that, even if the nurse were an employee of the hospital and her negligence caused the death of plaintiff’s husband, the Captain of the Ship doctrine would preclude recovery against the hospital.6 It relied on a precedent-setting case that held that once the operating surgeon assumed control in the operating room, the surgeon is liable for the negligence of all persons working there.
Likewise, California has recently breathed new life into the doctrine.7 A case in 2006 involved a patient who underwent arterial bypass surgery in his right leg. A case in which a nurse’s counting error led to a retained sponge ended up with the patient losing his leg. The surgeon initially escaped liability by virtue of the court’s refusal to include Captain of the Ship instructions to the jury, which found the doctor not negligent. The state court of appeals reversed, however, concluding that it was reasonably probable that the jury might have reached a different result had it been so instructed.
Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. For additional information, readers may contact the author at [email protected].
References
1. McConnell v. Williams, 361 Pa. 355, 65 A.2d 243 (1949).
2. ED Legal Letter, Feb 1, 2018.
3. Collins v. Hand, 246 A.2d 398 (Pa 1968).
4. AORN J. 2001 Oct;74(4):525-8.
5. Lewis v. Physicians Insurance Company et al., 627 NW2d 484 (Wis 2001).
6. Krane v. St. Anthony Hospital Systems, 738 P.2d 75 (Co 1987).
7. Fields v. Yusuf, 144 Cal.App.4th 1381 (2006).
Question: The “Captain of the Ship” doctrine:
A. Is a legal principle used mostly in maritime law.
B. Is applicable only to surgeons in the operating room.
C. Is good law in all jurisdictions.
D. May be used by plaintiffs in emergency department triage litigation.
E. Originated when hospitals lost their charitable immunity.
Answer: D. Historically, the Captain of the Ship doctrine imputes liability to the surgeon who has the authority and right to control the actions of his assistants in the operating room.
Pennsylvania famously saw the use of the phrase in a 1949 case: “In the course of an operation in the operating room of a hospital, and until the surgeon leaves that room at the conclusion of the operation … he is in the same complete charge of those who are present and assisting him as is the captain of a ship over all on board.”1
Public hospitals in the 1940s were immune from liability because they were charitable organizations, so the Captain of the Ship doctrine emerged as a means for injured patients to recover damages against the surgeon instead. Courts have used various legal theories to justify this doctrine, which is basically grounded in vicarious liability, e.g., master-servant relationship (respondeat superior), borrowed servant, a nondelegable duty, or more broadly, principles of agency.
Use of the doctrine to shift liability to the surgeon in the operating room is well exemplified in litigation over retained sponges, left-behind instruments, burns in the operating room, administration of the wrong blood type, and allergic reaction to penicillin. Actual control of the surgeon’s assistants is not essential, but the right to merely supervise is insufficient. What is dispositive is the right and authority to determine an assistant’s actions.
However, what constitutes an “operating room” has been in dispute. It may simply mean a circumscribed and controlled area for medical procedures and/or treatment. Thus, the term has been extended to a room where only local anesthesia was used for esophageal dilation. Reasoning by analogy, the modern-day heart catheterization lab or interventional radiology suite would arguably count as “operating rooms” where the procedurist-doctor, usually a nonsurgeon, may be deemed to function as the captain of the ship.
Another place where a nonsurgeon may be involved is the hospital ED. It has been stated that emergency physicians have been held liable for adverse outcomes resulting from the patients under triage, based on the Captain of the Ship doctrine.2 Once a patient arrives in the ED, a legal duty to provide care arises, even if the physician has yet to see the patient. The federal Emergency Medical Treatment and Labor Act, which regulates much of what happens in the nation’s emergency departments, covers “any individual ... [who] comes to the emergency department and a request is made on the individual’s behalf for examination or treatment for a medical condition.”
Still, the doctrine is less likely to be invoked in a more spread-out area such as a general medical ward, where a physician’s control cannot be reasonably expected.
For example, courts have held that ward nurses giving injections into the buttock causing permanent neuropathy to a patient’s leg were not the agents of the prescribing physician, but just of the hospital employing them. The doctrine also was rejected in Collins v. Hand by the Pennsylvania Supreme Court, which reversed a judgment against a psychiatrist defendant.3 In the Collins case, notwithstanding the fact that the psychiatrist, Dr. Hand, had personally arranged for the patient’s transfer to another hospital and wrote orders for electroconvulsive therapy (which was complicated by fractures), Dr. Hand did not choose the doctor who was to administer the therapy, nor did he hire, compensate, or control any of the team members.
In the 1960s, hospitals began losing their charitable immunity status and assumed direct as well as vicarious liability for injuries to patients from the negligent acts of their employees, such as nurses. The key policy reason for having the Captain of the Ship doctrine then no longer existed. Besides, operating rooms became increasingly complex, and the senior surgeon was thought to be incapable of being in charge of all activities there.
Wisconsin is typical: A retained sponge following a laparoscopic cholecystectomy led to complications, and the patient sued the hospital and surgeon, claiming each was responsible for the nurses’ sponge-count error. The lower court had found that “as a matter of law [the surgeon] is in fact responsible and liable for the actions of the parties that were in the operating room with him and working under his supervision ... [the] doctor is the captain of the ship. That doctor is responsible for everything.”
Upon appeal, the Wisconsin Supreme Court reversed the decision of the lower court by rejecting the doctrine altogether, finding that it failed to reflect the emergence of hospitals as modern health care facilities.5
Still, the doctrine is by no means obsolete. In a Colorado case, the court wrote that, even if the nurse were an employee of the hospital and her negligence caused the death of plaintiff’s husband, the Captain of the Ship doctrine would preclude recovery against the hospital.6 It relied on a precedent-setting case that held that once the operating surgeon assumed control in the operating room, the surgeon is liable for the negligence of all persons working there.
Likewise, California has recently breathed new life into the doctrine.7 A case in 2006 involved a patient who underwent arterial bypass surgery in his right leg. A case in which a nurse’s counting error led to a retained sponge ended up with the patient losing his leg. The surgeon initially escaped liability by virtue of the court’s refusal to include Captain of the Ship instructions to the jury, which found the doctor not negligent. The state court of appeals reversed, however, concluding that it was reasonably probable that the jury might have reached a different result had it been so instructed.
Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. For additional information, readers may contact the author at [email protected].
References
1. McConnell v. Williams, 361 Pa. 355, 65 A.2d 243 (1949).
2. ED Legal Letter, Feb 1, 2018.
3. Collins v. Hand, 246 A.2d 398 (Pa 1968).
4. AORN J. 2001 Oct;74(4):525-8.
5. Lewis v. Physicians Insurance Company et al., 627 NW2d 484 (Wis 2001).
6. Krane v. St. Anthony Hospital Systems, 738 P.2d 75 (Co 1987).
7. Fields v. Yusuf, 144 Cal.App.4th 1381 (2006).
Question: The “Captain of the Ship” doctrine:
A. Is a legal principle used mostly in maritime law.
B. Is applicable only to surgeons in the operating room.
C. Is good law in all jurisdictions.
D. May be used by plaintiffs in emergency department triage litigation.
E. Originated when hospitals lost their charitable immunity.
Answer: D. Historically, the Captain of the Ship doctrine imputes liability to the surgeon who has the authority and right to control the actions of his assistants in the operating room.
Pennsylvania famously saw the use of the phrase in a 1949 case: “In the course of an operation in the operating room of a hospital, and until the surgeon leaves that room at the conclusion of the operation … he is in the same complete charge of those who are present and assisting him as is the captain of a ship over all on board.”1
Public hospitals in the 1940s were immune from liability because they were charitable organizations, so the Captain of the Ship doctrine emerged as a means for injured patients to recover damages against the surgeon instead. Courts have used various legal theories to justify this doctrine, which is basically grounded in vicarious liability, e.g., master-servant relationship (respondeat superior), borrowed servant, a nondelegable duty, or more broadly, principles of agency.
Use of the doctrine to shift liability to the surgeon in the operating room is well exemplified in litigation over retained sponges, left-behind instruments, burns in the operating room, administration of the wrong blood type, and allergic reaction to penicillin. Actual control of the surgeon’s assistants is not essential, but the right to merely supervise is insufficient. What is dispositive is the right and authority to determine an assistant’s actions.
However, what constitutes an “operating room” has been in dispute. It may simply mean a circumscribed and controlled area for medical procedures and/or treatment. Thus, the term has been extended to a room where only local anesthesia was used for esophageal dilation. Reasoning by analogy, the modern-day heart catheterization lab or interventional radiology suite would arguably count as “operating rooms” where the procedurist-doctor, usually a nonsurgeon, may be deemed to function as the captain of the ship.
Another place where a nonsurgeon may be involved is the hospital ED. It has been stated that emergency physicians have been held liable for adverse outcomes resulting from the patients under triage, based on the Captain of the Ship doctrine.2 Once a patient arrives in the ED, a legal duty to provide care arises, even if the physician has yet to see the patient. The federal Emergency Medical Treatment and Labor Act, which regulates much of what happens in the nation’s emergency departments, covers “any individual ... [who] comes to the emergency department and a request is made on the individual’s behalf for examination or treatment for a medical condition.”
Still, the doctrine is less likely to be invoked in a more spread-out area such as a general medical ward, where a physician’s control cannot be reasonably expected.
For example, courts have held that ward nurses giving injections into the buttock causing permanent neuropathy to a patient’s leg were not the agents of the prescribing physician, but just of the hospital employing them. The doctrine also was rejected in Collins v. Hand by the Pennsylvania Supreme Court, which reversed a judgment against a psychiatrist defendant.3 In the Collins case, notwithstanding the fact that the psychiatrist, Dr. Hand, had personally arranged for the patient’s transfer to another hospital and wrote orders for electroconvulsive therapy (which was complicated by fractures), Dr. Hand did not choose the doctor who was to administer the therapy, nor did he hire, compensate, or control any of the team members.
In the 1960s, hospitals began losing their charitable immunity status and assumed direct as well as vicarious liability for injuries to patients from the negligent acts of their employees, such as nurses. The key policy reason for having the Captain of the Ship doctrine then no longer existed. Besides, operating rooms became increasingly complex, and the senior surgeon was thought to be incapable of being in charge of all activities there.
Wisconsin is typical: A retained sponge following a laparoscopic cholecystectomy led to complications, and the patient sued the hospital and surgeon, claiming each was responsible for the nurses’ sponge-count error. The lower court had found that “as a matter of law [the surgeon] is in fact responsible and liable for the actions of the parties that were in the operating room with him and working under his supervision ... [the] doctor is the captain of the ship. That doctor is responsible for everything.”
Upon appeal, the Wisconsin Supreme Court reversed the decision of the lower court by rejecting the doctrine altogether, finding that it failed to reflect the emergence of hospitals as modern health care facilities.5
Still, the doctrine is by no means obsolete. In a Colorado case, the court wrote that, even if the nurse were an employee of the hospital and her negligence caused the death of plaintiff’s husband, the Captain of the Ship doctrine would preclude recovery against the hospital.6 It relied on a precedent-setting case that held that once the operating surgeon assumed control in the operating room, the surgeon is liable for the negligence of all persons working there.
Likewise, California has recently breathed new life into the doctrine.7 A case in 2006 involved a patient who underwent arterial bypass surgery in his right leg. A case in which a nurse’s counting error led to a retained sponge ended up with the patient losing his leg. The surgeon initially escaped liability by virtue of the court’s refusal to include Captain of the Ship instructions to the jury, which found the doctor not negligent. The state court of appeals reversed, however, concluding that it was reasonably probable that the jury might have reached a different result had it been so instructed.
Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. For additional information, readers may contact the author at [email protected].
References
1. McConnell v. Williams, 361 Pa. 355, 65 A.2d 243 (1949).
2. ED Legal Letter, Feb 1, 2018.
3. Collins v. Hand, 246 A.2d 398 (Pa 1968).
4. AORN J. 2001 Oct;74(4):525-8.
5. Lewis v. Physicians Insurance Company et al., 627 NW2d 484 (Wis 2001).
6. Krane v. St. Anthony Hospital Systems, 738 P.2d 75 (Co 1987).
7. Fields v. Yusuf, 144 Cal.App.4th 1381 (2006).
A combination hormone capsule for vasomotor symptoms
A capsule containing a combination of 17-beta-estradiol and progesterone significantly improved vasomotor symptoms in menopausal women without causing a single case of endometrial hyperplasia.
The results of the 12-week REPLENISH study suggested that this preparation effectively treats vasomotor symptoms and could be a safe alternative to the popular, but unstudied, compounded bioidentical hormones that millions of women turned to after the Women’s Health Initiative study cast doubt on the safety of hormone therapy, Rogerio A. Lobo, MD, and his colleagues wrote in Obstetrics and Gynecology.
“17-beta-estradiol–progesterone may represent a new option, using natural hormones, for postmenopausal women, including the estimated millions currently using inadequately studied, non–FDA approved, compounded [hormone therapy],” wrote Dr. Lobo of Columbia University, New York.
REPLENISH randomized 1,845 postmenopausal women (mean age 55 years) to placebo or one of four active, daily, oral estradiol-progesterone doses (1 mg/100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, or 0.25 mg/50 mg). The primary safety outcome was endometrial hyperplasia. There were two primary efficacy endpoints: mean changes in frequency and severity of moderate to severe vasomotor symptoms from baseline at weeks 4 and 12.
There were no cases of endometrial hyperplasia with any estradiol-progesterone dose, nor were there any endometrial cancers. The rates of endometrial proliferation and endometrial polyps were low (about 3% each).
The frequency of vasomotor symptoms decreased significantly, compared with placebo, in all active groups. The severity of vasomotor symptoms also decreased significantly and in a dose-dependent manner. Onset of action was similarly dose-dependent, with the 1 mg/100 mg group experiencing a clinically meaningful benefit by week 3 and the 0.5 mg/50 mg group by week 6.
Adverse events were mild-moderate and included breast tenderness, headache, nausea, pelvic pain, vaginal bleeding, and vaginal discharge. Serious adverse events included acute pancreatitis, deep vein thrombosis (in a woman with prior left femoral popliteal bypass surgery and a family history of deep vein thrombosis), chronic obstructive pulmonary disease, infective cholecystitis, and breast cancer.
TherapeuticsMD sponsored the study; Dr. Lobo has received research grants from TherapeuticsMD and has served as a consultant for the company and several others. Some coauthors report additional research support from and consulting with TherapeuticsMD and other companies, and three coauthors are stock-holding employees of TherapeuticsMD.
SOURCE: Lobo RA et al. Obstet Gynecol. 2018 Jan;132(1):161-70.
A capsule containing a combination of 17-beta-estradiol and progesterone significantly improved vasomotor symptoms in menopausal women without causing a single case of endometrial hyperplasia.
The results of the 12-week REPLENISH study suggested that this preparation effectively treats vasomotor symptoms and could be a safe alternative to the popular, but unstudied, compounded bioidentical hormones that millions of women turned to after the Women’s Health Initiative study cast doubt on the safety of hormone therapy, Rogerio A. Lobo, MD, and his colleagues wrote in Obstetrics and Gynecology.
“17-beta-estradiol–progesterone may represent a new option, using natural hormones, for postmenopausal women, including the estimated millions currently using inadequately studied, non–FDA approved, compounded [hormone therapy],” wrote Dr. Lobo of Columbia University, New York.
REPLENISH randomized 1,845 postmenopausal women (mean age 55 years) to placebo or one of four active, daily, oral estradiol-progesterone doses (1 mg/100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, or 0.25 mg/50 mg). The primary safety outcome was endometrial hyperplasia. There were two primary efficacy endpoints: mean changes in frequency and severity of moderate to severe vasomotor symptoms from baseline at weeks 4 and 12.
There were no cases of endometrial hyperplasia with any estradiol-progesterone dose, nor were there any endometrial cancers. The rates of endometrial proliferation and endometrial polyps were low (about 3% each).
The frequency of vasomotor symptoms decreased significantly, compared with placebo, in all active groups. The severity of vasomotor symptoms also decreased significantly and in a dose-dependent manner. Onset of action was similarly dose-dependent, with the 1 mg/100 mg group experiencing a clinically meaningful benefit by week 3 and the 0.5 mg/50 mg group by week 6.
Adverse events were mild-moderate and included breast tenderness, headache, nausea, pelvic pain, vaginal bleeding, and vaginal discharge. Serious adverse events included acute pancreatitis, deep vein thrombosis (in a woman with prior left femoral popliteal bypass surgery and a family history of deep vein thrombosis), chronic obstructive pulmonary disease, infective cholecystitis, and breast cancer.
TherapeuticsMD sponsored the study; Dr. Lobo has received research grants from TherapeuticsMD and has served as a consultant for the company and several others. Some coauthors report additional research support from and consulting with TherapeuticsMD and other companies, and three coauthors are stock-holding employees of TherapeuticsMD.
SOURCE: Lobo RA et al. Obstet Gynecol. 2018 Jan;132(1):161-70.
A capsule containing a combination of 17-beta-estradiol and progesterone significantly improved vasomotor symptoms in menopausal women without causing a single case of endometrial hyperplasia.
The results of the 12-week REPLENISH study suggested that this preparation effectively treats vasomotor symptoms and could be a safe alternative to the popular, but unstudied, compounded bioidentical hormones that millions of women turned to after the Women’s Health Initiative study cast doubt on the safety of hormone therapy, Rogerio A. Lobo, MD, and his colleagues wrote in Obstetrics and Gynecology.
“17-beta-estradiol–progesterone may represent a new option, using natural hormones, for postmenopausal women, including the estimated millions currently using inadequately studied, non–FDA approved, compounded [hormone therapy],” wrote Dr. Lobo of Columbia University, New York.
REPLENISH randomized 1,845 postmenopausal women (mean age 55 years) to placebo or one of four active, daily, oral estradiol-progesterone doses (1 mg/100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, or 0.25 mg/50 mg). The primary safety outcome was endometrial hyperplasia. There were two primary efficacy endpoints: mean changes in frequency and severity of moderate to severe vasomotor symptoms from baseline at weeks 4 and 12.
There were no cases of endometrial hyperplasia with any estradiol-progesterone dose, nor were there any endometrial cancers. The rates of endometrial proliferation and endometrial polyps were low (about 3% each).
The frequency of vasomotor symptoms decreased significantly, compared with placebo, in all active groups. The severity of vasomotor symptoms also decreased significantly and in a dose-dependent manner. Onset of action was similarly dose-dependent, with the 1 mg/100 mg group experiencing a clinically meaningful benefit by week 3 and the 0.5 mg/50 mg group by week 6.
Adverse events were mild-moderate and included breast tenderness, headache, nausea, pelvic pain, vaginal bleeding, and vaginal discharge. Serious adverse events included acute pancreatitis, deep vein thrombosis (in a woman with prior left femoral popliteal bypass surgery and a family history of deep vein thrombosis), chronic obstructive pulmonary disease, infective cholecystitis, and breast cancer.
TherapeuticsMD sponsored the study; Dr. Lobo has received research grants from TherapeuticsMD and has served as a consultant for the company and several others. Some coauthors report additional research support from and consulting with TherapeuticsMD and other companies, and three coauthors are stock-holding employees of TherapeuticsMD.
SOURCE: Lobo RA et al. Obstet Gynecol. 2018 Jan;132(1):161-70.
FROM OBSTETRICS & GYNECOLOGY
Key clinical point: A 17-beta-estradiol–progesterone capsule significantly decreased the frequency and severity of vasomotor symptoms.
Major finding: The compound reduced vasomotor symptoms, with no cases of endometrial hyperplasia.
Study details: The study randomized 1,845 women to placebo or one of four active hormone doses.
Disclosures: TherapeuticsMD sponsored the study; Dr. Lobo is a consultant for the company.
Source: Lobo RA et al. Obstet Gynecol. 2018 Jan;132:161-70.
New NIH consortium aims to coordinate pediatric research programs
across its institutes and centers.
Almost all of the 27 institutes and centers of the NIH fund at least some kind of child health research, totaling more than $4 billion in the 2017 fiscal year, according to an NIH statement. “The new consortium aims to harmonize these activities, explore gaps and opportunities in the overall pediatric research portfolio, and set priorities.”
Research funded by NIH “has resulted in tremendous advances against diseases and conditions that affect child health and well-being, including asthma, cancer, autism, obesity, and intellectual and developmental disabilities,” explained Diana W. Bianchi, MD, in the statement. Dr. Bianchi is director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the lead NIH institute for the consortium.
The new consortium, which will be led by the NICHD director, will meet several times a year.
across its institutes and centers.
Almost all of the 27 institutes and centers of the NIH fund at least some kind of child health research, totaling more than $4 billion in the 2017 fiscal year, according to an NIH statement. “The new consortium aims to harmonize these activities, explore gaps and opportunities in the overall pediatric research portfolio, and set priorities.”
Research funded by NIH “has resulted in tremendous advances against diseases and conditions that affect child health and well-being, including asthma, cancer, autism, obesity, and intellectual and developmental disabilities,” explained Diana W. Bianchi, MD, in the statement. Dr. Bianchi is director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the lead NIH institute for the consortium.
The new consortium, which will be led by the NICHD director, will meet several times a year.
across its institutes and centers.
Almost all of the 27 institutes and centers of the NIH fund at least some kind of child health research, totaling more than $4 billion in the 2017 fiscal year, according to an NIH statement. “The new consortium aims to harmonize these activities, explore gaps and opportunities in the overall pediatric research portfolio, and set priorities.”
Research funded by NIH “has resulted in tremendous advances against diseases and conditions that affect child health and well-being, including asthma, cancer, autism, obesity, and intellectual and developmental disabilities,” explained Diana W. Bianchi, MD, in the statement. Dr. Bianchi is director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the lead NIH institute for the consortium.
The new consortium, which will be led by the NICHD director, will meet several times a year.
RBC transfusions with surgery may increase VTE risk
In patients undergoing surgery, RBC transfusions may be associated with the development of new or progressive venous thromboembolism within 30 days of the procedure, results of a recent registry study suggest.
Patients who received perioperative RBC transfusions had significantly higher odds of developing postoperative venous thromboembolism (VTE) overall, as well as higher odds specifically for deep venous thrombosis (DVT) and pulmonary embolism (PE), according to results published in JAMA Surgery.
“In a subset of patients receiving perioperative RBC transfusions, a synergistic and incremental dose-related risk for VTE development may exist,” Dr. Goel and her coauthors wrote.
The analysis was based on prospectively collected North American registry data including 750,937 patients who underwent a surgical procedure in 2014, of which 47,410 (6.3%) received one or more perioperative RBC transfusions. VTE occurred in 6,309 patients (0.8%), of which 4,336 cases were DVT (0.6%) and 2,514 were PE (0.3%).
The patients who received perioperative RBC transfusions had significantly increased odds of developing VTE in the 30-day postoperative period (adjusted odds ratio, 2.1; 95% confidence interval, 2.0-2.3) versus those who had no transfusions, according to results of a multivariable analysis adjusting for age, sex, length of hospital stay, use of mechanical ventilation, and other potentially confounding factors.
Similarly, researchers found transfused patients had higher odds of both DVT (aOR, 2.2; 95% CI, 2.1-2.4), and PE (aOR, 1.9; 95% CI, 1.7-2.1).
Odds of VTE increased significantly along with increasing number of perioperative RBC transfusions from an aOR of 2.1 for those with just one transfusion to 4.5 for those who had three or more transfusion events (P less than .001 for trend), results of a dose-response analysis showed.
The association between RBC transfusions perioperatively and VTE postoperatively remained robust after propensity score matching and was statistically significant in all surgical subspecialties, the researchers reported.
However, they also noted that these results will require validation in prospective cohort studies and randomized clinical trials. “If proven, they underscore the continued need for more stringent and optimal perioperative blood management practices in addition to rigorous VTE prophylaxis in patients undergoing surgery.”
The study was funded in part by grants from the National Institutes of Health and Cornell University. The researchers reported having no conflicts of interest.
SOURCE: Goel R et al. JAMA Surg. 2018 Jun 13. doi: 10.1001/jamasurg.2018.1565.
In patients undergoing surgery, RBC transfusions may be associated with the development of new or progressive venous thromboembolism within 30 days of the procedure, results of a recent registry study suggest.
Patients who received perioperative RBC transfusions had significantly higher odds of developing postoperative venous thromboembolism (VTE) overall, as well as higher odds specifically for deep venous thrombosis (DVT) and pulmonary embolism (PE), according to results published in JAMA Surgery.
“In a subset of patients receiving perioperative RBC transfusions, a synergistic and incremental dose-related risk for VTE development may exist,” Dr. Goel and her coauthors wrote.
The analysis was based on prospectively collected North American registry data including 750,937 patients who underwent a surgical procedure in 2014, of which 47,410 (6.3%) received one or more perioperative RBC transfusions. VTE occurred in 6,309 patients (0.8%), of which 4,336 cases were DVT (0.6%) and 2,514 were PE (0.3%).
The patients who received perioperative RBC transfusions had significantly increased odds of developing VTE in the 30-day postoperative period (adjusted odds ratio, 2.1; 95% confidence interval, 2.0-2.3) versus those who had no transfusions, according to results of a multivariable analysis adjusting for age, sex, length of hospital stay, use of mechanical ventilation, and other potentially confounding factors.
Similarly, researchers found transfused patients had higher odds of both DVT (aOR, 2.2; 95% CI, 2.1-2.4), and PE (aOR, 1.9; 95% CI, 1.7-2.1).
Odds of VTE increased significantly along with increasing number of perioperative RBC transfusions from an aOR of 2.1 for those with just one transfusion to 4.5 for those who had three or more transfusion events (P less than .001 for trend), results of a dose-response analysis showed.
The association between RBC transfusions perioperatively and VTE postoperatively remained robust after propensity score matching and was statistically significant in all surgical subspecialties, the researchers reported.
However, they also noted that these results will require validation in prospective cohort studies and randomized clinical trials. “If proven, they underscore the continued need for more stringent and optimal perioperative blood management practices in addition to rigorous VTE prophylaxis in patients undergoing surgery.”
The study was funded in part by grants from the National Institutes of Health and Cornell University. The researchers reported having no conflicts of interest.
SOURCE: Goel R et al. JAMA Surg. 2018 Jun 13. doi: 10.1001/jamasurg.2018.1565.
In patients undergoing surgery, RBC transfusions may be associated with the development of new or progressive venous thromboembolism within 30 days of the procedure, results of a recent registry study suggest.
Patients who received perioperative RBC transfusions had significantly higher odds of developing postoperative venous thromboembolism (VTE) overall, as well as higher odds specifically for deep venous thrombosis (DVT) and pulmonary embolism (PE), according to results published in JAMA Surgery.
“In a subset of patients receiving perioperative RBC transfusions, a synergistic and incremental dose-related risk for VTE development may exist,” Dr. Goel and her coauthors wrote.
The analysis was based on prospectively collected North American registry data including 750,937 patients who underwent a surgical procedure in 2014, of which 47,410 (6.3%) received one or more perioperative RBC transfusions. VTE occurred in 6,309 patients (0.8%), of which 4,336 cases were DVT (0.6%) and 2,514 were PE (0.3%).
The patients who received perioperative RBC transfusions had significantly increased odds of developing VTE in the 30-day postoperative period (adjusted odds ratio, 2.1; 95% confidence interval, 2.0-2.3) versus those who had no transfusions, according to results of a multivariable analysis adjusting for age, sex, length of hospital stay, use of mechanical ventilation, and other potentially confounding factors.
Similarly, researchers found transfused patients had higher odds of both DVT (aOR, 2.2; 95% CI, 2.1-2.4), and PE (aOR, 1.9; 95% CI, 1.7-2.1).
Odds of VTE increased significantly along with increasing number of perioperative RBC transfusions from an aOR of 2.1 for those with just one transfusion to 4.5 for those who had three or more transfusion events (P less than .001 for trend), results of a dose-response analysis showed.
The association between RBC transfusions perioperatively and VTE postoperatively remained robust after propensity score matching and was statistically significant in all surgical subspecialties, the researchers reported.
However, they also noted that these results will require validation in prospective cohort studies and randomized clinical trials. “If proven, they underscore the continued need for more stringent and optimal perioperative blood management practices in addition to rigorous VTE prophylaxis in patients undergoing surgery.”
The study was funded in part by grants from the National Institutes of Health and Cornell University. The researchers reported having no conflicts of interest.
SOURCE: Goel R et al. JAMA Surg. 2018 Jun 13. doi: 10.1001/jamasurg.2018.1565.
FROM JAMA SURGERY
Key clinical point:
Major finding: Patients who received perioperative RBC transfusions had significantly increased odds of developing VTE in the 30-day postoperative period (adjusted odds ratio, 2.1; 95% confidence interval, 2.0-2.3), compared with patients who did not receive transfusions.
Study details: An analysis of prospectively collected North American registry data including 750,937 patients who underwent a surgical procedure in 2014.
Disclosures: The study was funded in part by grants from the National Institutes of Health and Cornell University, New York. The researchers reported having no conflicts of interest.
Source: Goel R et al. JAMA Surg. 2018 Jun 13. doi: 10.1001/jamasurg.2018.1565.
Risk of Recurrent ICH Is Higher Among Blacks and Hispanics
The increased severity of hypertension among minorities does not fully account for their increased risk.
Compared with their white peers, black and Hispanic patients with intracerebral hemorrhage (ICH) have a higher risk of recurrence, according to data published online ahead of print June 6 in Neurology. Although black and Hispanic patients have more severe hypertension than whites do, severity of hypertension does not fully account for this increased risk. Future studies should examine whether novel biologic, socioeconomic, or cultural factors play a role, said the researchers.
The scientific literature indicates that blacks and Hispanics have a higher risk of first ICH than whites do. Alessandro Biffi, MD, head of the Aging and Brain Health Research group at Massachusetts General Hospital in Boston, and colleagues hypothesized that hypertension among these populations might contribute toward this increased risk. Because the subject had not been explored previously, Dr. Biffi and colleagues investigated the role of blood pressure and its variability in determining the risk of recurrent ICH among nonwhites. 
An Analysis of Two Studies
The authors examined data from a longitudinal study of ICH conducted by Massachusetts General Hospital and from the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study. They included patients who were 18 or older with a diagnosis of acute primary ICH in their analysis.
At enrollment, participants reported their race or ethnicity during a structured interview and underwent blood pressure measurement. The investigators performed follow-up through phone calls and reviews of medical records. Every six months, investigators recorded at least one blood-pressure measurement and quantified blood-pressure variability. Dr. Biffi and colleagues used Cox regression survival analysis to identify risk factors for ICH recurrence.
Systolic Blood Pressure Was Associated With Recurrence
Of the 2,291 patients included in the analysis, 1,121 were white, 529 were black, 605 were Hispanic, and 36 were of other race or ethnicity. The median systolic blood pressure during follow-up was 149 mm Hg for black participants, 146 mm Hg for Hispanic participants, and 141 mm Hg for white participants. Systolic blood pressure variability also was higher for black participants (median, 3.5%), compared with white participants (median
In all, 26 (1.7%) white participants had ICH recurrence, compared with 35 (6.6%) black participants and 37 (6.1%) Hispanic participants. In univariable analyses, higher systolic blood pressure and greater systolic blood pressure variability were associated with increased ICH recurrence risk. Diastolic blood pressure and diastolic blood pressure variability, however, were not associated with ICH recurrence risk.
In multivariable analyses, black and Hispanic race or ethnicity remained independently associated with increased ICH recurrence risk in both studies, even after adjustment for systolic blood pressure and systolic blood pressure variability. Exposure to antihypertensive agents during follow-up was not associated with ICH recurrence and did not affect the results significantly. The associations were consistent in both studies.
Suggested Reading
Rodriguez-Torres A, Murphy M, Kourkoulis C, et al. Hypertension and intracerebral hemorrhage recurrence among white, black, and Hispanic individuals. Neurology. 2018 Jun 6 [Epub ahead of print].
The increased severity of hypertension among minorities does not fully account for their increased risk.
The increased severity of hypertension among minorities does not fully account for their increased risk.
Compared with their white peers, black and Hispanic patients with intracerebral hemorrhage (ICH) have a higher risk of recurrence, according to data published online ahead of print June 6 in Neurology. Although black and Hispanic patients have more severe hypertension than whites do, severity of hypertension does not fully account for this increased risk. Future studies should examine whether novel biologic, socioeconomic, or cultural factors play a role, said the researchers.
The scientific literature indicates that blacks and Hispanics have a higher risk of first ICH than whites do. Alessandro Biffi, MD, head of the Aging and Brain Health Research group at Massachusetts General Hospital in Boston, and colleagues hypothesized that hypertension among these populations might contribute toward this increased risk. Because the subject had not been explored previously, Dr. Biffi and colleagues investigated the role of blood pressure and its variability in determining the risk of recurrent ICH among nonwhites.
An Analysis of Two Studies
The authors examined data from a longitudinal study of ICH conducted by Massachusetts General Hospital and from the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study. They included patients who were 18 or older with a diagnosis of acute primary ICH in their analysis.
At enrollment, participants reported their race or ethnicity during a structured interview and underwent blood pressure measurement. The investigators performed follow-up through phone calls and reviews of medical records. Every six months, investigators recorded at least one blood-pressure measurement and quantified blood-pressure variability. Dr. Biffi and colleagues used Cox regression survival analysis to identify risk factors for ICH recurrence.
Systolic Blood Pressure Was Associated With Recurrence
Of the 2,291 patients included in the analysis, 1,121 were white, 529 were black, 605 were Hispanic, and 36 were of other race or ethnicity. The median systolic blood pressure during follow-up was 149 mm Hg for black participants, 146 mm Hg for Hispanic participants, and 141 mm Hg for white participants. Systolic blood pressure variability also was higher for black participants (median, 3.5%), compared with white participants (median
In all, 26 (1.7%) white participants had ICH recurrence, compared with 35 (6.6%) black participants and 37 (6.1%) Hispanic participants. In univariable analyses, higher systolic blood pressure and greater systolic blood pressure variability were associated with increased ICH recurrence risk. Diastolic blood pressure and diastolic blood pressure variability, however, were not associated with ICH recurrence risk.
In multivariable analyses, black and Hispanic race or ethnicity remained independently associated with increased ICH recurrence risk in both studies, even after adjustment for systolic blood pressure and systolic blood pressure variability. Exposure to antihypertensive agents during follow-up was not associated with ICH recurrence and did not affect the results significantly. The associations were consistent in both studies.
Suggested Reading
Rodriguez-Torres A, Murphy M, Kourkoulis C, et al. Hypertension and intracerebral hemorrhage recurrence among white, black, and Hispanic individuals. Neurology. 2018 Jun 6 [Epub ahead of print].
Compared with their white peers, black and Hispanic patients with intracerebral hemorrhage (ICH) have a higher risk of recurrence, according to data published online ahead of print June 6 in Neurology. Although black and Hispanic patients have more severe hypertension than whites do, severity of hypertension does not fully account for this increased risk. Future studies should examine whether novel biologic, socioeconomic, or cultural factors play a role, said the researchers.
The scientific literature indicates that blacks and Hispanics have a higher risk of first ICH than whites do. Alessandro Biffi, MD, head of the Aging and Brain Health Research group at Massachusetts General Hospital in Boston, and colleagues hypothesized that hypertension among these populations might contribute toward this increased risk. Because the subject had not been explored previously, Dr. Biffi and colleagues investigated the role of blood pressure and its variability in determining the risk of recurrent ICH among nonwhites.
An Analysis of Two Studies
The authors examined data from a longitudinal study of ICH conducted by Massachusetts General Hospital and from the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study. They included patients who were 18 or older with a diagnosis of acute primary ICH in their analysis.
At enrollment, participants reported their race or ethnicity during a structured interview and underwent blood pressure measurement. The investigators performed follow-up through phone calls and reviews of medical records. Every six months, investigators recorded at least one blood-pressure measurement and quantified blood-pressure variability. Dr. Biffi and colleagues used Cox regression survival analysis to identify risk factors for ICH recurrence.
Systolic Blood Pressure Was Associated With Recurrence
Of the 2,291 patients included in the analysis, 1,121 were white, 529 were black, 605 were Hispanic, and 36 were of other race or ethnicity. The median systolic blood pressure during follow-up was 149 mm Hg for black participants, 146 mm Hg for Hispanic participants, and 141 mm Hg for white participants. Systolic blood pressure variability also was higher for black participants (median, 3.5%), compared with white participants (median
In all, 26 (1.7%) white participants had ICH recurrence, compared with 35 (6.6%) black participants and 37 (6.1%) Hispanic participants. In univariable analyses, higher systolic blood pressure and greater systolic blood pressure variability were associated with increased ICH recurrence risk. Diastolic blood pressure and diastolic blood pressure variability, however, were not associated with ICH recurrence risk.
In multivariable analyses, black and Hispanic race or ethnicity remained independently associated with increased ICH recurrence risk in both studies, even after adjustment for systolic blood pressure and systolic blood pressure variability. Exposure to antihypertensive agents during follow-up was not associated with ICH recurrence and did not affect the results significantly. The associations were consistent in both studies.
Suggested Reading
Rodriguez-Torres A, Murphy M, Kourkoulis C, et al. Hypertension and intracerebral hemorrhage recurrence among white, black, and Hispanic individuals. Neurology. 2018 Jun 6 [Epub ahead of print].
Giving hospitalists a larger clinical footprint
Sneak Peek: The Hospital Leader blog
“We are playing the same sport, but a different game,” the wise, thoughtful emergency medicine attending physician once told me. “I am playing speed chess – I need to make a move quickly, or I lose – no matter what. My moves have to be right, but they don’t always necessarily need to be the optimal one. I am not always thinking five moves ahead. You guys [in internal medicine] are playing master chess. You have more time, but that means you are trying to always think about the whole game and make the best move possible.”
The pendulum has swung quickly from, “problem #7, chronic anemia: stable but I am not sure it has been worked up before, so I ordered a smear, retic count, and iron panel,” to “problem #1, acute blood loss anemia: now stable after transfusion, seems safe for discharge and GI follow-up.” (NOTE: “Acute blood loss anemia” is a phrase I learned from our “clinical documentation integrity specialist” – I think it gets me “50 CDI points” or something.)
Our job is not merely to work shifts and stabilize patients – there already is a specialty for that, and it is not the one we chose.
Clearly the correct balance is somewhere between the two extremes of “working up everything” and “deferring (nearly) everything to the outpatient setting.”
There are many forces that are contributing to current hospitalist work styles. As the work continues to become more exhaustingly intense and the average number of patients seen by a hospitalist grows impossibly upward, the duration of on-service stints has shortened.
In most settings, long gone are the days of the month-long teaching attending rotation. By day 12, I feel worn and ragged. For “nonteaching” services, hospitalists seem to increasingly treat each day as a separate shift to be covered, oftentimes handing the service back-and-forth every few days, or a week at most. With this structure, who can possibly think about the “whole patient”? Whose patient is this anyways?
Read the full post at hospitalleader.org.
Also on The Hospital Leader …
- How Hospitalists See the Forgotten Victims of Gun Violence by Vineet Arora, MD, MAPP, MHM
- Hospitals, Hospice and SNFs: The Big Deceit by Brad Flansbaum, DO, MPH, MHM
- But He’s a Good Doctor by Leslie Flores, MHA, SFHM
Sneak Peek: The Hospital Leader blog
Sneak Peek: The Hospital Leader blog
“We are playing the same sport, but a different game,” the wise, thoughtful emergency medicine attending physician once told me. “I am playing speed chess – I need to make a move quickly, or I lose – no matter what. My moves have to be right, but they don’t always necessarily need to be the optimal one. I am not always thinking five moves ahead. You guys [in internal medicine] are playing master chess. You have more time, but that means you are trying to always think about the whole game and make the best move possible.”
The pendulum has swung quickly from, “problem #7, chronic anemia: stable but I am not sure it has been worked up before, so I ordered a smear, retic count, and iron panel,” to “problem #1, acute blood loss anemia: now stable after transfusion, seems safe for discharge and GI follow-up.” (NOTE: “Acute blood loss anemia” is a phrase I learned from our “clinical documentation integrity specialist” – I think it gets me “50 CDI points” or something.)
Our job is not merely to work shifts and stabilize patients – there already is a specialty for that, and it is not the one we chose.
Clearly the correct balance is somewhere between the two extremes of “working up everything” and “deferring (nearly) everything to the outpatient setting.”
There are many forces that are contributing to current hospitalist work styles. As the work continues to become more exhaustingly intense and the average number of patients seen by a hospitalist grows impossibly upward, the duration of on-service stints has shortened.
In most settings, long gone are the days of the month-long teaching attending rotation. By day 12, I feel worn and ragged. For “nonteaching” services, hospitalists seem to increasingly treat each day as a separate shift to be covered, oftentimes handing the service back-and-forth every few days, or a week at most. With this structure, who can possibly think about the “whole patient”? Whose patient is this anyways?
Read the full post at hospitalleader.org.
Also on The Hospital Leader …
- How Hospitalists See the Forgotten Victims of Gun Violence by Vineet Arora, MD, MAPP, MHM
- Hospitals, Hospice and SNFs: The Big Deceit by Brad Flansbaum, DO, MPH, MHM
- But He’s a Good Doctor by Leslie Flores, MHA, SFHM
“We are playing the same sport, but a different game,” the wise, thoughtful emergency medicine attending physician once told me. “I am playing speed chess – I need to make a move quickly, or I lose – no matter what. My moves have to be right, but they don’t always necessarily need to be the optimal one. I am not always thinking five moves ahead. You guys [in internal medicine] are playing master chess. You have more time, but that means you are trying to always think about the whole game and make the best move possible.”
The pendulum has swung quickly from, “problem #7, chronic anemia: stable but I am not sure it has been worked up before, so I ordered a smear, retic count, and iron panel,” to “problem #1, acute blood loss anemia: now stable after transfusion, seems safe for discharge and GI follow-up.” (NOTE: “Acute blood loss anemia” is a phrase I learned from our “clinical documentation integrity specialist” – I think it gets me “50 CDI points” or something.)
Our job is not merely to work shifts and stabilize patients – there already is a specialty for that, and it is not the one we chose.
Clearly the correct balance is somewhere between the two extremes of “working up everything” and “deferring (nearly) everything to the outpatient setting.”
There are many forces that are contributing to current hospitalist work styles. As the work continues to become more exhaustingly intense and the average number of patients seen by a hospitalist grows impossibly upward, the duration of on-service stints has shortened.
In most settings, long gone are the days of the month-long teaching attending rotation. By day 12, I feel worn and ragged. For “nonteaching” services, hospitalists seem to increasingly treat each day as a separate shift to be covered, oftentimes handing the service back-and-forth every few days, or a week at most. With this structure, who can possibly think about the “whole patient”? Whose patient is this anyways?
Read the full post at hospitalleader.org.
Also on The Hospital Leader …
- How Hospitalists See the Forgotten Victims of Gun Violence by Vineet Arora, MD, MAPP, MHM
- Hospitals, Hospice and SNFs: The Big Deceit by Brad Flansbaum, DO, MPH, MHM
- But He’s a Good Doctor by Leslie Flores, MHA, SFHM
How congenital heart disease affects brain development
Congenital heart disease (CHD) is the most common congenital anomaly, with an estimated incidence of 6-12 per 1,000 live births. It is also the congenital anomaly that most often leads to death or significant morbidity. Advances in surgical procedures and operating room care as well as specialized care in the ICU have led to significant improvements in survival over the past 10-20 years – even for the most complex cases of CHD. We now expect the majority of newborns with CHD not only to survive, but to grow up into adulthood.
The focus of clinical research has thus transitioned from survival to issues of long-term morbidity and outcomes, and the more recent literature has clearly shown us that children with CHD are at high risk of learning disabilities and other neurodevelopmental abnormalities. The prevalence of impairment rises with the complexity of CHD, from a prevalence of approximately 20% in mild CHD to as much as 75% in severe CHD. Almost all neonates and infants who undergo palliative surgical procedures have neurodevelopmental impairments.
The neurobehavioral “signature” of CHD includes cognitive defects (usually mild), short attention span, fine and gross motor delays, speech and language delays, visual motor integration, and executive function deficits. Executive function deficits and attention deficits are among the problems that often do not present in children until they reach middle school and beyond, when they are expected to learn more complicated material and handle more complex tasks. Long-term surveillance and care have thus become a major focus at our institution and others throughout the country.
At the same time, evidence has increased in the past 5-10 years that adverse neurodevelopmental outcomes in children with complex CHD may stem from genetic factors as well as compromise to the brain in utero because of altered blood flow, compromise at the time of delivery, and insults during and after corrective or palliative surgery. Surgical strategies and operating room teams have become significantly better at protecting the brain, and new research now is directed toward understanding the neurologic abnormalities that are present in newborns prior to surgical intervention.
Increasingly, researchers are now focused on looking at the in utero origins of brain impairments in children with CHD and trying to understand specific prenatal causes, mechanisms, and potentially modifiable factors. We’re asking what we can do during pregnancy to improve neurodevelopmental outcomes.
Impaired brain growth
The question of how CHD affects blood flow to the fetal brain is an important one. We found some time ago in a study using Doppler ultrasound that 44% of fetuses with CHD had blood flow abnormalities in the middle cerebral artery at some point in the late second or third trimester, suggesting that the blood vessels had dilated to allow more cerebral perfusion. This phenomenon, termed “brain sparing,” is believed to be an autoregulatory mechanism that occurs as a result of diminished oxygen delivery or inadequate blood flow to the brain (Pediatr Cardiol. 2003 Jan;24[5]:436-43).
Subsequent studies have similarly documented abnormal cerebral blood flow in fetuses with various types of congenital heart lesions. What is left to be determined is whether this autoregulatory mechanism is adequate to maintain perfusion in the presence of specific, high-risk CHD.
Abnormalities were more often seen in CHD with obstructed aortic flow, such as hypoplastic left heart syndrome (HLHS) in which the aorta is perfused retrograde through the fetal ductus arteriosus (Circulation. 2010 Jan 4;121:26-33).
Other fetal imaging studies have similarly demonstrated a progressive third-trimester decrease in both cortical gray and white matter and in gyrification (cortical folding) (Cereb Cortex. 2013;23:2932-43), as well as decreased cerebral oxygen delivery and consumption (Circulation. 2015;131:1313-23) in fetuses with severe CHD. It appears that the brain may start out normal in size, but in the third trimester, the accelerated metabolic demands that come with rapid growth and development are not sufficiently met by the fetal cardiovascular circulation in CHD.
In the newborn with CHD, preoperative brain imaging studies have demonstrated structural abnormalities suggesting delayed development (for example, microcephaly and a widened operculum), microstructural abnormalities suggesting abnormal myelination and neuroaxonal development, and lower brain maturity scores (a composite score that combines multiple factors, such as myelination and cortical in-folding, to represent “brain age”).
Moreover, some of the newborn brain imaging studies have correlated brain MRI findings with neonatal neurodevelopmental assessments. For instance, investigators found that full-term newborns with CHD had decreased gray matter brain volume and increased cerebrospinal fluid volume and that these impairments were associated with poor behavioral state regulation and poor visual orienting (J Pediatr. 2014;164:1121-7).
Interestingly, it has been found that the full-term baby with specific complex CHD, including newborns with single ventricle CHD or transposition of the great arteries, is more likely to have a brain maturity score that is equivalent to that of a baby born at 35 weeks’ gestation. This means that, in some infants with CHD, the brain has lagged in growth by about a month, resulting in a pattern of disturbed development and subsequent injury that is similar to that of premature infants.
It also means that infants with CHD and an immature brain are especially vulnerable to brain injury when open-heart surgery is needed. In short, we now appreciate that the brain in patients with CHD is likely more fragile than we previously thought – and that this fragility is prenatal in its origins.
Delivery room planning
Ideally, our goal is to find ways of changing the circulation in utero to improve cerebral oxygenation and blood flow, and, consequently, improve brain development and long-term neurocognitive function. Despite significant efforts in this area, we’re not there yet.
Examples of strategies that are being tested include catheter intervention to open the aortic valve in utero for fetuses with critical aortic stenosis. This procedure currently is being performed to try to prevent progression of the valve abnormality to HLHS, but it has not been determined whether the intervention affects cerebral blood flow. Maternal oxygen therapy has been shown to change cerebral blood flow in the short term for fetuses with HLHS, but its long-term use has not been studied. At the time of birth, to prevent injury in the potentially more fragile brain of the newborn with CHD, what we can do is to identify those fetuses who are more likely to be at risk for hypoxia low cardiac output and hemodynamic compromise in the delivery room, and plan for specialized delivery room and perinatal management beyond standard neonatal care.
Most newborns with CHD are assigned to Level 1; they have no predicted risk of compromise in the delivery room – or even in the first couple weeks of life – and can deliver at a local hospital with neonatal evaluation and then consult with the pediatric cardiologist. Defects include shunt lesions such as septal defects or mild valve abnormalities.
Patients assigned to Level 2 have minimal risk of compromise in the delivery room but are expected to require postnatal surgery, cardiac catheterization, or another procedure before going home. They can be stabilized by the neonatologist, usually with initiation of a prostaglandin infusion, before transfer to the cardiac center for the planned intervention. Defects include single ventricle CHD and severe Tetralogy of Fallot.
Fetuses assigned to Level 3 and Level 4 are expected to have hemodynamic instability at cord clamping, requiring immediate specialty care in the delivery room that is likely to include urgent cardiac catheterization or surgical intervention. These defects are rare and include diagnoses such as transposition of the great arteries, HLHS with a restrictive or closed foramen ovale, and CHD with associated heart failure and hydrops.
We have found that fetal echocardiography accurately predicts postnatal risk and the need for specialized delivery room care in newborns diagnosed in utero with CHD and that level-of-care protocols ensure safe delivery and optimize fetal outcomes (J Am Soc Echocardiogr. 2015;28:1339-49; Am J Cardiol. 2013;111:737-47).
Such delivery planning, which is coordinated between obstetric, neonatal, cardiology, and surgical services with specialty teams as needed (for example, cardiac intensive care, interventional cardiology, and cardiac surgery), is recommended in a 2014 AHA statement on the diagnosis and treatment of fetal cardiac disease. In recent years it has become the standard of care in many health systems (Circulation. 2014;129[21]:2183-242).
The effect of maternal stress on the in utero environment is also getting increased attention in pediatric cardiology. Alterations in neurocognitive development and fetal and child cardiovascular health are likely to be associated with maternal stress during pregnancy, and studies have shown that maternal stress is high with prenatal diagnoses of CHD. We have to ask: Is stress a modifiable risk factor? There must be ways in which we can do better with prenatal counseling and support after a fetal diagnosis of CHD.
Screening for CHD
Initiating strategies to improve neurodevelopmental outcomes in infants with CHD rests partly on identifying babies with CHD before birth through improved fetal cardiac screening. Research cited in the 2014 AHA statement indicates that nearly all women giving birth to babies with CHD in the United States have obstetric ultrasound examinations in the second or third trimesters, but that only about 30% of the fetuses are diagnosed prenatally.
Current indications for referral for a fetal echocardiogram – in addition to suspicion of a structural heart abnormality on obstetric ultrasound – include maternal factors, such as diabetes mellitus, that raise the risk of CHD above the baseline population risk for low-risk pregnancies.
Women with pregestational diabetes mellitus have a nearly fivefold increase in CHD, compared with the general population (3%-5%), and should be referred for fetal echocardiography. Women with gestational diabetes mellitus have no or minimally increased risk for fetal CHD, but it has been shown that there is an increased risk for cardiac hypertrophy – particularly late in gestation – if glycemic levels are poorly controlled. The 2014 AHA guidelines recommend that fetal echocardiographic evaluation be considered in those who have HbA1c levels greater than 6% in the second half of pregnancy.
Dr. Mary T. Donofrio is a pediatric cardiologist and director of the fetal heart program and critical care delivery program at Children’s National Medical Center, Washington. She reported that she has no disclosures relevant to this article.
Congenital heart disease (CHD) is the most common congenital anomaly, with an estimated incidence of 6-12 per 1,000 live births. It is also the congenital anomaly that most often leads to death or significant morbidity. Advances in surgical procedures and operating room care as well as specialized care in the ICU have led to significant improvements in survival over the past 10-20 years – even for the most complex cases of CHD. We now expect the majority of newborns with CHD not only to survive, but to grow up into adulthood.
The focus of clinical research has thus transitioned from survival to issues of long-term morbidity and outcomes, and the more recent literature has clearly shown us that children with CHD are at high risk of learning disabilities and other neurodevelopmental abnormalities. The prevalence of impairment rises with the complexity of CHD, from a prevalence of approximately 20% in mild CHD to as much as 75% in severe CHD. Almost all neonates and infants who undergo palliative surgical procedures have neurodevelopmental impairments.
The neurobehavioral “signature” of CHD includes cognitive defects (usually mild), short attention span, fine and gross motor delays, speech and language delays, visual motor integration, and executive function deficits. Executive function deficits and attention deficits are among the problems that often do not present in children until they reach middle school and beyond, when they are expected to learn more complicated material and handle more complex tasks. Long-term surveillance and care have thus become a major focus at our institution and others throughout the country.
At the same time, evidence has increased in the past 5-10 years that adverse neurodevelopmental outcomes in children with complex CHD may stem from genetic factors as well as compromise to the brain in utero because of altered blood flow, compromise at the time of delivery, and insults during and after corrective or palliative surgery. Surgical strategies and operating room teams have become significantly better at protecting the brain, and new research now is directed toward understanding the neurologic abnormalities that are present in newborns prior to surgical intervention.
Increasingly, researchers are now focused on looking at the in utero origins of brain impairments in children with CHD and trying to understand specific prenatal causes, mechanisms, and potentially modifiable factors. We’re asking what we can do during pregnancy to improve neurodevelopmental outcomes.
Impaired brain growth
The question of how CHD affects blood flow to the fetal brain is an important one. We found some time ago in a study using Doppler ultrasound that 44% of fetuses with CHD had blood flow abnormalities in the middle cerebral artery at some point in the late second or third trimester, suggesting that the blood vessels had dilated to allow more cerebral perfusion. This phenomenon, termed “brain sparing,” is believed to be an autoregulatory mechanism that occurs as a result of diminished oxygen delivery or inadequate blood flow to the brain (Pediatr Cardiol. 2003 Jan;24[5]:436-43).
Subsequent studies have similarly documented abnormal cerebral blood flow in fetuses with various types of congenital heart lesions. What is left to be determined is whether this autoregulatory mechanism is adequate to maintain perfusion in the presence of specific, high-risk CHD.
Abnormalities were more often seen in CHD with obstructed aortic flow, such as hypoplastic left heart syndrome (HLHS) in which the aorta is perfused retrograde through the fetal ductus arteriosus (Circulation. 2010 Jan 4;121:26-33).
Other fetal imaging studies have similarly demonstrated a progressive third-trimester decrease in both cortical gray and white matter and in gyrification (cortical folding) (Cereb Cortex. 2013;23:2932-43), as well as decreased cerebral oxygen delivery and consumption (Circulation. 2015;131:1313-23) in fetuses with severe CHD. It appears that the brain may start out normal in size, but in the third trimester, the accelerated metabolic demands that come with rapid growth and development are not sufficiently met by the fetal cardiovascular circulation in CHD.
In the newborn with CHD, preoperative brain imaging studies have demonstrated structural abnormalities suggesting delayed development (for example, microcephaly and a widened operculum), microstructural abnormalities suggesting abnormal myelination and neuroaxonal development, and lower brain maturity scores (a composite score that combines multiple factors, such as myelination and cortical in-folding, to represent “brain age”).
Moreover, some of the newborn brain imaging studies have correlated brain MRI findings with neonatal neurodevelopmental assessments. For instance, investigators found that full-term newborns with CHD had decreased gray matter brain volume and increased cerebrospinal fluid volume and that these impairments were associated with poor behavioral state regulation and poor visual orienting (J Pediatr. 2014;164:1121-7).
Interestingly, it has been found that the full-term baby with specific complex CHD, including newborns with single ventricle CHD or transposition of the great arteries, is more likely to have a brain maturity score that is equivalent to that of a baby born at 35 weeks’ gestation. This means that, in some infants with CHD, the brain has lagged in growth by about a month, resulting in a pattern of disturbed development and subsequent injury that is similar to that of premature infants.
It also means that infants with CHD and an immature brain are especially vulnerable to brain injury when open-heart surgery is needed. In short, we now appreciate that the brain in patients with CHD is likely more fragile than we previously thought – and that this fragility is prenatal in its origins.
Delivery room planning
Ideally, our goal is to find ways of changing the circulation in utero to improve cerebral oxygenation and blood flow, and, consequently, improve brain development and long-term neurocognitive function. Despite significant efforts in this area, we’re not there yet.
Examples of strategies that are being tested include catheter intervention to open the aortic valve in utero for fetuses with critical aortic stenosis. This procedure currently is being performed to try to prevent progression of the valve abnormality to HLHS, but it has not been determined whether the intervention affects cerebral blood flow. Maternal oxygen therapy has been shown to change cerebral blood flow in the short term for fetuses with HLHS, but its long-term use has not been studied. At the time of birth, to prevent injury in the potentially more fragile brain of the newborn with CHD, what we can do is to identify those fetuses who are more likely to be at risk for hypoxia low cardiac output and hemodynamic compromise in the delivery room, and plan for specialized delivery room and perinatal management beyond standard neonatal care.
Most newborns with CHD are assigned to Level 1; they have no predicted risk of compromise in the delivery room – or even in the first couple weeks of life – and can deliver at a local hospital with neonatal evaluation and then consult with the pediatric cardiologist. Defects include shunt lesions such as septal defects or mild valve abnormalities.
Patients assigned to Level 2 have minimal risk of compromise in the delivery room but are expected to require postnatal surgery, cardiac catheterization, or another procedure before going home. They can be stabilized by the neonatologist, usually with initiation of a prostaglandin infusion, before transfer to the cardiac center for the planned intervention. Defects include single ventricle CHD and severe Tetralogy of Fallot.
Fetuses assigned to Level 3 and Level 4 are expected to have hemodynamic instability at cord clamping, requiring immediate specialty care in the delivery room that is likely to include urgent cardiac catheterization or surgical intervention. These defects are rare and include diagnoses such as transposition of the great arteries, HLHS with a restrictive or closed foramen ovale, and CHD with associated heart failure and hydrops.
We have found that fetal echocardiography accurately predicts postnatal risk and the need for specialized delivery room care in newborns diagnosed in utero with CHD and that level-of-care protocols ensure safe delivery and optimize fetal outcomes (J Am Soc Echocardiogr. 2015;28:1339-49; Am J Cardiol. 2013;111:737-47).
Such delivery planning, which is coordinated between obstetric, neonatal, cardiology, and surgical services with specialty teams as needed (for example, cardiac intensive care, interventional cardiology, and cardiac surgery), is recommended in a 2014 AHA statement on the diagnosis and treatment of fetal cardiac disease. In recent years it has become the standard of care in many health systems (Circulation. 2014;129[21]:2183-242).
The effect of maternal stress on the in utero environment is also getting increased attention in pediatric cardiology. Alterations in neurocognitive development and fetal and child cardiovascular health are likely to be associated with maternal stress during pregnancy, and studies have shown that maternal stress is high with prenatal diagnoses of CHD. We have to ask: Is stress a modifiable risk factor? There must be ways in which we can do better with prenatal counseling and support after a fetal diagnosis of CHD.
Screening for CHD
Initiating strategies to improve neurodevelopmental outcomes in infants with CHD rests partly on identifying babies with CHD before birth through improved fetal cardiac screening. Research cited in the 2014 AHA statement indicates that nearly all women giving birth to babies with CHD in the United States have obstetric ultrasound examinations in the second or third trimesters, but that only about 30% of the fetuses are diagnosed prenatally.
Current indications for referral for a fetal echocardiogram – in addition to suspicion of a structural heart abnormality on obstetric ultrasound – include maternal factors, such as diabetes mellitus, that raise the risk of CHD above the baseline population risk for low-risk pregnancies.
Women with pregestational diabetes mellitus have a nearly fivefold increase in CHD, compared with the general population (3%-5%), and should be referred for fetal echocardiography. Women with gestational diabetes mellitus have no or minimally increased risk for fetal CHD, but it has been shown that there is an increased risk for cardiac hypertrophy – particularly late in gestation – if glycemic levels are poorly controlled. The 2014 AHA guidelines recommend that fetal echocardiographic evaluation be considered in those who have HbA1c levels greater than 6% in the second half of pregnancy.
Dr. Mary T. Donofrio is a pediatric cardiologist and director of the fetal heart program and critical care delivery program at Children’s National Medical Center, Washington. She reported that she has no disclosures relevant to this article.
Congenital heart disease (CHD) is the most common congenital anomaly, with an estimated incidence of 6-12 per 1,000 live births. It is also the congenital anomaly that most often leads to death or significant morbidity. Advances in surgical procedures and operating room care as well as specialized care in the ICU have led to significant improvements in survival over the past 10-20 years – even for the most complex cases of CHD. We now expect the majority of newborns with CHD not only to survive, but to grow up into adulthood.
The focus of clinical research has thus transitioned from survival to issues of long-term morbidity and outcomes, and the more recent literature has clearly shown us that children with CHD are at high risk of learning disabilities and other neurodevelopmental abnormalities. The prevalence of impairment rises with the complexity of CHD, from a prevalence of approximately 20% in mild CHD to as much as 75% in severe CHD. Almost all neonates and infants who undergo palliative surgical procedures have neurodevelopmental impairments.
The neurobehavioral “signature” of CHD includes cognitive defects (usually mild), short attention span, fine and gross motor delays, speech and language delays, visual motor integration, and executive function deficits. Executive function deficits and attention deficits are among the problems that often do not present in children until they reach middle school and beyond, when they are expected to learn more complicated material and handle more complex tasks. Long-term surveillance and care have thus become a major focus at our institution and others throughout the country.
At the same time, evidence has increased in the past 5-10 years that adverse neurodevelopmental outcomes in children with complex CHD may stem from genetic factors as well as compromise to the brain in utero because of altered blood flow, compromise at the time of delivery, and insults during and after corrective or palliative surgery. Surgical strategies and operating room teams have become significantly better at protecting the brain, and new research now is directed toward understanding the neurologic abnormalities that are present in newborns prior to surgical intervention.
Increasingly, researchers are now focused on looking at the in utero origins of brain impairments in children with CHD and trying to understand specific prenatal causes, mechanisms, and potentially modifiable factors. We’re asking what we can do during pregnancy to improve neurodevelopmental outcomes.
Impaired brain growth
The question of how CHD affects blood flow to the fetal brain is an important one. We found some time ago in a study using Doppler ultrasound that 44% of fetuses with CHD had blood flow abnormalities in the middle cerebral artery at some point in the late second or third trimester, suggesting that the blood vessels had dilated to allow more cerebral perfusion. This phenomenon, termed “brain sparing,” is believed to be an autoregulatory mechanism that occurs as a result of diminished oxygen delivery or inadequate blood flow to the brain (Pediatr Cardiol. 2003 Jan;24[5]:436-43).
Subsequent studies have similarly documented abnormal cerebral blood flow in fetuses with various types of congenital heart lesions. What is left to be determined is whether this autoregulatory mechanism is adequate to maintain perfusion in the presence of specific, high-risk CHD.
Abnormalities were more often seen in CHD with obstructed aortic flow, such as hypoplastic left heart syndrome (HLHS) in which the aorta is perfused retrograde through the fetal ductus arteriosus (Circulation. 2010 Jan 4;121:26-33).
Other fetal imaging studies have similarly demonstrated a progressive third-trimester decrease in both cortical gray and white matter and in gyrification (cortical folding) (Cereb Cortex. 2013;23:2932-43), as well as decreased cerebral oxygen delivery and consumption (Circulation. 2015;131:1313-23) in fetuses with severe CHD. It appears that the brain may start out normal in size, but in the third trimester, the accelerated metabolic demands that come with rapid growth and development are not sufficiently met by the fetal cardiovascular circulation in CHD.
In the newborn with CHD, preoperative brain imaging studies have demonstrated structural abnormalities suggesting delayed development (for example, microcephaly and a widened operculum), microstructural abnormalities suggesting abnormal myelination and neuroaxonal development, and lower brain maturity scores (a composite score that combines multiple factors, such as myelination and cortical in-folding, to represent “brain age”).
Moreover, some of the newborn brain imaging studies have correlated brain MRI findings with neonatal neurodevelopmental assessments. For instance, investigators found that full-term newborns with CHD had decreased gray matter brain volume and increased cerebrospinal fluid volume and that these impairments were associated with poor behavioral state regulation and poor visual orienting (J Pediatr. 2014;164:1121-7).
Interestingly, it has been found that the full-term baby with specific complex CHD, including newborns with single ventricle CHD or transposition of the great arteries, is more likely to have a brain maturity score that is equivalent to that of a baby born at 35 weeks’ gestation. This means that, in some infants with CHD, the brain has lagged in growth by about a month, resulting in a pattern of disturbed development and subsequent injury that is similar to that of premature infants.
It also means that infants with CHD and an immature brain are especially vulnerable to brain injury when open-heart surgery is needed. In short, we now appreciate that the brain in patients with CHD is likely more fragile than we previously thought – and that this fragility is prenatal in its origins.
Delivery room planning
Ideally, our goal is to find ways of changing the circulation in utero to improve cerebral oxygenation and blood flow, and, consequently, improve brain development and long-term neurocognitive function. Despite significant efforts in this area, we’re not there yet.
Examples of strategies that are being tested include catheter intervention to open the aortic valve in utero for fetuses with critical aortic stenosis. This procedure currently is being performed to try to prevent progression of the valve abnormality to HLHS, but it has not been determined whether the intervention affects cerebral blood flow. Maternal oxygen therapy has been shown to change cerebral blood flow in the short term for fetuses with HLHS, but its long-term use has not been studied. At the time of birth, to prevent injury in the potentially more fragile brain of the newborn with CHD, what we can do is to identify those fetuses who are more likely to be at risk for hypoxia low cardiac output and hemodynamic compromise in the delivery room, and plan for specialized delivery room and perinatal management beyond standard neonatal care.
Most newborns with CHD are assigned to Level 1; they have no predicted risk of compromise in the delivery room – or even in the first couple weeks of life – and can deliver at a local hospital with neonatal evaluation and then consult with the pediatric cardiologist. Defects include shunt lesions such as septal defects or mild valve abnormalities.
Patients assigned to Level 2 have minimal risk of compromise in the delivery room but are expected to require postnatal surgery, cardiac catheterization, or another procedure before going home. They can be stabilized by the neonatologist, usually with initiation of a prostaglandin infusion, before transfer to the cardiac center for the planned intervention. Defects include single ventricle CHD and severe Tetralogy of Fallot.
Fetuses assigned to Level 3 and Level 4 are expected to have hemodynamic instability at cord clamping, requiring immediate specialty care in the delivery room that is likely to include urgent cardiac catheterization or surgical intervention. These defects are rare and include diagnoses such as transposition of the great arteries, HLHS with a restrictive or closed foramen ovale, and CHD with associated heart failure and hydrops.
We have found that fetal echocardiography accurately predicts postnatal risk and the need for specialized delivery room care in newborns diagnosed in utero with CHD and that level-of-care protocols ensure safe delivery and optimize fetal outcomes (J Am Soc Echocardiogr. 2015;28:1339-49; Am J Cardiol. 2013;111:737-47).
Such delivery planning, which is coordinated between obstetric, neonatal, cardiology, and surgical services with specialty teams as needed (for example, cardiac intensive care, interventional cardiology, and cardiac surgery), is recommended in a 2014 AHA statement on the diagnosis and treatment of fetal cardiac disease. In recent years it has become the standard of care in many health systems (Circulation. 2014;129[21]:2183-242).
The effect of maternal stress on the in utero environment is also getting increased attention in pediatric cardiology. Alterations in neurocognitive development and fetal and child cardiovascular health are likely to be associated with maternal stress during pregnancy, and studies have shown that maternal stress is high with prenatal diagnoses of CHD. We have to ask: Is stress a modifiable risk factor? There must be ways in which we can do better with prenatal counseling and support after a fetal diagnosis of CHD.
Screening for CHD
Initiating strategies to improve neurodevelopmental outcomes in infants with CHD rests partly on identifying babies with CHD before birth through improved fetal cardiac screening. Research cited in the 2014 AHA statement indicates that nearly all women giving birth to babies with CHD in the United States have obstetric ultrasound examinations in the second or third trimesters, but that only about 30% of the fetuses are diagnosed prenatally.
Current indications for referral for a fetal echocardiogram – in addition to suspicion of a structural heart abnormality on obstetric ultrasound – include maternal factors, such as diabetes mellitus, that raise the risk of CHD above the baseline population risk for low-risk pregnancies.
Women with pregestational diabetes mellitus have a nearly fivefold increase in CHD, compared with the general population (3%-5%), and should be referred for fetal echocardiography. Women with gestational diabetes mellitus have no or minimally increased risk for fetal CHD, but it has been shown that there is an increased risk for cardiac hypertrophy – particularly late in gestation – if glycemic levels are poorly controlled. The 2014 AHA guidelines recommend that fetal echocardiographic evaluation be considered in those who have HbA1c levels greater than 6% in the second half of pregnancy.
Dr. Mary T. Donofrio is a pediatric cardiologist and director of the fetal heart program and critical care delivery program at Children’s National Medical Center, Washington. She reported that she has no disclosures relevant to this article.
How better imaging technology for prenatal diagnoses can improve outcomes
We live during an unprecedented time in the history of ob.gyn. practice. Only a relatively short time ago, the only way ob.gyns. could assess the health of the fetus was through the invasive and risky procedures of the amniocentesis and, later, chorionic villus sampling. A woman who might eventually have had a baby with a congenital abnormality would not have known of her fetus’s defect until after birth, when successful intervention might have been extremely difficult to achieve or even too late. At the time, in utero evaluation could be done only by static, low-resolution sonographic images of the fetus. By today’s standards of imaging technology, these once-revolutionary pictures are almost tantamount to cave paintings.
Therefore, while it is imperative that we employ all available technologies and techniques possible to detect and diagnose potential fetal developmental defects, we must also bear in mind that no test is ever infallible. It is our obligation to provide the very best information based on expert and thorough review.
This month we have invited Mary Donofrio, MD, director of the fetal heart program at Children’s National Medical Center, Washington, to discuss how the latest advances in imaging technology have enabled us to screen for and diagnose congenital heart diseases, and improve outcomes for mother and baby.
Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].
We live during an unprecedented time in the history of ob.gyn. practice. Only a relatively short time ago, the only way ob.gyns. could assess the health of the fetus was through the invasive and risky procedures of the amniocentesis and, later, chorionic villus sampling. A woman who might eventually have had a baby with a congenital abnormality would not have known of her fetus’s defect until after birth, when successful intervention might have been extremely difficult to achieve or even too late. At the time, in utero evaluation could be done only by static, low-resolution sonographic images of the fetus. By today’s standards of imaging technology, these once-revolutionary pictures are almost tantamount to cave paintings.
Therefore, while it is imperative that we employ all available technologies and techniques possible to detect and diagnose potential fetal developmental defects, we must also bear in mind that no test is ever infallible. It is our obligation to provide the very best information based on expert and thorough review.
This month we have invited Mary Donofrio, MD, director of the fetal heart program at Children’s National Medical Center, Washington, to discuss how the latest advances in imaging technology have enabled us to screen for and diagnose congenital heart diseases, and improve outcomes for mother and baby.
Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].
We live during an unprecedented time in the history of ob.gyn. practice. Only a relatively short time ago, the only way ob.gyns. could assess the health of the fetus was through the invasive and risky procedures of the amniocentesis and, later, chorionic villus sampling. A woman who might eventually have had a baby with a congenital abnormality would not have known of her fetus’s defect until after birth, when successful intervention might have been extremely difficult to achieve or even too late. At the time, in utero evaluation could be done only by static, low-resolution sonographic images of the fetus. By today’s standards of imaging technology, these once-revolutionary pictures are almost tantamount to cave paintings.
Therefore, while it is imperative that we employ all available technologies and techniques possible to detect and diagnose potential fetal developmental defects, we must also bear in mind that no test is ever infallible. It is our obligation to provide the very best information based on expert and thorough review.
This month we have invited Mary Donofrio, MD, director of the fetal heart program at Children’s National Medical Center, Washington, to discuss how the latest advances in imaging technology have enabled us to screen for and diagnose congenital heart diseases, and improve outcomes for mother and baby.
Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].