Jennie Smith

Two large U.S.-based studies have found the risk of intussusception, a rare type of bowel obstruction in infants, to be elevated after rotavirus vaccination.

Concerns about intussusception risk date back to 1999, when a tetravalent rotavirus vaccine was withdrawn by its manufacturer after being shown to be associated with between 1 and 2 excess cases per 10,000 infants vaccinated.

Findings from clinical trials of newer pentavalent and monovalent vaccines, introduced in 2006 and 2008, respectively, showed no such excess intussusception risk. However, recent studies from Australia, Mexico, and Brazil have indicated that excess risk is associated with these newer vaccines as well, though to a far lesser degree than with the earlier vaccine.

The first of the new studies, published online Jan. 14 in the New England Journal of Medicine (doi: 10.1056/NEJMoal1303164), offers evidence for a slight but statistically significant increase in intussusception risk associated with use of Merck’s pentavalent vaccine, RV5 (RotaTeq).

CDC/Dr. Erskine Palmer

For their research, Katherine Yih, Ph.D., of Harvard Medical School and the Harvard Pilgrim Health Care Institute, Boston, and her associates looked at data from more than 1.2 million doses of RV5. The Food and Drug Administration (FDA) sponsored the study, and data were derived from health plans included in the FDA’s Mini-Sentinel surveillance program.

Using data from 507,874 first doses and 1,277,556 total doses of RV5, Dr. Yih’s team found an excess risk of 1.5 cases per 100,000 within 21 days after the first dose (95% confidence interval, 0.2-3.2), with no further increases in risk seen after the second or third dose. This represents about one tenth of the excess risk seen with the first-generation vaccine.

Dr. Yih and her associates also looked at data from 103,098 doses of a monovalent vaccine, GlaxoSmithKline’s RV1 (Rotarix). Risk was seen as increased after the second dose. However, this study was insufficiently powered to demonstrate a statistically significant risk in association with the monovalent vaccine.

The team acknowledged that some missing chart information reduced the power and precision of their study.

A separate study, also published online Jan. 14 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1311708), looked at data from 207,955 doses of the monovalent vaccine, identifying intussusception cases recorded within 7 days after a first or second dose.

The investigators, led by Eric Weintraub, of the Centers for Disease Control and Prevention (CDC) in Atlanta, found 5.3 excess cases over expected background rates per 100,000 infants vaccinated with two doses. The authors acknowledged that their findings of elevated risk could be due to chance, given the small number of cases seen in the study.

In the same study, Mr. Weintraub and his colleagues found no increase in risk associated with the pentavalent vaccine, for which there were data on 1,301,810 doses. However, they noted, the confidence intervals for this finding were wide.

The data used in Mr. Weintraub and colleagues’ study came from the Vaccine Safety Datalink surveillance program run by the CDC. The CDC program collects data from health care plans different from those used in the FDA’s program.

Mr. Weintraub and his associates acknowledged that other studies, including that of Dr. Yih and colleagues, had shown elevated risk associated with the pentavalent vaccine. The difference in results, the investigators wrote, might be attributable to different study methodologies, uncontrolled confounding, and varying background rates of intussusception in the study populations.

Mr. Weintraub’s study was funded by the CDC. Three of his coauthors reported commercial grant support from GlaxoSmithKline, Inviragen, Merck, and other companies. One of Dr. Yih’s coauthors disclosed being an employee and stockholder of Aetna, which participates in the Mini-Sentinel program.

Two large U.S.-based studies have found the risk of intussusception, a rare type of bowel obstruction in infants, to be elevated after rotavirus vaccination.

Concerns about intussusception risk date back to 1999, when a tetravalent rotavirus vaccine was withdrawn by its manufacturer after being shown to be associated with between 1 and 2 excess cases per 10,000 infants vaccinated.

Findings from clinical trials of newer pentavalent and monovalent vaccines, introduced in 2006 and 2008, respectively, showed no such excess intussusception risk. However, recent studies from Australia, Mexico, and Brazil have indicated that excess risk is associated with these newer vaccines as well, though to a far lesser degree than with the earlier vaccine.

The first of the new studies, published online Jan. 14 in the New England Journal of Medicine (doi: 10.1056/NEJMoal1303164), offers evidence for a slight but statistically significant increase in intussusception risk associated with use of Merck’s pentavalent vaccine, RV5 (RotaTeq).

CDC/Dr. Erskine Palmer

For their research, Katherine Yih, Ph.D., of Harvard Medical School and the Harvard Pilgrim Health Care Institute, Boston, and her associates looked at data from more than 1.2 million doses of RV5. The Food and Drug Administration (FDA) sponsored the study, and data were derived from health plans included in the FDA’s Mini-Sentinel surveillance program.

Using data from 507,874 first doses and 1,277,556 total doses of RV5, Dr. Yih’s team found an excess risk of 1.5 cases per 100,000 within 21 days after the first dose (95% confidence interval, 0.2-3.2), with no further increases in risk seen after the second or third dose. This represents about one tenth of the excess risk seen with the first-generation vaccine.

Dr. Yih and her associates also looked at data from 103,098 doses of a monovalent vaccine, GlaxoSmithKline’s RV1 (Rotarix). Risk was seen as increased after the second dose. However, this study was insufficiently powered to demonstrate a statistically significant risk in association with the monovalent vaccine.

The team acknowledged that some missing chart information reduced the power and precision of their study.

A separate study, also published online Jan. 14 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1311708), looked at data from 207,955 doses of the monovalent vaccine, identifying intussusception cases recorded within 7 days after a first or second dose.

The investigators, led by Eric Weintraub, of the Centers for Disease Control and Prevention (CDC) in Atlanta, found 5.3 excess cases over expected background rates per 100,000 infants vaccinated with two doses. The authors acknowledged that their findings of elevated risk could be due to chance, given the small number of cases seen in the study.

In the same study, Mr. Weintraub and his colleagues found no increase in risk associated with the pentavalent vaccine, for which there were data on 1,301,810 doses. However, they noted, the confidence intervals for this finding were wide.

The data used in Mr. Weintraub and colleagues’ study came from the Vaccine Safety Datalink surveillance program run by the CDC. The CDC program collects data from health care plans different from those used in the FDA’s program.

Mr. Weintraub and his associates acknowledged that other studies, including that of Dr. Yih and colleagues, had shown elevated risk associated with the pentavalent vaccine. The difference in results, the investigators wrote, might be attributable to different study methodologies, uncontrolled confounding, and varying background rates of intussusception in the study populations.

Mr. Weintraub’s study was funded by the CDC. Three of his coauthors reported commercial grant support from GlaxoSmithKline, Inviragen, Merck, and other companies. One of Dr. Yih’s coauthors disclosed being an employee and stockholder of Aetna, which participates in the Mini-Sentinel program.

Two large U.S.-based studies have found the risk of intussusception, a rare type of bowel obstruction in infants, to be elevated after rotavirus vaccination.

Concerns about intussusception risk date back to 1999, when a tetravalent rotavirus vaccine was withdrawn by its manufacturer after being shown to be associated with between 1 and 2 excess cases per 10,000 infants vaccinated.

Findings from clinical trials of newer pentavalent and monovalent vaccines, introduced in 2006 and 2008, respectively, showed no such excess intussusception risk. However, recent studies from Australia, Mexico, and Brazil have indicated that excess risk is associated with these newer vaccines as well, though to a far lesser degree than with the earlier vaccine.

The first of the new studies, published online Jan. 14 in the New England Journal of Medicine (doi: 10.1056/NEJMoal1303164), offers evidence for a slight but statistically significant increase in intussusception risk associated with use of Merck’s pentavalent vaccine, RV5 (RotaTeq).

CDC/Dr. Erskine Palmer

For their research, Katherine Yih, Ph.D., of Harvard Medical School and the Harvard Pilgrim Health Care Institute, Boston, and her associates looked at data from more than 1.2 million doses of RV5. The Food and Drug Administration (FDA) sponsored the study, and data were derived from health plans included in the FDA’s Mini-Sentinel surveillance program.

Using data from 507,874 first doses and 1,277,556 total doses of RV5, Dr. Yih’s team found an excess risk of 1.5 cases per 100,000 within 21 days after the first dose (95% confidence interval, 0.2-3.2), with no further increases in risk seen after the second or third dose. This represents about one tenth of the excess risk seen with the first-generation vaccine.

Dr. Yih and her associates also looked at data from 103,098 doses of a monovalent vaccine, GlaxoSmithKline’s RV1 (Rotarix). Risk was seen as increased after the second dose. However, this study was insufficiently powered to demonstrate a statistically significant risk in association with the monovalent vaccine.

The team acknowledged that some missing chart information reduced the power and precision of their study.

A separate study, also published online Jan. 14 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1311708), looked at data from 207,955 doses of the monovalent vaccine, identifying intussusception cases recorded within 7 days after a first or second dose.

The investigators, led by Eric Weintraub, of the Centers for Disease Control and Prevention (CDC) in Atlanta, found 5.3 excess cases over expected background rates per 100,000 infants vaccinated with two doses. The authors acknowledged that their findings of elevated risk could be due to chance, given the small number of cases seen in the study.

In the same study, Mr. Weintraub and his colleagues found no increase in risk associated with the pentavalent vaccine, for which there were data on 1,301,810 doses. However, they noted, the confidence intervals for this finding were wide.

The data used in Mr. Weintraub and colleagues’ study came from the Vaccine Safety Datalink surveillance program run by the CDC. The CDC program collects data from health care plans different from those used in the FDA’s program.

Mr. Weintraub and his associates acknowledged that other studies, including that of Dr. Yih and colleagues, had shown elevated risk associated with the pentavalent vaccine. The difference in results, the investigators wrote, might be attributable to different study methodologies, uncontrolled confounding, and varying background rates of intussusception in the study populations.

Mr. Weintraub’s study was funded by the CDC. Three of his coauthors reported commercial grant support from GlaxoSmithKline, Inviragen, Merck, and other companies. One of Dr. Yih’s coauthors disclosed being an employee and stockholder of Aetna, which participates in the Mini-Sentinel program.

A novel agent shown in clinical trials to improve sex drive in women has been turned down by the Food and Drug Administration, leaving clinicians with no approved treatment options for a commonly reported disorder unless a manufacturer appeal proves successful.

Flibanserin, a drug originally investigated in the 1990s as an antidepressant, was later studied as a treatment for hypoactive sexual desire disorder (HSDD) in premenopausal women.

HSDD is characterized by a stress-inducing loss of sex drive without an identifiable physical or psychological cause. Flibanserin works by increasing dopamine and norepinephrine, both associated with sexual excitement, and by decreasing serotonin, which is associated with sexual inhibition. In studies, 100 mg of flibanserin daily was associated with statistically significant improvements in the number of satisfying sexual episodes per month as well as improvements in reported sexual desire over placebo, and reduction in stress associated with sexual dysfunction.

Sheryl Kingsberg, Ph.D., chief of behavioral medicine at University Hospitals Case Medical Center in Cleveland, and an investigator on some of the flibanserin research submitted to the FDA, said in an interview that there remains a "huge vacuum" in options for women with HSDD.

"For women for whom the primary loss of sexual desire is drive, which is the biological component to desire, there is nothing," she said. "For postmenopausal women for whom drive is related to declining testosterone, testosterone is an option – but off-label. There are no FDA-approved testosterone options for women."

The FDA cited concerns about flibanserin’s risks compared with its "modest" effect size, according to Sprout Pharmaceuticals, which has already moved to appeal the agency’s decision. In one manufacturer-sponsored randomized controlled trial published this year (n = 1,087), the results of which were submitted to the FDA, flibanserin was seen increasing satisfying sexual events per month by an average of 2.5, compared with 1.5 for placebo (J. Sex. Med. 2013;10:1807-15 [doi: 10.1111/jsm.12189]).

"I know the data very well, and I was convinced that it hit every endpoint," Dr. Kingsberg said. "FDA says they’re concerned about the modest efficacy in light of a risk profile not different from an SSRI [selective serotonin reuptake inhibitor], or even an antihistamine. How much more can women be expected to have in terms of number of events? Any more would push them to be having sex more than women without sexual desire problems."

To Dr. Kingsberg, the FDA’s reluctance to approve flibanserin harks back to 2004, when the FDA said it was unconvinced by the evidence in support of Intrinsa, a transdermal testosterone patch also shown to significantly increase satisfying sexual episodes per month in surgically menopausal women. Then, too, the FDA cited concerns about a modest effect size in light of risk.

In trials, the most frequently reported adverse events associated with flibanserin were somnolence, dizziness, and nausea.

Dr. James A. Simon, clinical professor of obstetrics and gynecology at George Washington University in Washington, said in an interview that he was concerned about what he considered a "double standard for men and women in the regulatory process."

Both flibanserin and the testosterone patch were shown to work in women, he noted, yet both met regulatory obstacles. Meanwhile, dozens of treatments have been approved in the past 20 years for male sexual dysfunction.

HSDD "is a common problem; it’s not a made-up issue," Dr. Simon said. "But right now all we have to try and treat it with are testosterone, some antidepressants that work on dopamine, and some drugs for restless legs syndrome. None of them is approved for this indication."

Dr. Kingsberg disclosed a consulting relationship with Sprout Pharmaceuticals. Dr. Simon disclosed he was a coauthor on several studies of flibanserin, and a former consultant for Sprout.

Dr. Jan Shifren, director of the Midlife Women’s Health Center at Massachusetts General Hospital, Boston, said that she found the FDA’s position understandable, but agreed that there appeared to be higher hurdles for women’s sexual health interventions. Dr. Shifren was an investigator in manufacturer-sponsored trials of flibanserin in postmenopausal women but does not have a consulting relationship with the company.

Testosterone replacement treatments for men received fast approval and are in widespread use, she noted, despite lingering safety concerns.

Dr. Shifren said that she was uncertain as to why flibanserin’s manufacturer would aim first to approve the drug for premenopausal women, when studies have found that women in midlife are more likely to report distress related to sexual dysfunction.

In Dr. Shifren and colleagues’ 2008 survey study (Obstet. Gynecol. 2008;112:970-8) in which they evaluated responses from more than 30,000 women, they learned that distress related to low sex drive is more commonly reported by women aged 45-64 years (14.8%) than by younger women (10.8%).

A novel agent shown in clinical trials to improve sex drive in women has been turned down by the Food and Drug Administration, leaving clinicians with no approved treatment options for a commonly reported disorder unless a manufacturer appeal proves successful.

Flibanserin, a drug originally investigated in the 1990s as an antidepressant, was later studied as a treatment for hypoactive sexual desire disorder (HSDD) in premenopausal women.

HSDD is characterized by a stress-inducing loss of sex drive without an identifiable physical or psychological cause. Flibanserin works by increasing dopamine and norepinephrine, both associated with sexual excitement, and by decreasing serotonin, which is associated with sexual inhibition. In studies, 100 mg of flibanserin daily was associated with statistically significant improvements in the number of satisfying sexual episodes per month as well as improvements in reported sexual desire over placebo, and reduction in stress associated with sexual dysfunction.

Sheryl Kingsberg, Ph.D., chief of behavioral medicine at University Hospitals Case Medical Center in Cleveland, and an investigator on some of the flibanserin research submitted to the FDA, said in an interview that there remains a "huge vacuum" in options for women with HSDD.

"For women for whom the primary loss of sexual desire is drive, which is the biological component to desire, there is nothing," she said. "For postmenopausal women for whom drive is related to declining testosterone, testosterone is an option – but off-label. There are no FDA-approved testosterone options for women."

The FDA cited concerns about flibanserin’s risks compared with its "modest" effect size, according to Sprout Pharmaceuticals, which has already moved to appeal the agency’s decision. In one manufacturer-sponsored randomized controlled trial published this year (n = 1,087), the results of which were submitted to the FDA, flibanserin was seen increasing satisfying sexual events per month by an average of 2.5, compared with 1.5 for placebo (J. Sex. Med. 2013;10:1807-15 [doi: 10.1111/jsm.12189]).

"I know the data very well, and I was convinced that it hit every endpoint," Dr. Kingsberg said. "FDA says they’re concerned about the modest efficacy in light of a risk profile not different from an SSRI [selective serotonin reuptake inhibitor], or even an antihistamine. How much more can women be expected to have in terms of number of events? Any more would push them to be having sex more than women without sexual desire problems."

To Dr. Kingsberg, the FDA’s reluctance to approve flibanserin harks back to 2004, when the FDA said it was unconvinced by the evidence in support of Intrinsa, a transdermal testosterone patch also shown to significantly increase satisfying sexual episodes per month in surgically menopausal women. Then, too, the FDA cited concerns about a modest effect size in light of risk.

In trials, the most frequently reported adverse events associated with flibanserin were somnolence, dizziness, and nausea.

Dr. James A. Simon, clinical professor of obstetrics and gynecology at George Washington University in Washington, said in an interview that he was concerned about what he considered a "double standard for men and women in the regulatory process."

Both flibanserin and the testosterone patch were shown to work in women, he noted, yet both met regulatory obstacles. Meanwhile, dozens of treatments have been approved in the past 20 years for male sexual dysfunction.

HSDD "is a common problem; it’s not a made-up issue," Dr. Simon said. "But right now all we have to try and treat it with are testosterone, some antidepressants that work on dopamine, and some drugs for restless legs syndrome. None of them is approved for this indication."

Dr. Kingsberg disclosed a consulting relationship with Sprout Pharmaceuticals. Dr. Simon disclosed he was a coauthor on several studies of flibanserin, and a former consultant for Sprout.

Dr. Jan Shifren, director of the Midlife Women’s Health Center at Massachusetts General Hospital, Boston, said that she found the FDA’s position understandable, but agreed that there appeared to be higher hurdles for women’s sexual health interventions. Dr. Shifren was an investigator in manufacturer-sponsored trials of flibanserin in postmenopausal women but does not have a consulting relationship with the company.

Testosterone replacement treatments for men received fast approval and are in widespread use, she noted, despite lingering safety concerns.

Dr. Shifren said that she was uncertain as to why flibanserin’s manufacturer would aim first to approve the drug for premenopausal women, when studies have found that women in midlife are more likely to report distress related to sexual dysfunction.

In Dr. Shifren and colleagues’ 2008 survey study (Obstet. Gynecol. 2008;112:970-8) in which they evaluated responses from more than 30,000 women, they learned that distress related to low sex drive is more commonly reported by women aged 45-64 years (14.8%) than by younger women (10.8%).

A novel agent shown in clinical trials to improve sex drive in women has been turned down by the Food and Drug Administration, leaving clinicians with no approved treatment options for a commonly reported disorder unless a manufacturer appeal proves successful.

Flibanserin, a drug originally investigated in the 1990s as an antidepressant, was later studied as a treatment for hypoactive sexual desire disorder (HSDD) in premenopausal women.

HSDD is characterized by a stress-inducing loss of sex drive without an identifiable physical or psychological cause. Flibanserin works by increasing dopamine and norepinephrine, both associated with sexual excitement, and by decreasing serotonin, which is associated with sexual inhibition. In studies, 100 mg of flibanserin daily was associated with statistically significant improvements in the number of satisfying sexual episodes per month as well as improvements in reported sexual desire over placebo, and reduction in stress associated with sexual dysfunction.

Sheryl Kingsberg, Ph.D., chief of behavioral medicine at University Hospitals Case Medical Center in Cleveland, and an investigator on some of the flibanserin research submitted to the FDA, said in an interview that there remains a "huge vacuum" in options for women with HSDD.

"For women for whom the primary loss of sexual desire is drive, which is the biological component to desire, there is nothing," she said. "For postmenopausal women for whom drive is related to declining testosterone, testosterone is an option – but off-label. There are no FDA-approved testosterone options for women."

The FDA cited concerns about flibanserin’s risks compared with its "modest" effect size, according to Sprout Pharmaceuticals, which has already moved to appeal the agency’s decision. In one manufacturer-sponsored randomized controlled trial published this year (n = 1,087), the results of which were submitted to the FDA, flibanserin was seen increasing satisfying sexual events per month by an average of 2.5, compared with 1.5 for placebo (J. Sex. Med. 2013;10:1807-15 [doi: 10.1111/jsm.12189]).

"I know the data very well, and I was convinced that it hit every endpoint," Dr. Kingsberg said. "FDA says they’re concerned about the modest efficacy in light of a risk profile not different from an SSRI [selective serotonin reuptake inhibitor], or even an antihistamine. How much more can women be expected to have in terms of number of events? Any more would push them to be having sex more than women without sexual desire problems."

To Dr. Kingsberg, the FDA’s reluctance to approve flibanserin harks back to 2004, when the FDA said it was unconvinced by the evidence in support of Intrinsa, a transdermal testosterone patch also shown to significantly increase satisfying sexual episodes per month in surgically menopausal women. Then, too, the FDA cited concerns about a modest effect size in light of risk.

In trials, the most frequently reported adverse events associated with flibanserin were somnolence, dizziness, and nausea.

Dr. James A. Simon, clinical professor of obstetrics and gynecology at George Washington University in Washington, said in an interview that he was concerned about what he considered a "double standard for men and women in the regulatory process."

Both flibanserin and the testosterone patch were shown to work in women, he noted, yet both met regulatory obstacles. Meanwhile, dozens of treatments have been approved in the past 20 years for male sexual dysfunction.

HSDD "is a common problem; it’s not a made-up issue," Dr. Simon said. "But right now all we have to try and treat it with are testosterone, some antidepressants that work on dopamine, and some drugs for restless legs syndrome. None of them is approved for this indication."

Dr. Kingsberg disclosed a consulting relationship with Sprout Pharmaceuticals. Dr. Simon disclosed he was a coauthor on several studies of flibanserin, and a former consultant for Sprout.

Dr. Jan Shifren, director of the Midlife Women’s Health Center at Massachusetts General Hospital, Boston, said that she found the FDA’s position understandable, but agreed that there appeared to be higher hurdles for women’s sexual health interventions. Dr. Shifren was an investigator in manufacturer-sponsored trials of flibanserin in postmenopausal women but does not have a consulting relationship with the company.

Testosterone replacement treatments for men received fast approval and are in widespread use, she noted, despite lingering safety concerns.

Dr. Shifren said that she was uncertain as to why flibanserin’s manufacturer would aim first to approve the drug for premenopausal women, when studies have found that women in midlife are more likely to report distress related to sexual dysfunction.

In Dr. Shifren and colleagues’ 2008 survey study (Obstet. Gynecol. 2008;112:970-8) in which they evaluated responses from more than 30,000 women, they learned that distress related to low sex drive is more commonly reported by women aged 45-64 years (14.8%) than by younger women (10.8%).

Oral iron supplementation and the dopamine-inhibiting drug pramipexole are equally effective for treating patients with restless legs syndrome, and work along similar time frames, a South Korean research team has found.

While both iron and pramipexole are established treatments for restless legs syndrome (RLS), the new study (n = 30) was the first randomized trial to compare them head to head. The results, published online in the European Journal of Neurology (doi:10.1111/ene.12286), suggest that, because of the similar responses seen with both, the therapies might be combined in iron-deficient patients with RLS.

© Saipg/iStockphoto

For their research, Dr. C.S. Lee of Seoul National University Bundang Hospital (SNUBH) and colleagues randomized RLS patients with a serum ferritin of 15-50 ng/mL to receive either pramipexole, starting at 0.25 mg daily and titrated to up to 0.75 mg, or ferrous sulfate 325 mg twice daily. Subjects and investigators were not blinded to treatment allocation.

Subjects in both groups were statistically similar in terms of age, sex (all but one were women), disease severity, and serum ferritin levels at baseline. In the pramipexole group, four patients dropped out because of adverse events, mostly gastrointestinal complaints; in the iron group, three were lost because of perceived lack of treatment effect or inability to meet appointments.

At 2, 4, 8, and 12 weeks, subjects were assessed using the international restless legs syndrome (IRLS) study group disease severity scale, and also evaluated using published depression and sleep quality scores.

Dr. Lee and colleagues found that at 12 weeks, disease severity scores were similarly reduced from baseline in both groups (iron: –9.1, plus or minus 7.07; P less than .001; pramipexole: –8.7, plus or minus 8.31; P = .001). Changes in scores from baseline were also similar between the two groups at each visit, suggesting that both treatments worked along similar time frames, a finding that the researchers said was unexpected. The percentage of patients whose IRLS score decreased by 50% or more during the study period was the same for both groups: 46.7%.

The study attempted in part to answer the question of which treatment – iron or pramipexole – should be tried first in this patient group. The researchers noted that iron deficiency is not always seen in RLS patients, suggesting that low iron alone cannot explain RLS, and that iron supplementation is likely not sufficient to control symptoms in all RLS patients with low iron.

Still, iron treatment is generally the first line in clinical practice, with supplementation lasting 3 months after iron levels return to normal, then stopped. Pramipexole tends to be used for longer periods; long-term use of pramipexole has been associated with tolerance and augmentation, a phenomenon in which symptoms start appearing earlier in the day (Sleep Med. 2004;5:9-14).

"To avoid long-term treatment and augmentation, oral iron supplementation is preferred to dopamine agonists in RLS patients with iron deficiency, but considering the moderate response rate to oral iron alone, a dopamine agonist or other treatment could be added in selected RLS patients with a low-normal serum ferritin," the researchers wrote in their analysis.

While additional studies are needed to corroborate the results, Dr. Lee and colleagues wrote, "the treatment guideline that RLS patients with iron deficiency can be treated by iron supplementation alone may need to be revised."

The investigators noted as weaknesses of their study its small size, lack of a placebo control arm, and nonblinded design.

The study was funded by a grant from the SNUBH Research Fund, and none of its authors declared conflicts of interest.

Oral iron supplementation and the dopamine-inhibiting drug pramipexole are equally effective for treating patients with restless legs syndrome, and work along similar time frames, a South Korean research team has found.

While both iron and pramipexole are established treatments for restless legs syndrome (RLS), the new study (n = 30) was the first randomized trial to compare them head to head. The results, published online in the European Journal of Neurology (doi:10.1111/ene.12286), suggest that, because of the similar responses seen with both, the therapies might be combined in iron-deficient patients with RLS.

© Saipg/iStockphoto

For their research, Dr. C.S. Lee of Seoul National University Bundang Hospital (SNUBH) and colleagues randomized RLS patients with a serum ferritin of 15-50 ng/mL to receive either pramipexole, starting at 0.25 mg daily and titrated to up to 0.75 mg, or ferrous sulfate 325 mg twice daily. Subjects and investigators were not blinded to treatment allocation.

Subjects in both groups were statistically similar in terms of age, sex (all but one were women), disease severity, and serum ferritin levels at baseline. In the pramipexole group, four patients dropped out because of adverse events, mostly gastrointestinal complaints; in the iron group, three were lost because of perceived lack of treatment effect or inability to meet appointments.

At 2, 4, 8, and 12 weeks, subjects were assessed using the international restless legs syndrome (IRLS) study group disease severity scale, and also evaluated using published depression and sleep quality scores.

Dr. Lee and colleagues found that at 12 weeks, disease severity scores were similarly reduced from baseline in both groups (iron: –9.1, plus or minus 7.07; P less than .001; pramipexole: –8.7, plus or minus 8.31; P = .001). Changes in scores from baseline were also similar between the two groups at each visit, suggesting that both treatments worked along similar time frames, a finding that the researchers said was unexpected. The percentage of patients whose IRLS score decreased by 50% or more during the study period was the same for both groups: 46.7%.

The study attempted in part to answer the question of which treatment – iron or pramipexole – should be tried first in this patient group. The researchers noted that iron deficiency is not always seen in RLS patients, suggesting that low iron alone cannot explain RLS, and that iron supplementation is likely not sufficient to control symptoms in all RLS patients with low iron.

Still, iron treatment is generally the first line in clinical practice, with supplementation lasting 3 months after iron levels return to normal, then stopped. Pramipexole tends to be used for longer periods; long-term use of pramipexole has been associated with tolerance and augmentation, a phenomenon in which symptoms start appearing earlier in the day (Sleep Med. 2004;5:9-14).

"To avoid long-term treatment and augmentation, oral iron supplementation is preferred to dopamine agonists in RLS patients with iron deficiency, but considering the moderate response rate to oral iron alone, a dopamine agonist or other treatment could be added in selected RLS patients with a low-normal serum ferritin," the researchers wrote in their analysis.

While additional studies are needed to corroborate the results, Dr. Lee and colleagues wrote, "the treatment guideline that RLS patients with iron deficiency can be treated by iron supplementation alone may need to be revised."

The investigators noted as weaknesses of their study its small size, lack of a placebo control arm, and nonblinded design.

The study was funded by a grant from the SNUBH Research Fund, and none of its authors declared conflicts of interest.

Oral iron supplementation and the dopamine-inhibiting drug pramipexole are equally effective for treating patients with restless legs syndrome, and work along similar time frames, a South Korean research team has found.

While both iron and pramipexole are established treatments for restless legs syndrome (RLS), the new study (n = 30) was the first randomized trial to compare them head to head. The results, published online in the European Journal of Neurology (doi:10.1111/ene.12286), suggest that, because of the similar responses seen with both, the therapies might be combined in iron-deficient patients with RLS.

© Saipg/iStockphoto

For their research, Dr. C.S. Lee of Seoul National University Bundang Hospital (SNUBH) and colleagues randomized RLS patients with a serum ferritin of 15-50 ng/mL to receive either pramipexole, starting at 0.25 mg daily and titrated to up to 0.75 mg, or ferrous sulfate 325 mg twice daily. Subjects and investigators were not blinded to treatment allocation.

Subjects in both groups were statistically similar in terms of age, sex (all but one were women), disease severity, and serum ferritin levels at baseline. In the pramipexole group, four patients dropped out because of adverse events, mostly gastrointestinal complaints; in the iron group, three were lost because of perceived lack of treatment effect or inability to meet appointments.

At 2, 4, 8, and 12 weeks, subjects were assessed using the international restless legs syndrome (IRLS) study group disease severity scale, and also evaluated using published depression and sleep quality scores.

Dr. Lee and colleagues found that at 12 weeks, disease severity scores were similarly reduced from baseline in both groups (iron: –9.1, plus or minus 7.07; P less than .001; pramipexole: –8.7, plus or minus 8.31; P = .001). Changes in scores from baseline were also similar between the two groups at each visit, suggesting that both treatments worked along similar time frames, a finding that the researchers said was unexpected. The percentage of patients whose IRLS score decreased by 50% or more during the study period was the same for both groups: 46.7%.

The study attempted in part to answer the question of which treatment – iron or pramipexole – should be tried first in this patient group. The researchers noted that iron deficiency is not always seen in RLS patients, suggesting that low iron alone cannot explain RLS, and that iron supplementation is likely not sufficient to control symptoms in all RLS patients with low iron.

Still, iron treatment is generally the first line in clinical practice, with supplementation lasting 3 months after iron levels return to normal, then stopped. Pramipexole tends to be used for longer periods; long-term use of pramipexole has been associated with tolerance and augmentation, a phenomenon in which symptoms start appearing earlier in the day (Sleep Med. 2004;5:9-14).

"To avoid long-term treatment and augmentation, oral iron supplementation is preferred to dopamine agonists in RLS patients with iron deficiency, but considering the moderate response rate to oral iron alone, a dopamine agonist or other treatment could be added in selected RLS patients with a low-normal serum ferritin," the researchers wrote in their analysis.

While additional studies are needed to corroborate the results, Dr. Lee and colleagues wrote, "the treatment guideline that RLS patients with iron deficiency can be treated by iron supplementation alone may need to be revised."

The investigators noted as weaknesses of their study its small size, lack of a placebo control arm, and nonblinded design.

The study was funded by a grant from the SNUBH Research Fund, and none of its authors declared conflicts of interest.

Proteinuria, or elevated protein in the urine, should no longer be considered the signature criterion besides new-onset hypertension in diagnosing preeclampsia, says the American College of Obstetricians and Gynecologists.

In exhaustive new clinical guidelines on hypertension in pregnancy, ACOG says that equal weight should be given to reduced platelet counts, renal insufficiency, severe headache, heart-lung compromise, and impaired liver function. Any one of these concurrent with new-onset hypertension at 20 weeks of pregnancy or beyond is enough to establish preeclampsia, even in the absence of proteinuria.

"Clinicians like hard numbers," said Dr. James N. Martin, chief of the division of maternal-fetal medicine at the University of Mississippi Medical Center in Jackson, a past ACOG president, and an author of the guidelines. "But sometimes we can be misled by them." Reviews of maternal mortality data have shown that waiting for proteinuria to present can result in delayed intervention or missed diagnosis, as not all women with preeclampsia will develop proteinuria.

The new guidelines replace recommendations from a 2002 ACOG Practice Bulletin (Obstet. Gynecol. 2002;99:159-67). In addition to the revised diagnostic recommendations and precisely defined measures to determine severity of disease, they address several important management challenges: preeclampsia on top of an existing hypertensive disorder; timing of induction for preeclampsia with and without severe symptoms; use of corticosteroids; and recognizing and managing preeclampsia in the postpartum period.

The guidelines do emphasize one hard number that should be useful to clinicians: Delivery at 37 weeks is advised for women with preeclampsia without severe features.

Dr. Martin said that the 37-week delivery recommendation was based largely on results from a 2009 trial in Holland in which 756 women were randomized to induction at the 36- to 37-week point or expectant monitoring to await labor; induction at 37 weeks was associated with poor outcomes in only 31% of subjects, compared with 44% of those receiving expectant monitoring.

The guidelines distinguish extensively between preeclampsia with and without severe features, but discourage the use of the phrase "mild preeclampsia," considering it misleading. "Preeclampsia in any form should never be minimized as ‘mild,’ " Dr. Martin said.

Proteinuria, in addition to being downgraded as the signature diagnostic finding in preeclampsia, should no longer be considered as useful in classifying preeclampsia as severe or in deciding whether to induce, the guidelines say, because the amount of protein in the urine has not been shown to predict either maternal or fetal outcomes.

Fetal growth restriction, once considered a major criterion to make the diagnosis of severe preeclampsia, is now to be used not for diagnosis of preeclampsia, but for indicated delivery in a patient with preeclampsia who also has an extremely small fetus (less than 5th centile) that is associated with abnormal blood flow findings in the umbilical cord connecting the fetus to the placenta.

The guidelines emphasize that preeclampsia can appear for the first time following delivery, or worsen rather than improve during in the postnatal period. It is advisable that all postpartum patients become educated about symptoms suggestive of new or worsening preeclampsia after leaving the hospital so that the patient’s doctors can be alerted and treatment begun in time to prevent problems.

On the prevention front, the guidelines have less to recommend. The use of vitamins C and E is not advised in preventing preeclampsia. Low-dose aspirin, however, is recommended starting late in the first trimester for patients who experience preterm severe preeclampsia.

"What we really need are biomarkers," Dr. Martin said, adding that despite encouraging science on placental growth factor and other potential early markers, none is yet ready for routine clinical use.

Some of the guidelines’ coauthors reported financial relationships or potential conflicts of interest. Dr. George Bakris disclosed associations with Takeda, CVRx, and other companies. Dr. John Barton disclosed relationships with Alere and Beckman Coulter. Dr. Ananth Karumanchi disclosed relationships with Beckman Coulter, Roche, and others. Dr. Baha Sibai disclosed a relationship with Alere. The remaining task force members said they had no relevant financial disclosures.

Proteinuria, or elevated protein in the urine, should no longer be considered the signature criterion besides new-onset hypertension in diagnosing preeclampsia, says the American College of Obstetricians and Gynecologists.

In exhaustive new clinical guidelines on hypertension in pregnancy, ACOG says that equal weight should be given to reduced platelet counts, renal insufficiency, severe headache, heart-lung compromise, and impaired liver function. Any one of these concurrent with new-onset hypertension at 20 weeks of pregnancy or beyond is enough to establish preeclampsia, even in the absence of proteinuria.

"Clinicians like hard numbers," said Dr. James N. Martin, chief of the division of maternal-fetal medicine at the University of Mississippi Medical Center in Jackson, a past ACOG president, and an author of the guidelines. "But sometimes we can be misled by them." Reviews of maternal mortality data have shown that waiting for proteinuria to present can result in delayed intervention or missed diagnosis, as not all women with preeclampsia will develop proteinuria.

The new guidelines replace recommendations from a 2002 ACOG Practice Bulletin (Obstet. Gynecol. 2002;99:159-67). In addition to the revised diagnostic recommendations and precisely defined measures to determine severity of disease, they address several important management challenges: preeclampsia on top of an existing hypertensive disorder; timing of induction for preeclampsia with and without severe symptoms; use of corticosteroids; and recognizing and managing preeclampsia in the postpartum period.

The guidelines do emphasize one hard number that should be useful to clinicians: Delivery at 37 weeks is advised for women with preeclampsia without severe features.

Dr. Martin said that the 37-week delivery recommendation was based largely on results from a 2009 trial in Holland in which 756 women were randomized to induction at the 36- to 37-week point or expectant monitoring to await labor; induction at 37 weeks was associated with poor outcomes in only 31% of subjects, compared with 44% of those receiving expectant monitoring.

The guidelines distinguish extensively between preeclampsia with and without severe features, but discourage the use of the phrase "mild preeclampsia," considering it misleading. "Preeclampsia in any form should never be minimized as ‘mild,’ " Dr. Martin said.

Proteinuria, in addition to being downgraded as the signature diagnostic finding in preeclampsia, should no longer be considered as useful in classifying preeclampsia as severe or in deciding whether to induce, the guidelines say, because the amount of protein in the urine has not been shown to predict either maternal or fetal outcomes.

Fetal growth restriction, once considered a major criterion to make the diagnosis of severe preeclampsia, is now to be used not for diagnosis of preeclampsia, but for indicated delivery in a patient with preeclampsia who also has an extremely small fetus (less than 5th centile) that is associated with abnormal blood flow findings in the umbilical cord connecting the fetus to the placenta.

The guidelines emphasize that preeclampsia can appear for the first time following delivery, or worsen rather than improve during in the postnatal period. It is advisable that all postpartum patients become educated about symptoms suggestive of new or worsening preeclampsia after leaving the hospital so that the patient’s doctors can be alerted and treatment begun in time to prevent problems.

On the prevention front, the guidelines have less to recommend. The use of vitamins C and E is not advised in preventing preeclampsia. Low-dose aspirin, however, is recommended starting late in the first trimester for patients who experience preterm severe preeclampsia.

"What we really need are biomarkers," Dr. Martin said, adding that despite encouraging science on placental growth factor and other potential early markers, none is yet ready for routine clinical use.

Some of the guidelines’ coauthors reported financial relationships or potential conflicts of interest. Dr. George Bakris disclosed associations with Takeda, CVRx, and other companies. Dr. John Barton disclosed relationships with Alere and Beckman Coulter. Dr. Ananth Karumanchi disclosed relationships with Beckman Coulter, Roche, and others. Dr. Baha Sibai disclosed a relationship with Alere. The remaining task force members said they had no relevant financial disclosures.

Proteinuria, or elevated protein in the urine, should no longer be considered the signature criterion besides new-onset hypertension in diagnosing preeclampsia, says the American College of Obstetricians and Gynecologists.

In exhaustive new clinical guidelines on hypertension in pregnancy, ACOG says that equal weight should be given to reduced platelet counts, renal insufficiency, severe headache, heart-lung compromise, and impaired liver function. Any one of these concurrent with new-onset hypertension at 20 weeks of pregnancy or beyond is enough to establish preeclampsia, even in the absence of proteinuria.

"Clinicians like hard numbers," said Dr. James N. Martin, chief of the division of maternal-fetal medicine at the University of Mississippi Medical Center in Jackson, a past ACOG president, and an author of the guidelines. "But sometimes we can be misled by them." Reviews of maternal mortality data have shown that waiting for proteinuria to present can result in delayed intervention or missed diagnosis, as not all women with preeclampsia will develop proteinuria.

The new guidelines replace recommendations from a 2002 ACOG Practice Bulletin (Obstet. Gynecol. 2002;99:159-67). In addition to the revised diagnostic recommendations and precisely defined measures to determine severity of disease, they address several important management challenges: preeclampsia on top of an existing hypertensive disorder; timing of induction for preeclampsia with and without severe symptoms; use of corticosteroids; and recognizing and managing preeclampsia in the postpartum period.

The guidelines do emphasize one hard number that should be useful to clinicians: Delivery at 37 weeks is advised for women with preeclampsia without severe features.

Dr. Martin said that the 37-week delivery recommendation was based largely on results from a 2009 trial in Holland in which 756 women were randomized to induction at the 36- to 37-week point or expectant monitoring to await labor; induction at 37 weeks was associated with poor outcomes in only 31% of subjects, compared with 44% of those receiving expectant monitoring.

The guidelines distinguish extensively between preeclampsia with and without severe features, but discourage the use of the phrase "mild preeclampsia," considering it misleading. "Preeclampsia in any form should never be minimized as ‘mild,’ " Dr. Martin said.

Proteinuria, in addition to being downgraded as the signature diagnostic finding in preeclampsia, should no longer be considered as useful in classifying preeclampsia as severe or in deciding whether to induce, the guidelines say, because the amount of protein in the urine has not been shown to predict either maternal or fetal outcomes.

Fetal growth restriction, once considered a major criterion to make the diagnosis of severe preeclampsia, is now to be used not for diagnosis of preeclampsia, but for indicated delivery in a patient with preeclampsia who also has an extremely small fetus (less than 5th centile) that is associated with abnormal blood flow findings in the umbilical cord connecting the fetus to the placenta.

The guidelines emphasize that preeclampsia can appear for the first time following delivery, or worsen rather than improve during in the postnatal period. It is advisable that all postpartum patients become educated about symptoms suggestive of new or worsening preeclampsia after leaving the hospital so that the patient’s doctors can be alerted and treatment begun in time to prevent problems.

On the prevention front, the guidelines have less to recommend. The use of vitamins C and E is not advised in preventing preeclampsia. Low-dose aspirin, however, is recommended starting late in the first trimester for patients who experience preterm severe preeclampsia.

"What we really need are biomarkers," Dr. Martin said, adding that despite encouraging science on placental growth factor and other potential early markers, none is yet ready for routine clinical use.

Some of the guidelines’ coauthors reported financial relationships or potential conflicts of interest. Dr. George Bakris disclosed associations with Takeda, CVRx, and other companies. Dr. John Barton disclosed relationships with Alere and Beckman Coulter. Dr. Ananth Karumanchi disclosed relationships with Beckman Coulter, Roche, and others. Dr. Baha Sibai disclosed a relationship with Alere. The remaining task force members said they had no relevant financial disclosures.

Infants who are introduced to their first solid foods before 17 weeks of age have a higher likelihood of developing food allergies by 2 years, a U.K. team of researchers found.

Additionally, the researchers discovered that infants who receive their first cow’s milk products while still being breastfed were less likely to develop allergies than were those introduced to cow’s milk after breastfeeding had stopped.

The research, led by Kate E.C. Grimshaw, Ph.D., of the University of Southampton, England, and published online Nov. 18 in Pediatrics (2013 [doi:10.1542/peds.2012-3692]), supports current recommendations by the American Academy of Pediatrics that solid food be introduced at between 4 and 6 months*, concurrent with breastfeeding, to prevent allergies (Pediatrics 2008;121:183-91; Pediatrics 2012;129:e827-41).

Dr. Grimshaw and her colleagues’ study identified the 17-week mark as the "crucial time point," with solid food introduced before this time appearing to promote food allergies, while solid food introduced after this time apparently not doing so.

For their research, Dr. Grimshaw and her colleagues used a large prospective cohort study (n = 1,140) to identify mothers of 41 infants diagnosed with food allergies by age 2 years. These infants were matched with 82 controls born on close to the same date. All mothers of infants in the cohort study kept detailed daily food diaries describing their feeding practices through the first year after birth.

Dr. Grimshaw and her colleagues found that solid foods were introduced significantly earlier among the infants with allergies, with 35% of the former receiving their first solids before and including 16 weeks, compared with 14% of control infants (P = .011).

Of the infants who received cow’s milk concurrently with breast milk, the duration of concurrent feeding was longer – 9 weeks – in the control group, compared with 5.5 weeks in the allergy group (P = 0.47), suggesting that the duration of overlap was important and that longer overlap was helpful. However, there was no significant difference between the two groups in terms of the age at when the cow’s milk was introduced into the diet, they said.

Dr. Grimshaw and her colleagues listed as strengths of their study its prospective design that allowed for data collection from birth onward, and before any signs of allergy could become evident; only three infants in the study had evidence of allergy before 24 months. Also, they noted, a thorough diagnostic standard was used to identify allergies.

Although the optimum duration of exclusive breastfeeding has yet to be established, "Health professionals can provide advice that is consistent by encouraging exclusive breastfeeding for as long as possible followed by continued breastfeeding alongside the introduction of complementary foods to maximize the duration of concurrent breastfeeding and solid food introduction," Dr. Grimshaw and her colleagues wrote in their analysis.

The study was funded by the U.K. Food Standards Agency. Dr. Grimshaw declared an advisory relationship with Nutricia, while her coauthor Dr. Graham Roberts disclosed a relationship with Danone Baby Nutrition. Another coauthor on the study, Clare Mills, Ph.D., disclosed associations with Novartis, PepsiCo International, and DBV Technologies.

 *Correction, 11/25/13: A previous version of this story misstated the AAP's recommendation for when solid foods should be introduced.

Infants who are introduced to their first solid foods before 17 weeks of age have a higher likelihood of developing food allergies by 2 years, a U.K. team of researchers found.

Additionally, the researchers discovered that infants who receive their first cow’s milk products while still being breastfed were less likely to develop allergies than were those introduced to cow’s milk after breastfeeding had stopped.

The research, led by Kate E.C. Grimshaw, Ph.D., of the University of Southampton, England, and published online Nov. 18 in Pediatrics (2013 [doi:10.1542/peds.2012-3692]), supports current recommendations by the American Academy of Pediatrics that solid food be introduced at between 4 and 6 months*, concurrent with breastfeeding, to prevent allergies (Pediatrics 2008;121:183-91; Pediatrics 2012;129:e827-41).

Dr. Grimshaw and her colleagues’ study identified the 17-week mark as the "crucial time point," with solid food introduced before this time appearing to promote food allergies, while solid food introduced after this time apparently not doing so.

For their research, Dr. Grimshaw and her colleagues used a large prospective cohort study (n = 1,140) to identify mothers of 41 infants diagnosed with food allergies by age 2 years. These infants were matched with 82 controls born on close to the same date. All mothers of infants in the cohort study kept detailed daily food diaries describing their feeding practices through the first year after birth.

Dr. Grimshaw and her colleagues found that solid foods were introduced significantly earlier among the infants with allergies, with 35% of the former receiving their first solids before and including 16 weeks, compared with 14% of control infants (P = .011).

Of the infants who received cow’s milk concurrently with breast milk, the duration of concurrent feeding was longer – 9 weeks – in the control group, compared with 5.5 weeks in the allergy group (P = 0.47), suggesting that the duration of overlap was important and that longer overlap was helpful. However, there was no significant difference between the two groups in terms of the age at when the cow’s milk was introduced into the diet, they said.

Dr. Grimshaw and her colleagues listed as strengths of their study its prospective design that allowed for data collection from birth onward, and before any signs of allergy could become evident; only three infants in the study had evidence of allergy before 24 months. Also, they noted, a thorough diagnostic standard was used to identify allergies.

Although the optimum duration of exclusive breastfeeding has yet to be established, "Health professionals can provide advice that is consistent by encouraging exclusive breastfeeding for as long as possible followed by continued breastfeeding alongside the introduction of complementary foods to maximize the duration of concurrent breastfeeding and solid food introduction," Dr. Grimshaw and her colleagues wrote in their analysis.

The study was funded by the U.K. Food Standards Agency. Dr. Grimshaw declared an advisory relationship with Nutricia, while her coauthor Dr. Graham Roberts disclosed a relationship with Danone Baby Nutrition. Another coauthor on the study, Clare Mills, Ph.D., disclosed associations with Novartis, PepsiCo International, and DBV Technologies.

 *Correction, 11/25/13: A previous version of this story misstated the AAP's recommendation for when solid foods should be introduced.

Infants who are introduced to their first solid foods before 17 weeks of age have a higher likelihood of developing food allergies by 2 years, a U.K. team of researchers found.

Additionally, the researchers discovered that infants who receive their first cow’s milk products while still being breastfed were less likely to develop allergies than were those introduced to cow’s milk after breastfeeding had stopped.

The research, led by Kate E.C. Grimshaw, Ph.D., of the University of Southampton, England, and published online Nov. 18 in Pediatrics (2013 [doi:10.1542/peds.2012-3692]), supports current recommendations by the American Academy of Pediatrics that solid food be introduced at between 4 and 6 months*, concurrent with breastfeeding, to prevent allergies (Pediatrics 2008;121:183-91; Pediatrics 2012;129:e827-41).

Dr. Grimshaw and her colleagues’ study identified the 17-week mark as the "crucial time point," with solid food introduced before this time appearing to promote food allergies, while solid food introduced after this time apparently not doing so.

For their research, Dr. Grimshaw and her colleagues used a large prospective cohort study (n = 1,140) to identify mothers of 41 infants diagnosed with food allergies by age 2 years. These infants were matched with 82 controls born on close to the same date. All mothers of infants in the cohort study kept detailed daily food diaries describing their feeding practices through the first year after birth.

Dr. Grimshaw and her colleagues found that solid foods were introduced significantly earlier among the infants with allergies, with 35% of the former receiving their first solids before and including 16 weeks, compared with 14% of control infants (P = .011).

Of the infants who received cow’s milk concurrently with breast milk, the duration of concurrent feeding was longer – 9 weeks – in the control group, compared with 5.5 weeks in the allergy group (P = 0.47), suggesting that the duration of overlap was important and that longer overlap was helpful. However, there was no significant difference between the two groups in terms of the age at when the cow’s milk was introduced into the diet, they said.

Dr. Grimshaw and her colleagues listed as strengths of their study its prospective design that allowed for data collection from birth onward, and before any signs of allergy could become evident; only three infants in the study had evidence of allergy before 24 months. Also, they noted, a thorough diagnostic standard was used to identify allergies.

Although the optimum duration of exclusive breastfeeding has yet to be established, "Health professionals can provide advice that is consistent by encouraging exclusive breastfeeding for as long as possible followed by continued breastfeeding alongside the introduction of complementary foods to maximize the duration of concurrent breastfeeding and solid food introduction," Dr. Grimshaw and her colleagues wrote in their analysis.

The study was funded by the U.K. Food Standards Agency. Dr. Grimshaw declared an advisory relationship with Nutricia, while her coauthor Dr. Graham Roberts disclosed a relationship with Danone Baby Nutrition. Another coauthor on the study, Clare Mills, Ph.D., disclosed associations with Novartis, PepsiCo International, and DBV Technologies.

 *Correction, 11/25/13: A previous version of this story misstated the AAP's recommendation for when solid foods should be introduced.

A large prospective study of infants hospitalized for bronchiolitis has revealed a number of previously unknown risk factors associated with apnea, a potentially life-threatening complication.

While high preadmission respiratory rates were found associated with increased apnea risk, so were low respiratory rates, a surprising finding that investigators could not explain. Low room air oxygen saturation was seen as contributing to risk. And one usual-suspect risk factor in apnea – respiratory syncytial virus – turned out not to be more dangerous than other viruses in terms of apnea risk.

Clinicians should not be reassured by either a low respiratory rate or infection with an organism other than RSV in assessing apnea risk, said Dr. Alan R. Schroeder of the Santa Clara Medical Center in San Jose, Calif., and his colleagues.

At 16 study sites nationwide starting in 2007, the researchers collected enrollment and outcome data on 2,156 children under age 2 (median age 4 months, with age corrected for birth at less than 37 weeks). The patients were admitted with bronchiolitis over three consecutive winter seasons. Of these children, 108 (5%) developed apnea while hospitalized, according to the study, which was published online Oct. 7 in Pediatrics (2013;132:1-8 [doi: 10.1542/peds.2013-1501]). The study was part of the Multicenter Airway Research Collaboration, a program of the Emergency Medicine Network.

The study confirmed the known risk factors of young corrected age, low birth weight, and previous apnea during the same bronchiolitis episode. Dr. Schroeder and his colleagues found that the statistically significant predictors of apnea included age of less than 2 weeks (odds ratio, 9.67) and 2-8 weeks (OR, 4.72), compared with age 6 months or older; birth weight of less than 2.3 kg (OR, 2.15), compared with birth weight of 3.2 kg or more; and previous apnea during the same bronchiolitis episode (OR, 3.63).

There also was risk associated with preadmission respiratory rates of less than 30 (OR, 4.05) and 30-39 (OR, 2.35), compared with 40-49, as well as a preadmission respiratory rate of 70 or more (OR, 2.26). Risk of apnea was also associated with having a preadmission room air oxygen saturation of less than 90% (OR, 1.60).

Apnea risk was shown to be similar across the major viral infections seen in the cohort. While more infants presented with RSV than with other viruses, there was roughly equal apnea risk seen among children infected with human rhinovirus, adenovirus, human metapneumovirus, enterovirus, coronavirus, and parainfluenza virus.

"These data suggest that using RSV status to drive admission decisions and admission locations (e.g., ward, step-down unit, ICU) due to apnea concerns may be misguided," Dr. Schroeder and his colleagues wrote in their analysis.

The study contained a number of other novel findings. While a recent, smaller study of 42 patients had suggested a possible protective effect associated with acetaminophen administered the week before hospitalization (Resuscitation 2012;83:440-46), the study by Dr. Schroeder and his colleagues found no such effect.

It also shed light on the timing of apnea during the course of bronchiolitis. While previous studies had shown apnea occurring early in the course of RSV infection, "our results challenge this notion," the authors wrote. One-third of the infants with apnea in the study began having difficulty breathing 4 or more days before the preadmission visit. "Furthermore, the time from the beginning of the ‘difficulty breathing’ to the preadmission visit was not different between children with and without apnea. Therefore, using the duration of symptoms to predict future risk of apnea or need for hospitalization may be problematic."

The investigators acknowledged as limitations of their study the possibility that the reported incidence of apnea may have been biased by oversampling of sicker patients, as the investigators recruited 20% of patients from intensive care. Some infants may have been included based on chart data that did not meet strict criteria for apnea, allowing for overreporting, they said, and apnea may have been harder to detect in intubated patients, leading to underreporting in this population.

The study was funded by the National Institutes of Health. Dr. Schroeder and his colleagues reported no disclosures.

A large prospective study of infants hospitalized for bronchiolitis has revealed a number of previously unknown risk factors associated with apnea, a potentially life-threatening complication.

While high preadmission respiratory rates were found associated with increased apnea risk, so were low respiratory rates, a surprising finding that investigators could not explain. Low room air oxygen saturation was seen as contributing to risk. And one usual-suspect risk factor in apnea – respiratory syncytial virus – turned out not to be more dangerous than other viruses in terms of apnea risk.

Clinicians should not be reassured by either a low respiratory rate or infection with an organism other than RSV in assessing apnea risk, said Dr. Alan R. Schroeder of the Santa Clara Medical Center in San Jose, Calif., and his colleagues.

At 16 study sites nationwide starting in 2007, the researchers collected enrollment and outcome data on 2,156 children under age 2 (median age 4 months, with age corrected for birth at less than 37 weeks). The patients were admitted with bronchiolitis over three consecutive winter seasons. Of these children, 108 (5%) developed apnea while hospitalized, according to the study, which was published online Oct. 7 in Pediatrics (2013;132:1-8 [doi: 10.1542/peds.2013-1501]). The study was part of the Multicenter Airway Research Collaboration, a program of the Emergency Medicine Network.

The study confirmed the known risk factors of young corrected age, low birth weight, and previous apnea during the same bronchiolitis episode. Dr. Schroeder and his colleagues found that the statistically significant predictors of apnea included age of less than 2 weeks (odds ratio, 9.67) and 2-8 weeks (OR, 4.72), compared with age 6 months or older; birth weight of less than 2.3 kg (OR, 2.15), compared with birth weight of 3.2 kg or more; and previous apnea during the same bronchiolitis episode (OR, 3.63).

There also was risk associated with preadmission respiratory rates of less than 30 (OR, 4.05) and 30-39 (OR, 2.35), compared with 40-49, as well as a preadmission respiratory rate of 70 or more (OR, 2.26). Risk of apnea was also associated with having a preadmission room air oxygen saturation of less than 90% (OR, 1.60).

Apnea risk was shown to be similar across the major viral infections seen in the cohort. While more infants presented with RSV than with other viruses, there was roughly equal apnea risk seen among children infected with human rhinovirus, adenovirus, human metapneumovirus, enterovirus, coronavirus, and parainfluenza virus.

"These data suggest that using RSV status to drive admission decisions and admission locations (e.g., ward, step-down unit, ICU) due to apnea concerns may be misguided," Dr. Schroeder and his colleagues wrote in their analysis.

The study contained a number of other novel findings. While a recent, smaller study of 42 patients had suggested a possible protective effect associated with acetaminophen administered the week before hospitalization (Resuscitation 2012;83:440-46), the study by Dr. Schroeder and his colleagues found no such effect.

It also shed light on the timing of apnea during the course of bronchiolitis. While previous studies had shown apnea occurring early in the course of RSV infection, "our results challenge this notion," the authors wrote. One-third of the infants with apnea in the study began having difficulty breathing 4 or more days before the preadmission visit. "Furthermore, the time from the beginning of the ‘difficulty breathing’ to the preadmission visit was not different between children with and without apnea. Therefore, using the duration of symptoms to predict future risk of apnea or need for hospitalization may be problematic."

The investigators acknowledged as limitations of their study the possibility that the reported incidence of apnea may have been biased by oversampling of sicker patients, as the investigators recruited 20% of patients from intensive care. Some infants may have been included based on chart data that did not meet strict criteria for apnea, allowing for overreporting, they said, and apnea may have been harder to detect in intubated patients, leading to underreporting in this population.

The study was funded by the National Institutes of Health. Dr. Schroeder and his colleagues reported no disclosures.

A large prospective study of infants hospitalized for bronchiolitis has revealed a number of previously unknown risk factors associated with apnea, a potentially life-threatening complication.

While high preadmission respiratory rates were found associated with increased apnea risk, so were low respiratory rates, a surprising finding that investigators could not explain. Low room air oxygen saturation was seen as contributing to risk. And one usual-suspect risk factor in apnea – respiratory syncytial virus – turned out not to be more dangerous than other viruses in terms of apnea risk.

Clinicians should not be reassured by either a low respiratory rate or infection with an organism other than RSV in assessing apnea risk, said Dr. Alan R. Schroeder of the Santa Clara Medical Center in San Jose, Calif., and his colleagues.

At 16 study sites nationwide starting in 2007, the researchers collected enrollment and outcome data on 2,156 children under age 2 (median age 4 months, with age corrected for birth at less than 37 weeks). The patients were admitted with bronchiolitis over three consecutive winter seasons. Of these children, 108 (5%) developed apnea while hospitalized, according to the study, which was published online Oct. 7 in Pediatrics (2013;132:1-8 [doi: 10.1542/peds.2013-1501]). The study was part of the Multicenter Airway Research Collaboration, a program of the Emergency Medicine Network.

The study confirmed the known risk factors of young corrected age, low birth weight, and previous apnea during the same bronchiolitis episode. Dr. Schroeder and his colleagues found that the statistically significant predictors of apnea included age of less than 2 weeks (odds ratio, 9.67) and 2-8 weeks (OR, 4.72), compared with age 6 months or older; birth weight of less than 2.3 kg (OR, 2.15), compared with birth weight of 3.2 kg or more; and previous apnea during the same bronchiolitis episode (OR, 3.63).

There also was risk associated with preadmission respiratory rates of less than 30 (OR, 4.05) and 30-39 (OR, 2.35), compared with 40-49, as well as a preadmission respiratory rate of 70 or more (OR, 2.26). Risk of apnea was also associated with having a preadmission room air oxygen saturation of less than 90% (OR, 1.60).

Apnea risk was shown to be similar across the major viral infections seen in the cohort. While more infants presented with RSV than with other viruses, there was roughly equal apnea risk seen among children infected with human rhinovirus, adenovirus, human metapneumovirus, enterovirus, coronavirus, and parainfluenza virus.

"These data suggest that using RSV status to drive admission decisions and admission locations (e.g., ward, step-down unit, ICU) due to apnea concerns may be misguided," Dr. Schroeder and his colleagues wrote in their analysis.

The study contained a number of other novel findings. While a recent, smaller study of 42 patients had suggested a possible protective effect associated with acetaminophen administered the week before hospitalization (Resuscitation 2012;83:440-46), the study by Dr. Schroeder and his colleagues found no such effect.

It also shed light on the timing of apnea during the course of bronchiolitis. While previous studies had shown apnea occurring early in the course of RSV infection, "our results challenge this notion," the authors wrote. One-third of the infants with apnea in the study began having difficulty breathing 4 or more days before the preadmission visit. "Furthermore, the time from the beginning of the ‘difficulty breathing’ to the preadmission visit was not different between children with and without apnea. Therefore, using the duration of symptoms to predict future risk of apnea or need for hospitalization may be problematic."

The investigators acknowledged as limitations of their study the possibility that the reported incidence of apnea may have been biased by oversampling of sicker patients, as the investigators recruited 20% of patients from intensive care. Some infants may have been included based on chart data that did not meet strict criteria for apnea, allowing for overreporting, they said, and apnea may have been harder to detect in intubated patients, leading to underreporting in this population.

The study was funded by the National Institutes of Health. Dr. Schroeder and his colleagues reported no disclosures.

Critically ill patients with hypovolemic shock had the same rate of survival when resuscitated with crystalloid as with colloid solutions, a large randomized controlled trial has found.

In a randomized, international multicenter trial lasting 9 years and enrolling nearly 3,000 patients, 28-day mortality did not differ significantly between those treated with colloid solutions, such as gelatins, hydroxyethyl starches, or albumin, and those treated with crystalloid solutions, such as salines. Mortality at 90 days was found to be somewhat better for colloids than crystalloids, though investigators cautioned that the 90-day finding would require further study.

The question of whether to resuscitate patients with hypovolemic shock with colloids or crystalloids has long been controversial, and many large randomized trials have attempted, over the past decade, to define any differences in mortality and other outcomes between the two classes of fluid therapies.

The study, published in JAMA (doi:10.1001/jama2013.280502), supports previous studies in that no significant mortality differences were found at 28 days. Unlike some earlier studies, which showed adverse renal outcomes associated with colloid use (JAMA 2013;309:678-88), this study did not find a difference in renal outcomes.

For their research, Dr. Djillali Annane, of the University of Versailles, in Garches, France, and colleagues at 57 intensive care units in France, Belgium, Tunisia, and Canada, recruited 2,857 patients with hypovolemic shock over a 9-year period ending in 2012. Of these 1,414 were randomized to colloids and 1,443 to crystalloids. At 28 days the colloids group had 359 deaths (25.4%) and the crystalloids group, 390 (27%). At 90 days the colloids group had 434 deaths (30.7%) and the crystalloids group, 493 (34.2%).

Dr. Annane and colleagues called the 90-day mortality findings surprising. However, "given the null findings at 28 days and the fact that the confidence limit approaches 1, the finding of improved mortality with colloids should be considered exploratory until replicated in a study focusing on this outcome," the investigators wrote.

Colloid use did show other improved outcomes compared with crystalloid use. Patients on colloids had significantly more days alive without mechanical ventilation within 7 days, and more days without vasopressor therapy within 7 days.

Renal outcomes were similar, with 156 patients (11%) in the colloids group requiring renal replacement therapy compared with 181 patients (12.5%) in the crystalloids group.

The fact that the study did not find a higher rate of renal effects associated with colloids, the investigators said, could be due to the fact that the trial excluded patients with severe chronic renal failure, that total dose of starches never exceeded doses recommended by regulatory agencies in the study countries, or that the majority of the crystalloids patients received chloride-rich normal saline, which might increase the risk of kidney injuries compared with a chloride-restricted fluid therapy.

Dr. Annane and colleagues noted the study’s long recruitment period and open-label design as weaknesses.

In an editorial accompanying Dr. Annane and colleagues’ study, Dr. Christopher W. Seymour and Dr. Derek C. Angus, of the University of Pittsburgh, questioned the two-fluid-classes design of the trial, which, they argued, might not have been ideal to settle the question of ideal fluid therapies in hypovolemic shock. Rather, they wrote, "there are a number of complexities, including the type of shock requiring resuscitation, the resuscitation targets, and the use of adjunctive vasoactive therapies."

In addition, they wrote, "any given fluid choice could have both beneficial and harmful effects, with trade-offs that vary depending on the other complexities listed above. Thus, perhaps the most important message from the latest round of trials is that simply performing larger two-group trials with greater rigor will not bring the field to consensus. Instead, alternative study designs should be considered, perhaps with multiple study interventions and use of adaptive trial design methods."

Two of the 22 coinvestigators reported financial ties to industry. Dr. Seymour disclosed receiving institutional grants from the American Heart Association, the Society of Critical Care Medicine, and the MedicOne Foundation. The study was funded by the French Ministry of Health.

Critically ill patients with hypovolemic shock had the same rate of survival when resuscitated with crystalloid as with colloid solutions, a large randomized controlled trial has found.

In a randomized, international multicenter trial lasting 9 years and enrolling nearly 3,000 patients, 28-day mortality did not differ significantly between those treated with colloid solutions, such as gelatins, hydroxyethyl starches, or albumin, and those treated with crystalloid solutions, such as salines. Mortality at 90 days was found to be somewhat better for colloids than crystalloids, though investigators cautioned that the 90-day finding would require further study.

The question of whether to resuscitate patients with hypovolemic shock with colloids or crystalloids has long been controversial, and many large randomized trials have attempted, over the past decade, to define any differences in mortality and other outcomes between the two classes of fluid therapies.

The study, published in JAMA (doi:10.1001/jama2013.280502), supports previous studies in that no significant mortality differences were found at 28 days. Unlike some earlier studies, which showed adverse renal outcomes associated with colloid use (JAMA 2013;309:678-88), this study did not find a difference in renal outcomes.

For their research, Dr. Djillali Annane, of the University of Versailles, in Garches, France, and colleagues at 57 intensive care units in France, Belgium, Tunisia, and Canada, recruited 2,857 patients with hypovolemic shock over a 9-year period ending in 2012. Of these 1,414 were randomized to colloids and 1,443 to crystalloids. At 28 days the colloids group had 359 deaths (25.4%) and the crystalloids group, 390 (27%). At 90 days the colloids group had 434 deaths (30.7%) and the crystalloids group, 493 (34.2%).

Dr. Annane and colleagues called the 90-day mortality findings surprising. However, "given the null findings at 28 days and the fact that the confidence limit approaches 1, the finding of improved mortality with colloids should be considered exploratory until replicated in a study focusing on this outcome," the investigators wrote.

Colloid use did show other improved outcomes compared with crystalloid use. Patients on colloids had significantly more days alive without mechanical ventilation within 7 days, and more days without vasopressor therapy within 7 days.

Renal outcomes were similar, with 156 patients (11%) in the colloids group requiring renal replacement therapy compared with 181 patients (12.5%) in the crystalloids group.

The fact that the study did not find a higher rate of renal effects associated with colloids, the investigators said, could be due to the fact that the trial excluded patients with severe chronic renal failure, that total dose of starches never exceeded doses recommended by regulatory agencies in the study countries, or that the majority of the crystalloids patients received chloride-rich normal saline, which might increase the risk of kidney injuries compared with a chloride-restricted fluid therapy.

Dr. Annane and colleagues noted the study’s long recruitment period and open-label design as weaknesses.

In an editorial accompanying Dr. Annane and colleagues’ study, Dr. Christopher W. Seymour and Dr. Derek C. Angus, of the University of Pittsburgh, questioned the two-fluid-classes design of the trial, which, they argued, might not have been ideal to settle the question of ideal fluid therapies in hypovolemic shock. Rather, they wrote, "there are a number of complexities, including the type of shock requiring resuscitation, the resuscitation targets, and the use of adjunctive vasoactive therapies."

In addition, they wrote, "any given fluid choice could have both beneficial and harmful effects, with trade-offs that vary depending on the other complexities listed above. Thus, perhaps the most important message from the latest round of trials is that simply performing larger two-group trials with greater rigor will not bring the field to consensus. Instead, alternative study designs should be considered, perhaps with multiple study interventions and use of adaptive trial design methods."

Two of the 22 coinvestigators reported financial ties to industry. Dr. Seymour disclosed receiving institutional grants from the American Heart Association, the Society of Critical Care Medicine, and the MedicOne Foundation. The study was funded by the French Ministry of Health.

Critically ill patients with hypovolemic shock had the same rate of survival when resuscitated with crystalloid as with colloid solutions, a large randomized controlled trial has found.

In a randomized, international multicenter trial lasting 9 years and enrolling nearly 3,000 patients, 28-day mortality did not differ significantly between those treated with colloid solutions, such as gelatins, hydroxyethyl starches, or albumin, and those treated with crystalloid solutions, such as salines. Mortality at 90 days was found to be somewhat better for colloids than crystalloids, though investigators cautioned that the 90-day finding would require further study.

The question of whether to resuscitate patients with hypovolemic shock with colloids or crystalloids has long been controversial, and many large randomized trials have attempted, over the past decade, to define any differences in mortality and other outcomes between the two classes of fluid therapies.

The study, published in JAMA (doi:10.1001/jama2013.280502), supports previous studies in that no significant mortality differences were found at 28 days. Unlike some earlier studies, which showed adverse renal outcomes associated with colloid use (JAMA 2013;309:678-88), this study did not find a difference in renal outcomes.

For their research, Dr. Djillali Annane, of the University of Versailles, in Garches, France, and colleagues at 57 intensive care units in France, Belgium, Tunisia, and Canada, recruited 2,857 patients with hypovolemic shock over a 9-year period ending in 2012. Of these 1,414 were randomized to colloids and 1,443 to crystalloids. At 28 days the colloids group had 359 deaths (25.4%) and the crystalloids group, 390 (27%). At 90 days the colloids group had 434 deaths (30.7%) and the crystalloids group, 493 (34.2%).

Dr. Annane and colleagues called the 90-day mortality findings surprising. However, "given the null findings at 28 days and the fact that the confidence limit approaches 1, the finding of improved mortality with colloids should be considered exploratory until replicated in a study focusing on this outcome," the investigators wrote.

Colloid use did show other improved outcomes compared with crystalloid use. Patients on colloids had significantly more days alive without mechanical ventilation within 7 days, and more days without vasopressor therapy within 7 days.

Renal outcomes were similar, with 156 patients (11%) in the colloids group requiring renal replacement therapy compared with 181 patients (12.5%) in the crystalloids group.

The fact that the study did not find a higher rate of renal effects associated with colloids, the investigators said, could be due to the fact that the trial excluded patients with severe chronic renal failure, that total dose of starches never exceeded doses recommended by regulatory agencies in the study countries, or that the majority of the crystalloids patients received chloride-rich normal saline, which might increase the risk of kidney injuries compared with a chloride-restricted fluid therapy.

Dr. Annane and colleagues noted the study’s long recruitment period and open-label design as weaknesses.

In an editorial accompanying Dr. Annane and colleagues’ study, Dr. Christopher W. Seymour and Dr. Derek C. Angus, of the University of Pittsburgh, questioned the two-fluid-classes design of the trial, which, they argued, might not have been ideal to settle the question of ideal fluid therapies in hypovolemic shock. Rather, they wrote, "there are a number of complexities, including the type of shock requiring resuscitation, the resuscitation targets, and the use of adjunctive vasoactive therapies."

In addition, they wrote, "any given fluid choice could have both beneficial and harmful effects, with trade-offs that vary depending on the other complexities listed above. Thus, perhaps the most important message from the latest round of trials is that simply performing larger two-group trials with greater rigor will not bring the field to consensus. Instead, alternative study designs should be considered, perhaps with multiple study interventions and use of adaptive trial design methods."

Two of the 22 coinvestigators reported financial ties to industry. Dr. Seymour disclosed receiving institutional grants from the American Heart Association, the Society of Critical Care Medicine, and the MedicOne Foundation. The study was funded by the French Ministry of Health.

The short-acting, intravenous beta-blocker esmolol has been shown to reduce and stabilize heart rates without adverse effects in patients with severe septic shock, a new phase II study has found.

In an open-label study that randomized 154 patients with septic shock and a heart rate of 95 or higher to standard care or titrated esmolol, the beta-blocker was associated with successful reductions in heart rate to between 80 and 94 beats per minute over a 96-hour period: a median of –28 BPM for the esmolol group compared with –6 for controls (P less than .001).

For their research, Dr. Andrea Morelli of the University of Rome La Sapienza and colleagues recruited from the hospital’s intensive care unit patients with septic shock and a heart rate of 95 BPM or above (JAMA 2013;310:1683-91).

Patients with lower heart rates or with previous beta-blocker use were excluded. Subjects in both groups required norepinephrine to maintain a mean arterial pressure of 65 mm Hg or higher. The primary outcome measure was heart rate stabilization at between 80 and 94 BPM.

The esmolol group, which received a median continuous infusion of 100 mg/hr during the treatment period, also saw improved stroke work index and left ventricular stroke work, which investigators suspected was a result of improved diastolic filling. Esmolol treatment was associated with maintenance of mean arterial pressure and reduced need for norepinephrine. It was not associated with higher hepatic, renal, or myocardial injury compared with controls. Importantly, mortality at 28 days was considerably and significantly lower in the esmolol group than in controls: 49.4% vs. 80.5%. Each group comprised 77 patients.

In an editorial, Dr. Michael R. Pinsky of the department of critical care at the University of Pittsburgh called the findings "consistent with selective blockage of beta-adrenergic hyperactivity causing improved myocardial performance and decreased metabolic demand without compromising peripheral vascular function." Nonetheless, he cautioned clinicians against applying these results to all patients in septic shock (JAMA 2013;310:1677-8). "The reasons for this caution involve the limitations of this study and limitations in the current understanding of how beta-blocker therapy can cause such effects."

Dr. Morelli and colleagues acknowledged several limitations of their study. One was its single-center, open-label design. (As Dr. Pinsky noted in his editorial, a blinded study would be almost impossible to carry out because heart rate titration would be difficult to mask). The results should be replicated in a larger, multicenter trial, the researchers wrote. They noted that they had used "an arbitrary predefined heart rate threshold rather than an individualized approach titrated to specific myocardial characteristics or other biomarkers." Finally, the researchers allowed that the unexpectedly large mortality difference seen in the study could have been the result of confounding.

The study was funded by the University of Rome La Sapienza. Dr. Morelli disclosed honoraria from Baxter, the manufacturer of esmolol. A coauthor, Dr. Mervyn Singer, reported ties with Baxter. Dr. Pinsky did not report any disclosures relevant to his editorial.

The short-acting, intravenous beta-blocker esmolol has been shown to reduce and stabilize heart rates without adverse effects in patients with severe septic shock, a new phase II study has found.

In an open-label study that randomized 154 patients with septic shock and a heart rate of 95 or higher to standard care or titrated esmolol, the beta-blocker was associated with successful reductions in heart rate to between 80 and 94 beats per minute over a 96-hour period: a median of –28 BPM for the esmolol group compared with –6 for controls (P less than .001).

For their research, Dr. Andrea Morelli of the University of Rome La Sapienza and colleagues recruited from the hospital’s intensive care unit patients with septic shock and a heart rate of 95 BPM or above (JAMA 2013;310:1683-91).

Patients with lower heart rates or with previous beta-blocker use were excluded. Subjects in both groups required norepinephrine to maintain a mean arterial pressure of 65 mm Hg or higher. The primary outcome measure was heart rate stabilization at between 80 and 94 BPM.

The esmolol group, which received a median continuous infusion of 100 mg/hr during the treatment period, also saw improved stroke work index and left ventricular stroke work, which investigators suspected was a result of improved diastolic filling. Esmolol treatment was associated with maintenance of mean arterial pressure and reduced need for norepinephrine. It was not associated with higher hepatic, renal, or myocardial injury compared with controls. Importantly, mortality at 28 days was considerably and significantly lower in the esmolol group than in controls: 49.4% vs. 80.5%. Each group comprised 77 patients.

In an editorial, Dr. Michael R. Pinsky of the department of critical care at the University of Pittsburgh called the findings "consistent with selective blockage of beta-adrenergic hyperactivity causing improved myocardial performance and decreased metabolic demand without compromising peripheral vascular function." Nonetheless, he cautioned clinicians against applying these results to all patients in septic shock (JAMA 2013;310:1677-8). "The reasons for this caution involve the limitations of this study and limitations in the current understanding of how beta-blocker therapy can cause such effects."

Dr. Morelli and colleagues acknowledged several limitations of their study. One was its single-center, open-label design. (As Dr. Pinsky noted in his editorial, a blinded study would be almost impossible to carry out because heart rate titration would be difficult to mask). The results should be replicated in a larger, multicenter trial, the researchers wrote. They noted that they had used "an arbitrary predefined heart rate threshold rather than an individualized approach titrated to specific myocardial characteristics or other biomarkers." Finally, the researchers allowed that the unexpectedly large mortality difference seen in the study could have been the result of confounding.

The study was funded by the University of Rome La Sapienza. Dr. Morelli disclosed honoraria from Baxter, the manufacturer of esmolol. A coauthor, Dr. Mervyn Singer, reported ties with Baxter. Dr. Pinsky did not report any disclosures relevant to his editorial.

The short-acting, intravenous beta-blocker esmolol has been shown to reduce and stabilize heart rates without adverse effects in patients with severe septic shock, a new phase II study has found.

In an open-label study that randomized 154 patients with septic shock and a heart rate of 95 or higher to standard care or titrated esmolol, the beta-blocker was associated with successful reductions in heart rate to between 80 and 94 beats per minute over a 96-hour period: a median of –28 BPM for the esmolol group compared with –6 for controls (P less than .001).

For their research, Dr. Andrea Morelli of the University of Rome La Sapienza and colleagues recruited from the hospital’s intensive care unit patients with septic shock and a heart rate of 95 BPM or above (JAMA 2013;310:1683-91).

Patients with lower heart rates or with previous beta-blocker use were excluded. Subjects in both groups required norepinephrine to maintain a mean arterial pressure of 65 mm Hg or higher. The primary outcome measure was heart rate stabilization at between 80 and 94 BPM.

The esmolol group, which received a median continuous infusion of 100 mg/hr during the treatment period, also saw improved stroke work index and left ventricular stroke work, which investigators suspected was a result of improved diastolic filling. Esmolol treatment was associated with maintenance of mean arterial pressure and reduced need for norepinephrine. It was not associated with higher hepatic, renal, or myocardial injury compared with controls. Importantly, mortality at 28 days was considerably and significantly lower in the esmolol group than in controls: 49.4% vs. 80.5%. Each group comprised 77 patients.

In an editorial, Dr. Michael R. Pinsky of the department of critical care at the University of Pittsburgh called the findings "consistent with selective blockage of beta-adrenergic hyperactivity causing improved myocardial performance and decreased metabolic demand without compromising peripheral vascular function." Nonetheless, he cautioned clinicians against applying these results to all patients in septic shock (JAMA 2013;310:1677-8). "The reasons for this caution involve the limitations of this study and limitations in the current understanding of how beta-blocker therapy can cause such effects."

Dr. Morelli and colleagues acknowledged several limitations of their study. One was its single-center, open-label design. (As Dr. Pinsky noted in his editorial, a blinded study would be almost impossible to carry out because heart rate titration would be difficult to mask). The results should be replicated in a larger, multicenter trial, the researchers wrote. They noted that they had used "an arbitrary predefined heart rate threshold rather than an individualized approach titrated to specific myocardial characteristics or other biomarkers." Finally, the researchers allowed that the unexpectedly large mortality difference seen in the study could have been the result of confounding.

The study was funded by the University of Rome La Sapienza. Dr. Morelli disclosed honoraria from Baxter, the manufacturer of esmolol. A coauthor, Dr. Mervyn Singer, reported ties with Baxter. Dr. Pinsky did not report any disclosures relevant to his editorial.

A short, brisk walk can reduce the urge to drink alcohol among heavy drinkers, a group of researchers has found.

The results of the study mirror findings from research showing that moderate exercise can reduce signals of food and cigarette cravings. However, this was the first study to report that a single session of moderate exercise can significantly reduce attentional bias toward alcohol-related images as well as self-reported cravings (Ment. Health Phys. Act. 2013 Sept. 20 [doi: 10.1016/j.mhpa.2013.09.004]). A previous study in diagnosed alcoholics found that alcohol cravings were reduced during a brief period of exercise but not after it (Addict. 2004;99:1542-7).

©iStock/thinkstockphotos.com

Attentional bias, the tendency to focus on emotionally dominant stimuli, is an important measure used in studies of cravings, as it relies not on self-reporting but on visual attention paid to images presented by investigators. In the current study, led by Adrian H. Taylor, Ph.D., of the University of Exeter, in Devon, England, investigators measured two types of attentional bias – initial and maintained – related to alcohol imagery. The latter was found to be significantly reduced in the group that had exercised, compared with the controls. Self-reported cravings also were shown to be reduced.

For their research, Dr. Taylor and his colleagues recruited 20 healthy volunteers (mean age, 20.8 years; 11 women) who were not alcoholics seeking treatment but who self-reported drinking heavily. The women reported drinking 14 units of alcohol or more per week, and the men reported drinking 21 units or more per week.

Subjects were randomly assigned either to 15 minutes of sitting without access to reading materials or other stimuli or to 15 minutes of moderate walking on a treadmill. Before and after the period of sitting or walking, participants completed a task that matched neutral and alcohol images randomly presented for either 200 ms to measure initial attentional bias (IAB) or 1 second to measure maintained attentional bias (MAB). A standardized Alcohol Urge Questionnaire also was administered before, and three times after, the period of sitting or walking to collect information on self-reported cravings.

The study’s results showed that MAB was significantly reduced after exercise, compared with the control condition (P = .058).

The mechanisms mediating the effect of exercise on alcohol urges during exercise are unclear, Dr. Taylor and his colleagues said. Drinking alcohol regulates moods and reduces negative feelings. Perhaps exercise also enhances "affect and mood in a way that reduces drinking urges and salience of alcohol as a source of pleasure and reward." Animal research has suggested that numerous neurobiological mechanisms are implicated in drug use and might be modifiable by exercise, "including dopamine, glutamate, norepinephrine, opioids, PKA [protein kinase A], extracellular signal-related kinase, and brain-derived neurotropic factor," they wrote.

However, the investigators also acknowledged that they could not exclude the possibility that the effect seen in the intervention group was tied to distraction rather than physical activity. Future studies, they said, should include a third arm of subjects who would be allowed to watch television or participate in other distracting activity prior to being tested. Another limitation cited by the investigators was the fact that participants were not clinically diagnosed as alcoholics but self-reported as heavy drinkers.

Further research is needed to determine whether short bursts of exercise could help reduce alcohol cravings in people prone to them, the authors wrote. However, they said, the findings had some immediate implications for practice: "A short, brisk walk may be an attractive self-help strategy to manage cravings and provide immediate relief for those experiencing alcohol urges."

The authors received no external funding, and neither Dr. Taylor nor his coauthors had conflicts of interest.

A short, brisk walk can reduce the urge to drink alcohol among heavy drinkers, a group of researchers has found.

The results of the study mirror findings from research showing that moderate exercise can reduce signals of food and cigarette cravings. However, this was the first study to report that a single session of moderate exercise can significantly reduce attentional bias toward alcohol-related images as well as self-reported cravings (Ment. Health Phys. Act. 2013 Sept. 20 [doi: 10.1016/j.mhpa.2013.09.004]). A previous study in diagnosed alcoholics found that alcohol cravings were reduced during a brief period of exercise but not after it (Addict. 2004;99:1542-7).

©iStock/thinkstockphotos.com

Attentional bias, the tendency to focus on emotionally dominant stimuli, is an important measure used in studies of cravings, as it relies not on self-reporting but on visual attention paid to images presented by investigators. In the current study, led by Adrian H. Taylor, Ph.D., of the University of Exeter, in Devon, England, investigators measured two types of attentional bias – initial and maintained – related to alcohol imagery. The latter was found to be significantly reduced in the group that had exercised, compared with the controls. Self-reported cravings also were shown to be reduced.

For their research, Dr. Taylor and his colleagues recruited 20 healthy volunteers (mean age, 20.8 years; 11 women) who were not alcoholics seeking treatment but who self-reported drinking heavily. The women reported drinking 14 units of alcohol or more per week, and the men reported drinking 21 units or more per week.

Subjects were randomly assigned either to 15 minutes of sitting without access to reading materials or other stimuli or to 15 minutes of moderate walking on a treadmill. Before and after the period of sitting or walking, participants completed a task that matched neutral and alcohol images randomly presented for either 200 ms to measure initial attentional bias (IAB) or 1 second to measure maintained attentional bias (MAB). A standardized Alcohol Urge Questionnaire also was administered before, and three times after, the period of sitting or walking to collect information on self-reported cravings.

The study’s results showed that MAB was significantly reduced after exercise, compared with the control condition (P = .058).

The mechanisms mediating the effect of exercise on alcohol urges during exercise are unclear, Dr. Taylor and his colleagues said. Drinking alcohol regulates moods and reduces negative feelings. Perhaps exercise also enhances "affect and mood in a way that reduces drinking urges and salience of alcohol as a source of pleasure and reward." Animal research has suggested that numerous neurobiological mechanisms are implicated in drug use and might be modifiable by exercise, "including dopamine, glutamate, norepinephrine, opioids, PKA [protein kinase A], extracellular signal-related kinase, and brain-derived neurotropic factor," they wrote.

However, the investigators also acknowledged that they could not exclude the possibility that the effect seen in the intervention group was tied to distraction rather than physical activity. Future studies, they said, should include a third arm of subjects who would be allowed to watch television or participate in other distracting activity prior to being tested. Another limitation cited by the investigators was the fact that participants were not clinically diagnosed as alcoholics but self-reported as heavy drinkers.

Further research is needed to determine whether short bursts of exercise could help reduce alcohol cravings in people prone to them, the authors wrote. However, they said, the findings had some immediate implications for practice: "A short, brisk walk may be an attractive self-help strategy to manage cravings and provide immediate relief for those experiencing alcohol urges."

The authors received no external funding, and neither Dr. Taylor nor his coauthors had conflicts of interest.

A short, brisk walk can reduce the urge to drink alcohol among heavy drinkers, a group of researchers has found.

The results of the study mirror findings from research showing that moderate exercise can reduce signals of food and cigarette cravings. However, this was the first study to report that a single session of moderate exercise can significantly reduce attentional bias toward alcohol-related images as well as self-reported cravings (Ment. Health Phys. Act. 2013 Sept. 20 [doi: 10.1016/j.mhpa.2013.09.004]). A previous study in diagnosed alcoholics found that alcohol cravings were reduced during a brief period of exercise but not after it (Addict. 2004;99:1542-7).

©iStock/thinkstockphotos.com

Attentional bias, the tendency to focus on emotionally dominant stimuli, is an important measure used in studies of cravings, as it relies not on self-reporting but on visual attention paid to images presented by investigators. In the current study, led by Adrian H. Taylor, Ph.D., of the University of Exeter, in Devon, England, investigators measured two types of attentional bias – initial and maintained – related to alcohol imagery. The latter was found to be significantly reduced in the group that had exercised, compared with the controls. Self-reported cravings also were shown to be reduced.

For their research, Dr. Taylor and his colleagues recruited 20 healthy volunteers (mean age, 20.8 years; 11 women) who were not alcoholics seeking treatment but who self-reported drinking heavily. The women reported drinking 14 units of alcohol or more per week, and the men reported drinking 21 units or more per week.

Subjects were randomly assigned either to 15 minutes of sitting without access to reading materials or other stimuli or to 15 minutes of moderate walking on a treadmill. Before and after the period of sitting or walking, participants completed a task that matched neutral and alcohol images randomly presented for either 200 ms to measure initial attentional bias (IAB) or 1 second to measure maintained attentional bias (MAB). A standardized Alcohol Urge Questionnaire also was administered before, and three times after, the period of sitting or walking to collect information on self-reported cravings.

The study’s results showed that MAB was significantly reduced after exercise, compared with the control condition (P = .058).

The mechanisms mediating the effect of exercise on alcohol urges during exercise are unclear, Dr. Taylor and his colleagues said. Drinking alcohol regulates moods and reduces negative feelings. Perhaps exercise also enhances "affect and mood in a way that reduces drinking urges and salience of alcohol as a source of pleasure and reward." Animal research has suggested that numerous neurobiological mechanisms are implicated in drug use and might be modifiable by exercise, "including dopamine, glutamate, norepinephrine, opioids, PKA [protein kinase A], extracellular signal-related kinase, and brain-derived neurotropic factor," they wrote.

However, the investigators also acknowledged that they could not exclude the possibility that the effect seen in the intervention group was tied to distraction rather than physical activity. Future studies, they said, should include a third arm of subjects who would be allowed to watch television or participate in other distracting activity prior to being tested. Another limitation cited by the investigators was the fact that participants were not clinically diagnosed as alcoholics but self-reported as heavy drinkers.

Further research is needed to determine whether short bursts of exercise could help reduce alcohol cravings in people prone to them, the authors wrote. However, they said, the findings had some immediate implications for practice: "A short, brisk walk may be an attractive self-help strategy to manage cravings and provide immediate relief for those experiencing alcohol urges."

The authors received no external funding, and neither Dr. Taylor nor his coauthors had conflicts of interest.

Nearly half of heroin users who are hospitalized for medical or surgical treatment perceive themselves to be in good, very good, or excellent health, "underlining a disconnect between addiction and perceived health status," according to a study of 112 patients.

The apparent disparity between self-reported health and disease burden suggests that "perceptions of health status may not actually reflect physical health but a different construct altogether," Lidia Z. Meshesa and her colleagues wrote.

The investigators enrolled 112 non–treatment-seeking hospitalized heroin users in the study. The average age of the participants was 40 years, and 72% were male, reported Ms. Meshesa, of the Clinical Research and Education (CARE) Unit at Boston Medical Center, and her coauthors (Addict. Behav. 2013;38:2884-7). None was currently in treatment for substance abuse. All the participants completed a standard questionnaire on health-related quality of life and were asked detailed questions about their drug use and mental and physical health histories.

The investigators found that each day of heroin use in the previous month was associated with 8% lower odds of reporting health as good or better (odds ratio, 0.92; 95% confidence interval, 0.87-0.97; P less than .05). While about 47% of subjects self-reported their health status as good, very good, or excellent, some 68% also reported having been diagnosed with one or more chronic diseases, including diabetes, viral hepatitis, cardiovascular disease, HIV, or cancer. The main causes of hospitalization were cellulitis, drug overdose or withdrawal, pneumonia, endocarditis or sepsis, and HIV disease.

For this cohort, perceptions of good health could be associated more with absence of withdrawal symptoms than presence of disease, the investigators suggested. Of the 21 subjects reporting an accidental overdose within the previous 6 months, 62% also rated their health as good or better. Such subjects "may have a sense of immortality or lack of vulnerability after having survived a near-death experience," the investigators wrote in their analysis. "Therefore, it may be seen that using heroin frequently is a way of alleviating health problems."

Although the study found the number of days of heroin use in the previous month to be correlated with self-rated health status, use of other substances such as cocaine, marijuana, cigarettes, and alcohol did not show significant correlations to perceptions of overall health. Some 63% of the cohort had reported using cocaine in the previous month.

"Our study adds to this body of literature demonstrating that there is a graded effect between number of days using heroin and health status. However, this study also suggests that patients with opiate addiction may not recognize other risky drug use behaviors as being important to their health," the investigators wrote.

Because perceptions of poor health have been shown in other studies to affect users’ likelihood of seeking treatment (J. Subst. Abuse Treat. 2006;31:143-50; Addict. Behav. 2006;31:1904-18), the finding of good self-reported health status in nearly half of a cohort of hospitalized heroin users "suggests that a perception of good health may be a barrier to engaging in substance use treatment. Providers may need to help patients reframe addictions and risky behaviors as important components of overall health," Ms. Meshesha and her colleagues wrote.

The investigators described as limitations of their study the use of a single question to define self-perceived health status and the fact that all subjects were hospitalized when interviewed, limiting the generalizability of findings. Finally, "neurocognitive deficits due to drug use may contribute to impaired self-awareness," they wrote.

The study was funded by a grant from the National Institute on Drug Abuse. None of its authors declared conflicts of interest.

Nearly half of heroin users who are hospitalized for medical or surgical treatment perceive themselves to be in good, very good, or excellent health, "underlining a disconnect between addiction and perceived health status," according to a study of 112 patients.

The apparent disparity between self-reported health and disease burden suggests that "perceptions of health status may not actually reflect physical health but a different construct altogether," Lidia Z. Meshesa and her colleagues wrote.

The investigators enrolled 112 non–treatment-seeking hospitalized heroin users in the study. The average age of the participants was 40 years, and 72% were male, reported Ms. Meshesa, of the Clinical Research and Education (CARE) Unit at Boston Medical Center, and her coauthors (Addict. Behav. 2013;38:2884-7). None was currently in treatment for substance abuse. All the participants completed a standard questionnaire on health-related quality of life and were asked detailed questions about their drug use and mental and physical health histories.

The investigators found that each day of heroin use in the previous month was associated with 8% lower odds of reporting health as good or better (odds ratio, 0.92; 95% confidence interval, 0.87-0.97; P less than .05). While about 47% of subjects self-reported their health status as good, very good, or excellent, some 68% also reported having been diagnosed with one or more chronic diseases, including diabetes, viral hepatitis, cardiovascular disease, HIV, or cancer. The main causes of hospitalization were cellulitis, drug overdose or withdrawal, pneumonia, endocarditis or sepsis, and HIV disease.

For this cohort, perceptions of good health could be associated more with absence of withdrawal symptoms than presence of disease, the investigators suggested. Of the 21 subjects reporting an accidental overdose within the previous 6 months, 62% also rated their health as good or better. Such subjects "may have a sense of immortality or lack of vulnerability after having survived a near-death experience," the investigators wrote in their analysis. "Therefore, it may be seen that using heroin frequently is a way of alleviating health problems."

Although the study found the number of days of heroin use in the previous month to be correlated with self-rated health status, use of other substances such as cocaine, marijuana, cigarettes, and alcohol did not show significant correlations to perceptions of overall health. Some 63% of the cohort had reported using cocaine in the previous month.

"Our study adds to this body of literature demonstrating that there is a graded effect between number of days using heroin and health status. However, this study also suggests that patients with opiate addiction may not recognize other risky drug use behaviors as being important to their health," the investigators wrote.

Because perceptions of poor health have been shown in other studies to affect users’ likelihood of seeking treatment (J. Subst. Abuse Treat. 2006;31:143-50; Addict. Behav. 2006;31:1904-18), the finding of good self-reported health status in nearly half of a cohort of hospitalized heroin users "suggests that a perception of good health may be a barrier to engaging in substance use treatment. Providers may need to help patients reframe addictions and risky behaviors as important components of overall health," Ms. Meshesha and her colleagues wrote.

The investigators described as limitations of their study the use of a single question to define self-perceived health status and the fact that all subjects were hospitalized when interviewed, limiting the generalizability of findings. Finally, "neurocognitive deficits due to drug use may contribute to impaired self-awareness," they wrote.

The study was funded by a grant from the National Institute on Drug Abuse. None of its authors declared conflicts of interest.

Nearly half of heroin users who are hospitalized for medical or surgical treatment perceive themselves to be in good, very good, or excellent health, "underlining a disconnect between addiction and perceived health status," according to a study of 112 patients.

The apparent disparity between self-reported health and disease burden suggests that "perceptions of health status may not actually reflect physical health but a different construct altogether," Lidia Z. Meshesa and her colleagues wrote.

The investigators enrolled 112 non–treatment-seeking hospitalized heroin users in the study. The average age of the participants was 40 years, and 72% were male, reported Ms. Meshesa, of the Clinical Research and Education (CARE) Unit at Boston Medical Center, and her coauthors (Addict. Behav. 2013;38:2884-7). None was currently in treatment for substance abuse. All the participants completed a standard questionnaire on health-related quality of life and were asked detailed questions about their drug use and mental and physical health histories.

The investigators found that each day of heroin use in the previous month was associated with 8% lower odds of reporting health as good or better (odds ratio, 0.92; 95% confidence interval, 0.87-0.97; P less than .05). While about 47% of subjects self-reported their health status as good, very good, or excellent, some 68% also reported having been diagnosed with one or more chronic diseases, including diabetes, viral hepatitis, cardiovascular disease, HIV, or cancer. The main causes of hospitalization were cellulitis, drug overdose or withdrawal, pneumonia, endocarditis or sepsis, and HIV disease.

For this cohort, perceptions of good health could be associated more with absence of withdrawal symptoms than presence of disease, the investigators suggested. Of the 21 subjects reporting an accidental overdose within the previous 6 months, 62% also rated their health as good or better. Such subjects "may have a sense of immortality or lack of vulnerability after having survived a near-death experience," the investigators wrote in their analysis. "Therefore, it may be seen that using heroin frequently is a way of alleviating health problems."

Although the study found the number of days of heroin use in the previous month to be correlated with self-rated health status, use of other substances such as cocaine, marijuana, cigarettes, and alcohol did not show significant correlations to perceptions of overall health. Some 63% of the cohort had reported using cocaine in the previous month.

"Our study adds to this body of literature demonstrating that there is a graded effect between number of days using heroin and health status. However, this study also suggests that patients with opiate addiction may not recognize other risky drug use behaviors as being important to their health," the investigators wrote.

Because perceptions of poor health have been shown in other studies to affect users’ likelihood of seeking treatment (J. Subst. Abuse Treat. 2006;31:143-50; Addict. Behav. 2006;31:1904-18), the finding of good self-reported health status in nearly half of a cohort of hospitalized heroin users "suggests that a perception of good health may be a barrier to engaging in substance use treatment. Providers may need to help patients reframe addictions and risky behaviors as important components of overall health," Ms. Meshesha and her colleagues wrote.

The investigators described as limitations of their study the use of a single question to define self-perceived health status and the fact that all subjects were hospitalized when interviewed, limiting the generalizability of findings. Finally, "neurocognitive deficits due to drug use may contribute to impaired self-awareness," they wrote.

The study was funded by a grant from the National Institute on Drug Abuse. None of its authors declared conflicts of interest.