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BALTIMORE – Early initiation of caffeine treatment in premature neonates on mechanical ventilation did not cut the time to when these babies could successfully wean off the ventilator, according to findings of a single-center, randomized controlled study of 83 children.
The results also showed an “unexpected” trend toward increased mortality among the neonates who received early caffeine treatment, Dr. Cynthia M. Amaro reported at the annual meeting of the Pediatric Academic Societies. This signal of elevated mortality with caffeine treatment prompted the study’s data and safety monitoring board to prematurely stop the trial, limiting enrollment to just 75% of the number originally planned in the study’s design, thereby raising questions about the reliability of the primary-endpoint finding that early caffeine treatment did not result in the benefit of a reduced time to extubation.
Dr. Amaro said that she and her associates ran the study to address what had emerged as a significant area of doubt in routine U.S. practice on how to best use caffeine treatment in this neonatal population following publication of findings from the landmark Caffeine for Apnea of Prematurity (CAP) Trial (N Engl J Med. 2006 May 18;354[20]:2112-21). Results from the CAP Trial had shown in nearly 2,000 randomized, premature infants that treatment with caffeine led to significantly fewer episodes of bronchopulmonary dysplasia as well as quicker time to extubation of mechanical ventilation. Caffeine or other methylxanthines stimulate an infant’s respiratory center to allow faster extubation.
Ever since that publication a decade ago, “clinicians have been using caffeine earlier and more liberally, without really good data to support its early use in mechanically-ventilated preterm babies,” explained Dr. Amaro, a neonatologist at the University of Miami and Holtz Children’s Hospital in Miami.
Based on the new findings from the study she reported, “we are now not routinely initiating caffeine in mechanically ventilated preterm babies and just using caffeine immediately before extubation to treat apnea of prematurity. This returns caffeine treatment to the way it was used in the CAP Trial,” she said. “Further studies are needed before we can say what is best for early treatment of these preterm babies,” Dr. Amaro said in a video interview.
Her report led to a flurry of comments during the question period, with several pediatricians voicing concern about the reliability of results from a study that followed only 83 patients because of its premature termination.
“The data and safety monitoring board’s decision is a big issue,” said Dr. Carl E. Hunt, a pediatrician at the Uniformed Services University of the Health Sciences in Bethesda, Md. “There is a literature that shows results of studies can be very different when they stop early. It’s unfortunate because we don’t have other prospective data, and it may now be hard to do a large randomized, controlled trial” of early caffeine treatment, Dr. Hunt said.
While Dr. Amaro conceded that premature termination limited her study’s size, she also asserted that her analyses confirmed the validity of the finding of no benefit from early caffeine treatment. “We projected to full enrollment, and there still was no difference in the time to first successful extubation,” she said.
Her study enrolled preterm infants during January 2013–December 2015 born at 23-30 weeks’ gestation who required mechanical ventilation during their first 5 days. Randomization assigned 41 infants to receive a 20-mg/kg bolus of caffeine, followed by a maintenance dosage of 5 mg/kg that continued until extubation, while 42 patients received placebo and did not get caffeine until just before attempted extubation. The bolus and maintenance caffeine dosages tested were identical to those used in the CAP Trial.
The researchers defined successful extubation as keeping a child off restart of mechanical ventilation for more than 24 hours. The average gestational age of the enrolled neonates was 26 weeks, their average weight was 700 g, and intubation started an average of 3 hours after delivery.
The study’s primary endpoint, age at first successful extubation, was an average of 24 days among the neonates treated with caffeine and 20 days in those on placebo, Dr. Amaro reported. Mortality occurred at an average of 30 days after delivery in the caffeine recipients and after an average of 10 days in the controls. The incidence of death was 22% in those on early caffeine and 12% among those in the placebo group, an excess of four deaths in the intervention arm that was not statically significant.
A recent review of more than 29,000 matched very-low-birth-weight infants managed in routine practice showed that neonates who received early caffeine had an adjusted mortality risk that was 23% higher than that of matched infants not receiving early caffeine, Dr. Amaro noted (J Pediatrics. 2014 May;164[5]:992-8).
The incidence of bronchopulmonary dysplasia also did not show a statistically significant difference between the two study arms, 46% among those on early caffeine and 53% in the placebo group. Patients on early caffeine also had higher rates of necrotizing enterocolitis, more episodes of necrotizing enterocolitis requiring surgery, and more intraventricular hemorrhages, but none of these differences reached statistical significance.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @mitchelzoler
Clinicians need to be very cautious starting caffeine to treat premature neonates on mechanical ventilation with the goal of reducing the time to extubation. The findings from Dr. Amaro and her associates show that we do not really know whether starting caffeine treatment early is the right thing to do.
Because their study stopped sooner than planned, I don’t believe the number of enrolled patients was large enough to provide clear guidance on when to start treatment with caffeine or another methylxanthine. We still don’t know the answer. In addition, the suggestion of excess mortality with caffeine treatment gives us no reassurance that caffeine is safe in this setting. However, as was clear in the questions and comments from some members of the audience that heard this report, some people continue to believe that early treatment with caffeine of premature infants on mechanical ventilation is appropriate.
As a result of the equivocal results in Dr. Amaro’s study, the best option is probably to go back to using the protocol tested and shown safe and effective in the 2006 report from the Caffeine for Apnea of Prematurity Trial (N Engl J Med. 2006 May 18;354[20]:2112-21). Ideally, researchers will soon run a large, randomized trial that can better address the questions that Dr. Amaro and her associates attempted to answer with their study.
Dr. Clifford W. Bogue is professor of pediatrics at Yale University, New Haven, Conn., and chaired the session where Dr. Amaro presented her report. He had no relevant disclosures. He made these comments in an interview.
Clinicians need to be very cautious starting caffeine to treat premature neonates on mechanical ventilation with the goal of reducing the time to extubation. The findings from Dr. Amaro and her associates show that we do not really know whether starting caffeine treatment early is the right thing to do.
Because their study stopped sooner than planned, I don’t believe the number of enrolled patients was large enough to provide clear guidance on when to start treatment with caffeine or another methylxanthine. We still don’t know the answer. In addition, the suggestion of excess mortality with caffeine treatment gives us no reassurance that caffeine is safe in this setting. However, as was clear in the questions and comments from some members of the audience that heard this report, some people continue to believe that early treatment with caffeine of premature infants on mechanical ventilation is appropriate.
As a result of the equivocal results in Dr. Amaro’s study, the best option is probably to go back to using the protocol tested and shown safe and effective in the 2006 report from the Caffeine for Apnea of Prematurity Trial (N Engl J Med. 2006 May 18;354[20]:2112-21). Ideally, researchers will soon run a large, randomized trial that can better address the questions that Dr. Amaro and her associates attempted to answer with their study.
Dr. Clifford W. Bogue is professor of pediatrics at Yale University, New Haven, Conn., and chaired the session where Dr. Amaro presented her report. He had no relevant disclosures. He made these comments in an interview.
Clinicians need to be very cautious starting caffeine to treat premature neonates on mechanical ventilation with the goal of reducing the time to extubation. The findings from Dr. Amaro and her associates show that we do not really know whether starting caffeine treatment early is the right thing to do.
Because their study stopped sooner than planned, I don’t believe the number of enrolled patients was large enough to provide clear guidance on when to start treatment with caffeine or another methylxanthine. We still don’t know the answer. In addition, the suggestion of excess mortality with caffeine treatment gives us no reassurance that caffeine is safe in this setting. However, as was clear in the questions and comments from some members of the audience that heard this report, some people continue to believe that early treatment with caffeine of premature infants on mechanical ventilation is appropriate.
As a result of the equivocal results in Dr. Amaro’s study, the best option is probably to go back to using the protocol tested and shown safe and effective in the 2006 report from the Caffeine for Apnea of Prematurity Trial (N Engl J Med. 2006 May 18;354[20]:2112-21). Ideally, researchers will soon run a large, randomized trial that can better address the questions that Dr. Amaro and her associates attempted to answer with their study.
Dr. Clifford W. Bogue is professor of pediatrics at Yale University, New Haven, Conn., and chaired the session where Dr. Amaro presented her report. He had no relevant disclosures. He made these comments in an interview.
BALTIMORE – Early initiation of caffeine treatment in premature neonates on mechanical ventilation did not cut the time to when these babies could successfully wean off the ventilator, according to findings of a single-center, randomized controlled study of 83 children.
The results also showed an “unexpected” trend toward increased mortality among the neonates who received early caffeine treatment, Dr. Cynthia M. Amaro reported at the annual meeting of the Pediatric Academic Societies. This signal of elevated mortality with caffeine treatment prompted the study’s data and safety monitoring board to prematurely stop the trial, limiting enrollment to just 75% of the number originally planned in the study’s design, thereby raising questions about the reliability of the primary-endpoint finding that early caffeine treatment did not result in the benefit of a reduced time to extubation.
Dr. Amaro said that she and her associates ran the study to address what had emerged as a significant area of doubt in routine U.S. practice on how to best use caffeine treatment in this neonatal population following publication of findings from the landmark Caffeine for Apnea of Prematurity (CAP) Trial (N Engl J Med. 2006 May 18;354[20]:2112-21). Results from the CAP Trial had shown in nearly 2,000 randomized, premature infants that treatment with caffeine led to significantly fewer episodes of bronchopulmonary dysplasia as well as quicker time to extubation of mechanical ventilation. Caffeine or other methylxanthines stimulate an infant’s respiratory center to allow faster extubation.
Ever since that publication a decade ago, “clinicians have been using caffeine earlier and more liberally, without really good data to support its early use in mechanically-ventilated preterm babies,” explained Dr. Amaro, a neonatologist at the University of Miami and Holtz Children’s Hospital in Miami.
Based on the new findings from the study she reported, “we are now not routinely initiating caffeine in mechanically ventilated preterm babies and just using caffeine immediately before extubation to treat apnea of prematurity. This returns caffeine treatment to the way it was used in the CAP Trial,” she said. “Further studies are needed before we can say what is best for early treatment of these preterm babies,” Dr. Amaro said in a video interview.
Her report led to a flurry of comments during the question period, with several pediatricians voicing concern about the reliability of results from a study that followed only 83 patients because of its premature termination.
“The data and safety monitoring board’s decision is a big issue,” said Dr. Carl E. Hunt, a pediatrician at the Uniformed Services University of the Health Sciences in Bethesda, Md. “There is a literature that shows results of studies can be very different when they stop early. It’s unfortunate because we don’t have other prospective data, and it may now be hard to do a large randomized, controlled trial” of early caffeine treatment, Dr. Hunt said.
While Dr. Amaro conceded that premature termination limited her study’s size, she also asserted that her analyses confirmed the validity of the finding of no benefit from early caffeine treatment. “We projected to full enrollment, and there still was no difference in the time to first successful extubation,” she said.
Her study enrolled preterm infants during January 2013–December 2015 born at 23-30 weeks’ gestation who required mechanical ventilation during their first 5 days. Randomization assigned 41 infants to receive a 20-mg/kg bolus of caffeine, followed by a maintenance dosage of 5 mg/kg that continued until extubation, while 42 patients received placebo and did not get caffeine until just before attempted extubation. The bolus and maintenance caffeine dosages tested were identical to those used in the CAP Trial.
The researchers defined successful extubation as keeping a child off restart of mechanical ventilation for more than 24 hours. The average gestational age of the enrolled neonates was 26 weeks, their average weight was 700 g, and intubation started an average of 3 hours after delivery.
The study’s primary endpoint, age at first successful extubation, was an average of 24 days among the neonates treated with caffeine and 20 days in those on placebo, Dr. Amaro reported. Mortality occurred at an average of 30 days after delivery in the caffeine recipients and after an average of 10 days in the controls. The incidence of death was 22% in those on early caffeine and 12% among those in the placebo group, an excess of four deaths in the intervention arm that was not statically significant.
A recent review of more than 29,000 matched very-low-birth-weight infants managed in routine practice showed that neonates who received early caffeine had an adjusted mortality risk that was 23% higher than that of matched infants not receiving early caffeine, Dr. Amaro noted (J Pediatrics. 2014 May;164[5]:992-8).
The incidence of bronchopulmonary dysplasia also did not show a statistically significant difference between the two study arms, 46% among those on early caffeine and 53% in the placebo group. Patients on early caffeine also had higher rates of necrotizing enterocolitis, more episodes of necrotizing enterocolitis requiring surgery, and more intraventricular hemorrhages, but none of these differences reached statistical significance.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @mitchelzoler
BALTIMORE – Early initiation of caffeine treatment in premature neonates on mechanical ventilation did not cut the time to when these babies could successfully wean off the ventilator, according to findings of a single-center, randomized controlled study of 83 children.
The results also showed an “unexpected” trend toward increased mortality among the neonates who received early caffeine treatment, Dr. Cynthia M. Amaro reported at the annual meeting of the Pediatric Academic Societies. This signal of elevated mortality with caffeine treatment prompted the study’s data and safety monitoring board to prematurely stop the trial, limiting enrollment to just 75% of the number originally planned in the study’s design, thereby raising questions about the reliability of the primary-endpoint finding that early caffeine treatment did not result in the benefit of a reduced time to extubation.
Dr. Amaro said that she and her associates ran the study to address what had emerged as a significant area of doubt in routine U.S. practice on how to best use caffeine treatment in this neonatal population following publication of findings from the landmark Caffeine for Apnea of Prematurity (CAP) Trial (N Engl J Med. 2006 May 18;354[20]:2112-21). Results from the CAP Trial had shown in nearly 2,000 randomized, premature infants that treatment with caffeine led to significantly fewer episodes of bronchopulmonary dysplasia as well as quicker time to extubation of mechanical ventilation. Caffeine or other methylxanthines stimulate an infant’s respiratory center to allow faster extubation.
Ever since that publication a decade ago, “clinicians have been using caffeine earlier and more liberally, without really good data to support its early use in mechanically-ventilated preterm babies,” explained Dr. Amaro, a neonatologist at the University of Miami and Holtz Children’s Hospital in Miami.
Based on the new findings from the study she reported, “we are now not routinely initiating caffeine in mechanically ventilated preterm babies and just using caffeine immediately before extubation to treat apnea of prematurity. This returns caffeine treatment to the way it was used in the CAP Trial,” she said. “Further studies are needed before we can say what is best for early treatment of these preterm babies,” Dr. Amaro said in a video interview.
Her report led to a flurry of comments during the question period, with several pediatricians voicing concern about the reliability of results from a study that followed only 83 patients because of its premature termination.
“The data and safety monitoring board’s decision is a big issue,” said Dr. Carl E. Hunt, a pediatrician at the Uniformed Services University of the Health Sciences in Bethesda, Md. “There is a literature that shows results of studies can be very different when they stop early. It’s unfortunate because we don’t have other prospective data, and it may now be hard to do a large randomized, controlled trial” of early caffeine treatment, Dr. Hunt said.
While Dr. Amaro conceded that premature termination limited her study’s size, she also asserted that her analyses confirmed the validity of the finding of no benefit from early caffeine treatment. “We projected to full enrollment, and there still was no difference in the time to first successful extubation,” she said.
Her study enrolled preterm infants during January 2013–December 2015 born at 23-30 weeks’ gestation who required mechanical ventilation during their first 5 days. Randomization assigned 41 infants to receive a 20-mg/kg bolus of caffeine, followed by a maintenance dosage of 5 mg/kg that continued until extubation, while 42 patients received placebo and did not get caffeine until just before attempted extubation. The bolus and maintenance caffeine dosages tested were identical to those used in the CAP Trial.
The researchers defined successful extubation as keeping a child off restart of mechanical ventilation for more than 24 hours. The average gestational age of the enrolled neonates was 26 weeks, their average weight was 700 g, and intubation started an average of 3 hours after delivery.
The study’s primary endpoint, age at first successful extubation, was an average of 24 days among the neonates treated with caffeine and 20 days in those on placebo, Dr. Amaro reported. Mortality occurred at an average of 30 days after delivery in the caffeine recipients and after an average of 10 days in the controls. The incidence of death was 22% in those on early caffeine and 12% among those in the placebo group, an excess of four deaths in the intervention arm that was not statically significant.
A recent review of more than 29,000 matched very-low-birth-weight infants managed in routine practice showed that neonates who received early caffeine had an adjusted mortality risk that was 23% higher than that of matched infants not receiving early caffeine, Dr. Amaro noted (J Pediatrics. 2014 May;164[5]:992-8).
The incidence of bronchopulmonary dysplasia also did not show a statistically significant difference between the two study arms, 46% among those on early caffeine and 53% in the placebo group. Patients on early caffeine also had higher rates of necrotizing enterocolitis, more episodes of necrotizing enterocolitis requiring surgery, and more intraventricular hemorrhages, but none of these differences reached statistical significance.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @mitchelzoler
AT THE PAS ANNUAL MEETING
Key clinical point: Early caffeine treatment of premature neonates on mechanical ventilation did not reduce the time to extubation and produced a trend toward increased mortality.
Major finding: The age of first successful extubation averaged 24 days in infants receiving caffeine and 20 days among controls.
Data source: Single-center, randomized, controlled study of 83 premature neonates.
Disclosures: Dr. Amaro had no disclosures.
