NEONATOLOGY
Rethinking Old Reliable
CONTROL AIRWAY
Could the widely used drug acetaminophen potentially have harmful effects on premature babies ?
Over the last five years , providers in neonatal intensive care units across the globe have increasingly used acetaminophen , to treat patent ductus arteriosus , or PDA , a common heart defect in premature babies . Given the ubiquity of acetaminophen in our lives , most have considered this practice perfectly safe , but for Children ’ s Colorado neonatologist Clyde Wright , MD , this set off alarm bells . Dr . Wright ’ s research has long taken an interest in the liver-lung connection , and given acetaminophen ’ s impact on the liver , he wanted to know more about how it might affect premature lungs .
According to Dr . Wright , the rise in acetaminophen use in extremely premature babies in the NICU began when doctors discovered the common drug ’ s ability to close PDA ’ s characteristic gap between the two blood vessels leading away from the heart . This condition previously was treated using nonsteroidal antiinflammatory drugs , or NSAIDs , which come with some difficult side effects , making acetaminophen a welcome substitute . As a result of this change , some recent studies indicate that 70 % of premature babies in the NICU are prescribed acetaminophen ( 1 ).
“ People are looking at acetaminophen in these premature babies and saying , ‘ It ’ s safe . We don ’ t see any liver injury ,’ which is true ,” Dr . Wright says , “ but no one was looking at the lungs .”
Dr . Wright is doing just that through a nearly $ 3 million grant from the National Institute of Child Health and Human Development ( NICHD ). The grant will allow him to further study whether acetaminophen adversely impacts lung development and better understand the mechanism by which lung injury might occur .
Figure 1
Here ’ s what we know : When an adult takes acetaminophen for a headache or muscle soreness , the liver breaks it down into nontoxic metabolites . But when an overdose occurs , the pathways the liver uses to create that nontoxic metabolite become overwhelmed and another enzyme , CYP2E1 , comes into play . CYP2E1 turns acetaminophen into a mitochondrial toxin that can cause significant cell death and , ultimately , liver necrosis . That same enzyme is expressed in high levels in the developing lung . Whether CYP2E1 expression in the developing lung causes cellular injury is still unknown .
“ When you think of acetaminophen and organ injury , you think of the liver ,” Dr . Wright says . “ So , in the lab , I started to ask , ‘ If I injured the liver with acetaminophen , what would happen to the lungs ?’”
Dr . Wright and his team devised a series of research projects to explore the potential adverse pulmonary effects of acetaminophen use in premature babies . In the first of three studies , the team used preclinical models to determine how acetaminophen exposures that were sure to injure the liver impacted the mature lung ( 2 ). That research yielded notable results : significant cell death in the airways and alveolar injury ( see figure 2 , orange circles ).
This laid the foundation for the second study , which found that even with a smaller acetaminophen exposure — one that resulted in no liver toxicity — the lungs still showed signs of injury ( 3 ).
6 | CHILDREN ’ S HOSPITAL COLORADO