Gray baby syndrome (also termed gray syndrome or grey syndrome) is a rare but serious, even fatal, side effect that occurs in newborn infants (especially premature babies) following the accumulation of the antibiotic chloramphenicol. Chloramphenicol is a broad-spectrum antibiotic that has been used to treat a variety of bacteria infections like Streptococcus pneumoniae as well as typhoid fever, meningococcal sepsis, cholera, and eye infections. Chloramphenicol works by binding to ribosomal subunits which blocks transfer ribonucleic acid (RNA) and prevents the synthesis of bacterial proteins. Chloramphenicol has also been used to treat neonates born before 37 weeks of the gestational period for prophylactic purposes. In 1958, newborns born prematurely due to rupture of the amniotic sac were given chloramphenicol to prevent possible infections, and it was noticed that these newborns had a higher mortality rate compared with those who were not treated with the antibiotic. Over the years, chloramphenicol has been used less in clinical practice due to the risks of toxicity not only to neonates, but also to adults due to the risk of aplastic anemia. Chloramphenicol is now reserved to treat certain severe bacteria infections that were not successfully treated with other antibiotic medications.
Signs and symptoms
Since the syndrome is due to the accumulation of chloramphenicol, the signs and symptoms are dose related. According to Kasten's review published in the Mayo Clinic Proceedings, a serum concentration of more than 50 μg/mL is a warning sign, while Hammett-Stabler and John states that the common therapeutics peak level is 10-20 μg/mL and is expected to achieve after 0.5-1.5 hours of intravenous administration in their review of antimicrobial drugs. The common onset of signs and symptoms are 2 to 9 days after the initiation of the medication, which allows the serum concentration to build up to reach the toxic concentration above. Common signs and symptoms include loss of appetite, fussiness, vomiting, ashen gray color of the skin, hypotension (low blood pressure), cyanosis (blue discoloration of lips and skin), hypothermia, cardiovascular collapse, hypotonia (muscle stiffness), abdominal distension, irregular respiration, and increased blood lactate.
Pathophysiology
Two pathophysiologic mechanisms are thought to play a role in the development of gray baby syndrome after exposure to chloramphenicol. This condition is due to a lack of glucuronidation reactions occurring in the baby (phase II hepatic metabolism), thus leading to an accumulation of toxic chloramphenicol metabolites: Metabolism: The UDP-glucuronyl transferase enzyme system in infants, especially premature infants, is not fully developed and incapable of metabolizing the excessive drug load needed to excrete chloramphenicol. Elimination: Insufficient renal excretion of the unconjugated drug. Insufficient metabolism and excretion of chloramphenicol leads to increased blood concentrations of the drug, causing blockade of the electron transport of the liver, myocardium, and skeletal muscles. Since the electron transport is an essential part of cellular respiration, its blockade can result in cell damage. In addition, the presence of chloramphenicol weakens the binding of bilirubin and albumin, so increased levels of the drug can lead to high levels of free bilirubin in the blood, resulting in brain damage or kernicterus. If left untreated, possible bleeding, renal (kidney) and/or hepatic (liver) failure, anemia, infection, confusion, weakness, blurred vision, or eventually death are expected. Additionally, chloramphenicol is significantly insoluble due to an absence of acidic and basic groups in its molecular compound. As a result, larger amounts of the medication are required to achieve the desired therapeutic effect. High volumes of a medication that can cause various toxicities is another avenue how chloramphenicol can potentially lead to grey baby syndrome.