Gray Baby Syndrome


Article Author:
Earl Cummings


Article Editor:
Mary Ann Edens


Editors In Chief:
Chaddie Doerr


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
6/4/2019 6:44:53 PM

Introduction

Chloramphenicol is a bacteriostatic man-made antibiotic that was discovered in 1947. Initially designed for the treatment of typhoid fever, it has fallen out of favor due to the ubiquity of antibiotic-resistant Salmonella typhi. It was also historically used for the empiric treatment of pediatric patients presenting with petechial rash and fever for its excellent coverage of meningococcal sepsis and rickettsial disease. Due to its low-cost, wide spectrum of coverage, and low incidence of toxicity, chloramphenicol has been added to the World Health Organization’s List of Essential Medicines, and the growing problem of antimicrobial resistance to current broad-spectrum antibiotics has brought back interest in its use worldwide. Twelve years after its discovery, the first case report of a potentially fatal adverse reaction to chloramphenicol was discovered in neonates, with a predilection towards preterm infants. Neonates born at less than 37 weeks gestation were given chloramphenicol in an intravenous or oral formulation within two days of birth when they began to develop abdominal distention, vomiting, hypothermia, cyanosis, and cardiovascular instability. Vasomotor collapse resulting in mottling of skin and eventual ashen-gray skin discoloration led to the naming of this reaction as "gray-baby syndrome."[1]

Etiology

Elevated levels of chloramphenicol circulating in the plasma result from two distinct pathophysiologic processes. A normally functioning liver will metabolize the chloramphenicol parent molecule (primarily by glucuronidation). The immature neonatal liver is unable to synthesize and recycle the UDP-glucuronyltransferase enzyme efficiently. Similarly, the neonatal kidneys are unable to excrete chloramphenicol and its metabolites efficiently. These two deficiencies result in elevated serum levels of chloramphenicol. The chloramphenicol molecule displaces unconjugated bilirubin from albumin, leading to kernicterus and eventually death if untreated.[2]

Epidemiology

Premature infants and neonates are at the highest risk of the gray-baby syndrome from chloramphenicol exposure due to their decreased hepatic and renal function. Case reports of chloramphenicol toxicity have also been reported in children and adolescents. Various weight-based dosage adjustment has been suggested for newborns younger than 15 days, infants between 2 to 4 weeks days, and children older than one month.[3]

Pathophysiology

Gray-baby syndrome usually begins between 2 to 9 days after chloramphenicol therapy is initiated. The relative hepatic and renal dysfunction in neonates (especially in premature infants) result in elevated serum levels of chloramphenicol. This impairs electron transport within the mitochondrial and consequently cellular respiration, leading to direct cellular toxicity. The chloramphenicol parent molecule also displaces unconjugated bilirubin from albumin, giving way to kernicterus and eventually death or permanent neurological sequelae if left untreated.[4]

Toxicokinetics

Serum concentrations after a single oral or intravenous dose of chloramphenicol peak 1 to 2 hours after ingestion; chloramphenicol has excellent absorption in the gastrointestinal (GI) tract. Intramuscular chloramphenicol has variable absorption with serum concentrations reaching only 5% to 65% the concentration of the equivalent intravenous or oral dose. Roughly half of serum chloramphenicol is bound to albumin and other plasma proteins. Elimination happens primarily in the liver through O-glucuronidation, which puts neonates with immature hepatic metabolism at risk for the gray-baby syndrome. This syndrome has been seen in patients who were given doses greater than 200 mg daily. Urinary excretion of the parent chloramphenicol compound is approximately 20% in children and 10% to 12% in adults; the rest is excreted as the glucuronidated metabolite.

History and Physical

The presentation of the gray-baby syndrome will vary depending on the level of toxicity from chloramphenicol. Ideally, chloramphenicol exposure will be provided in the history from the caregiver. Poor feeding, fussiness, and vomiting are often elicited in the history. Exposure from maternal use has also been observed. Chloramphenicol has been assigned Pregnancy Category C (risk not ruled out) and is contraindicated during lactation (as it passes readily into breast milk). A physical exam may reveal altered mental status from lethargy to obtundation, ashen-gray cyanosis, pallor, and abdominal distention/tenderness.

Evaluation

In the undifferentiated sick neonate presenting with cyanosis, a broad differential diagnosis must be considered, including but not limited to neonatal sepsis, non-accidental trauma, midgut volvulus, congenital heart disease, and inborn errors of metabolism. Blood work should include glucose, complete blood count with differential, complete metabolic panel, blood gas analysis, serum ammonia, serum lactic acid, serum ketones, and consideration for cardiac biomarkers including troponin and brain natriuretic peptide. In the setting of chloramphenicol toxicity, serum chloramphenicol levels may be drawn. Radiologic studies should include chest and abdominal films, and CT head or abdominal ultrasound (depending on the history). An electrocardiogram should also be obtained.[5]

Treatment / Management

Management of chloramphenicol toxicity centers primarily around supportive care. The general approach to the ashen-gray hemodynamically unstable neonate starts with aggressive resuscitation and an early call to the pediatric intensive care unit or extracorporeal life support team, as some of these patients may be ideal candidates. These patients should be hemodynamically stabilized, appropriately oxygenated and ventilated, and intubated early. Checking a core temperature is critical as hypothermia is common in the gray neonate. Aggressive rewarming should be considered. A point-of-care glucose should also be checked, and hypoglycemia should be reversed if present. The differential diagnosis for an ashen-gray, cyanotic neonate should include chloramphenicol toxicity, congenital heart disease, adrenal insufficiency/hypothyroidism, inborn errors of metabolism, trauma, seizures, and of course, sepsis. Empiric administration of broad-spectrum antibiotics such as vancomycin, ampicillin (targeting Listeria), and a third-generation cephalosporin such as ceftriaxone or cefotaxime is recommended. Additional consideration should also be given to empiric prostaglandin administration in gray/cyanotic neonates, especially if a duct-dependent congenital cardiac lesion is present. 

Modalities that have been used for the treatment of gray-baby syndrome are primarily aimed towards direct removal of the parent chloramphenicol molecule. This has been achieved through charcoal hemoperfusion and exchange transfusion. There have also been reports of phenobarbital being used for induction of the UDP-glucuronyltransferase enzyme. Consideration for cardiopulmonary bypass including extracorporeal membrane oxygenation may also be considered.[6]

Prognosis

If the condition is diagnosed immediately and the drug is discontinued the prognosis is good but if the infant has developed organ dysfunction, the prognosis is guarded.

Complications

  • Bleeding
  • Renal and liver failure
  • Anemia
  • Infection
  • Confusion
  • Marked Weakness
  • Vision problems
  • Shock
  • Death

Consultations

Once gray baby syndrome has been diagnosed, consultation with a pediatrician and an infectious disease expert is recommended.

Pearls and Other Issues

Patients with gray baby syndrome should be admitted to a closely monitored telemetry setting, ideally in the intensive care unit. Changes in the dosing regimen (lower doses given at longer intervals) and careful monitoring of drug levels can help prevent this fatal complication of chloramphenicol administration in neonates and premature infants.

Enhancing Healthcare Team Outcomes

Gray baby syndrome is a preventable problem. With the number of antibiotics available today, there should be no valid reason to use this agent for the management of infection in babies. All healthcare workers should be aware of the serious complications of this antibiotic and the onus is on them not to start treatment unless there is no other choice. The pharmacist should fully question the prescription of this antibiotic for neonates and infants and should recommend other agents. Data suggest that when the drug is discontinued immediately after initiation of therapy, then the outcomes are good. But once the syndrome has developed, the prognosis is guarded. Deaths were once commonly reported in neonates when started on chloramphenicol. 

 


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Gray Baby Syndrome - Questions

Take a quiz of the questions on this article.

Take Quiz
Which of the following is known to cause gray baby syndrome?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following complications is linked to chloramphenicol exposure in the newborn?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A newborn shows lethargy, hypotension, ash-colored skin, and abdominal distention. History reveals that the mother had been taking a medication. What medication was the mother most likely taking?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A newborn shows lethargy, hypotension, scleral icterus, ashen colored skin, and abdominal distention. History reveals that the mother took an antibiotic during her pregnancy. What medication likely caused these symptoms?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following medications is associated with gray-baby syndrome?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
"Gray baby syndrome" can occur in neonates given chloramphenicol. In what hepatic enzymatic modification listed below is the deficit that leads to chloramphenicol toxicity?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Gray Baby Syndrome - References

References

Chloramphenicol null. 2006     [PubMed]
Beninger P, Pharmacovigilance: An Overview. Clinical therapeutics. 2018 Aug 17     [PubMed]
Knight M, Adverse drug reactions in neonates. Journal of clinical pharmacology. 1994 Feb     [PubMed]
Tonni G,Leoncini S,Signorini C,Ciccoli L,De Felice C, Pathology of perinatal brain damage: background and oxidative stress markers. Archives of gynecology and obstetrics. 2014 Jul     [PubMed]
Long SS, 50 Years Ago in The Journal of Pediatrics: Visual Disturbances in Cystic Fibrosis following Chloramphenicol Administration. The Journal of pediatrics. 2016 Jan     [PubMed]
Ingebrigtsen SG,Didriksen A,Johannessen M,Škalko-Basnet N,Holsæter AM, Old drug, new wrapping - A possible comeback for chloramphenicol? International journal of pharmaceutics. 2017 Jun 30     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Nurse-Maternal Newborn PN. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Nurse-Maternal Newborn PN, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Nurse-Maternal Newborn PN, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Nurse-Maternal Newborn PN. When it is time for the Nurse-Maternal Newborn PN board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Nurse-Maternal Newborn PN.