Blue baby syndrome#History

The main sign of blue baby syndrome is cyanosis. Depending on the underlying cause of the cyanosis, additional symptoms may be:{{cite book |last1=Enlow |first1=Elizabeth |last2=Greenberg |first2=James M. |chapter=Clinical Manifestations of Diseases in the Newborn Period |pages=910–913.e4 |chapter-url=https://books.google.com/books?id=LJuRDwAAQBAJ&pg=PA910 |editor1-last=Kliegman |editor1-first=Robert M. |editor2-last=St Geme |editor2-first=Joseph W. |title=Nelson Textbook of Pediatrics |date=2019 |publisher=Elsevier Health Sciences |isbn=978-0-323-56888-3 }}

• Failure to thrive
• Lethargy
• Nasal flaring
• Rapid heartbeat
• Rapid respiratory rate
• Seizures
• Shortness of breath

{{anchor|Cause}}

Blue baby syndrome has been attributed to cyanotic congenital heart diseases and methemoglobinemia, however there are additional causes that could result in a baby becoming cyanotic, such as:{{cite book |last1=Stack |first1=Anne M |chapter=Cyanosis |editor1-last=Fleisher |editor1-first=Gary Robert |editor2-last=Ludwig |editor2-first=Stephen |editor3-last=Henretig |editor3-first=Fred M |title=Textbook of Pediatric Emergency Medicine |date=2006 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-5074-5 }}

• Airway obstruction
• Decreased blood perfusion
• Disordered control of breathing (ex: cyanotic breath-holding spells, seizures)
• Pulmonary/lung disorders (ex: pulmonary hypertension, cystic fibrosis)
• Respiratory distress syndrome{{MedlinePlusEncyclopedia|001563|Neonatal respiratory distress syndrome}}

Specific types of congenital heart defects cause blood to bypass the lungs by shunting directly from the right side of the heart to the left side, leading to cyanosis.{{cite journal |last1=Lin |first1=Pei-Yi |last2=Hagan |first2=Katherine |last3=Fenoglio |first3=Angela |last4=Grant |first4=P. Ellen |last5=Franceschini |first5=Maria Angela |title=Reduced cerebral blood flow and oxygen metabolism in extremely preterm neonates with low-grade germinal matrix- intraventricular hemorrhage |journal=Scientific Reports |date=16 May 2016 |volume=6 |issue=1 |page=25903 |doi=10.1038/srep25903 |pmc=4867629 |pmid=27181339 |bibcode=2016NatSR...625903L }} In these defects, deoxygenated blood enters the systemic circulation, giving the skin a bluish color and causing the baby to appear cyanotic. Infants with these types of heart defects may have a persistent bluish tint to their skin, or they may have intermittent episodes of cyanosis. The degree of cyanosis is dependent on the extent of deoxygenated blood mixing with oxygenated blood before being pumped into the systemic circulation.

Cardiac conditions in which there is decreased blood flow to the lungs such as, tetralogy of Fallot or pulmonary valve atresia, result in less blood becoming oxygenated. There are also cardiac conditions such as transposition of the great arteries or truncus arteriosus, that results in an overall increase in blood flow to the lungs but with limited flow of the oxygenated blood to the rest of the body. Conditions in which there is poor blood flow to the systemic circulation, such as coarctation of the aorta suggests that the body does not receive the oxygenated blood it requires with resultant cyanosis.{{Cite book|last=Bernstein|first=Daniel|title=Nelson Textbook of Pediatrics|publisher=Elsevier Inc.|pages=2371–2373}}

The five most common cyanotic heart defects that may result in Blue Baby Syndrome include the following:

File:Oxyhaemoglobin dissociation curve.png

Methemoglobinemia can be acquired or congenital. It occurs when the iron in hemoglobin is oxidized from Fe²⁺ to Fe³⁺, leading to poor binding of oxygen. Additionally, the oxygen that is already bound is held more tightly to the hemoglobin due to a higher affinity, resulting in less oxygen delivery. A methemoglobin level > 1.5 g/dL causes cyanosis. The most common congenital cause is a deficiency in the enzyme cytochrome b5 reductase which reduces methemoglobin in the blood.

However, in infants the most common cause of methemoglobinemia is acquired through the ingestion of nitrates ({{Chem2|NO3-}}) through well water or foods. Nitrites ({{Chem2|NO2-}}) produced by the microbial reduction of nitrate (directly in the drinkwater, or after ingestion by the infant, in his digestive system) are more powerful oxidizers than nitrates and are the chemical agent really responsible of the oxidation of Fe²⁺ into Fe³⁺ in the tetrapyrrole heme of hemoglobin. Infants younger than 4 months are at greater risk given that they drink more water per body weight, they have a lower NADH- cytochrome b5 reductase activity, and they have a higher level of fetal hemoglobin which converts more easily to methemoglobin. Additionally, infants are at an increased risk after an episode of gastroenteritis due to the production of nitrites by bacteria.{{Cite book|last=Smith-Whitley, Kwiatkowski|title=Nelson Textbook of Pediatrics|publisher=Elsevier Inc.|pages=2540–2558}} The sources of nitrate can include fertilizers used in agricultural lands, waste dumps or pit latrines.{{cite journal|author=Majumdar Deepanjan|year=2003|title=The Blue Baby Syndrome|journal=Resonance|volume=8|issue=10|pages=20–30|doi=10.1007/BF02840703|s2cid=117099503}} For example, nitrate levels are subject to monitoring to comply with drinking water quality standards in the United States and other countries.{{cite web|date=30 November 2015|title=National Primary Drinking Water Regulations|url=https://www.epa.gov/ground-water-and-drinking-water/national-primary-drinking-water-regulations|access-date=14 July 2018|website=EPA: United States Environmental Protection Agency|language=en}}{{cite web|title=Water-related diseases|url=https://www.who.int/water_sanitation_health/diseases-risks/diseases/methaemoglob/en/|url-status=dead|archive-url=https://web.archive.org/web/20170421085256/http://www.who.int/water_sanitation_health/diseases-risks/diseases/methaemoglob/en/|archive-date=21 April 2017|access-date=14 July 2018|website=World Health Organization}} The link between blue baby syndrome and nitrates in drinking water is widely accepted, but as of 2006 some studies indicated that other contaminants or dietary nitrate sources, might also play a role in the syndrome.{{cite journal|last1=Fewtrell|first1=Lorna|date=22 July 2004|title=Drinking-Water Nitrate, Methemoglobinemia, and Global Burden of Disease: A Discussion|journal=Environmental Health Perspectives| volume=112|issue=14|pages=1371–1374|doi=10.1289/ehp.7216|pmc=1247562|pmid=15471727}}{{cite journal|last1=van Grinsven|first1=Hans JM|last2=Ward|first2=Mary H = 2006|year=2006|title=Does the evidence about health risks associated with nitrate ingestion warrant an increase of the nitrate standard for drinking water?|journal=Environ Health|volume=5|issue=1|pages=26|doi=10.1186/1476-069X-5-26|pmc=1586190|pmid=16989661 |doi-access=free |bibcode=2006EnvHe...5...26V }}{{cite journal|last1=Ward|first1=Mary H.|last2=deKok|first2=Theo M.|last3=Levallois|first3=Patrick|last4=Brender|first4=Jean|last5=Gulis|first5=Gabriel|last6=Nolan|first6=Bernard T.|last7=VanDerslice|first7=James|date=23 June 2005|title=Workgroup Report: Drinking-Water Nitrate and Health—Recent Findings and Research Needs|journal=Environmental Health Perspectives|volume=113|issue=11|pages=1607–1614|doi=10.1289/ehp.8043|pmc=1310926|pmid=16263519}}

When diagnosing blue baby syndrome, it is important to perform a thorough history and physical exam. When obtaining the history, it is important to determine the timing of symptoms and to ask about risk factors/exposures, such as prenatal history or access to well-water.{{Citation|last1=Bearl|first1=David W.|title=Approach to the Cyanotic Infant|date=2019|url=http://accesspediatrics.mhmedical.com/content.aspx?aid=1166463091|work=Clinical Guidelines in Neonatology|editor-last=Jain|editor-first=Lucky|place=New York, NY|publisher=McGraw-Hill Education|access-date=21 January 2022|last2=Hill|first2=Kevin|editor2-last=Suresh|editor2-first=Gautham K.}}

File:Pulse Oximeter.jpg on infant's foot.]]

On physical exam it is important to visualize where the cyanosis is present to differentiate between peripheral and central cyanosis. Central cyanosis is typically visible as a blueish discoloration over the entire body and mucous membranes. In contrast, peripheral cyanosis typically has a blueish discoloration over the extremities. Cyanosis can be noted in babies around the lips, tongue, and sublingual area, where the skin is thinnest.{{cite journal |last1=McMullen |first1=Sarah M. |last2=Patrick |first2=Ward |title=Cyanosis |journal=The American Journal of Medicine |date=March 2013 |volume=126 |issue=3 |pages=210–212 |doi=10.1016/j.amjmed.2012.11.004 |pmid=23410559 |s2cid=244083635 }} In addition, it is important to observe the infant for signs of respiratory distress, visualized as nasal flaring, subcostal retractions, etc. Examination should include a respiratory and cardiac assessment.

One of the key tools in diagnosing is a pulse oximeter to determine oxygen saturation. While severe cyanosis can be easily noticed, an oxygen saturation as low as 80 % causes only mild clinical cyanosis that is difficult to see.{{cite journal |last1=Silove |first1=E D |title=Assessment and management of congenital heart disease in the newborn by the district paediatrician. |journal=Archives of Disease in Childhood - Fetal and Neonatal Edition |date=1994 |volume=70 |issue=1 |pages=F71–F74 |doi=10.1136/fn.70.1.f71 |pmc=1060995 |pmid=8117134 }} Additionally an arterial blood gas is useful, for example in the case of methemoglobinemia the PO₂ can be expected to be normal even with a low oxygen saturation. Additional work up includes a complete blood count, blood glucose, blood culture, chest X-ray, and an echocardiography.

Babies with cyanosis due to congenital heart disease usually present with symptoms hours to days after birth. In addition to cyanosis, they often show signs of tachypnea (fast breathing), a heart murmur, and decreased peripheral pulses.{{cite journal |last1=Khalil |first1=Markus |last2=Jux |first2=Christian |last3=Rueblinger |first3=Lucie |last4=Behrje |first4=Johanna |last5=Esmaeili |first5=Anoosh |last6=Schranz |first6=Dietmar |title=Acute therapy of newborns with critical congenital heart disease |journal=Translational Pediatrics |date=April 2019 |volume=8 |issue=2 |pages=114–126 |doi=10.21037/tp.2019.04.06 |pmc=6514285 |pmid=31161078 |doi-access=free }} If congenital heart disease is suspected in a newborn, doctors will likely perform several tests to evaluate the heart, including a chest x-ray, echocardiogram, and electrocardiogram.{{Cite web|url=https://www.heart.org/en/health-topics/congenital-heart-defects/symptoms--diagnosis-of-congenital-heart-defects|title=Symptoms and Diagnosis of Congenital Heart Defects|website=www.heart.org|language=en|access-date=13 November 2019}} In tetralogy of Fallot, episodes in which infants become cyanotic are called tet spells, typically occurring during feeding or crying. When older, children may squat to feel relief since this increases the systemic vascular resistance causing more blood to go towards the lungs, resulting in increased oxygenation.

Babies with cyanosis due to methemoglobinemia also usually present with cyanosis in the neonatal period, but pulse oximetry may be falsely elevated and does not always reveal low blood oxygen saturation. A CO-oximeter can be used to detect levels of methemoglobin in the blood if methemoglobinemia is suspected, by seeing the difference between oxygen saturation on an arterial blood gas and the measurement on a co-oximeter. Additionally, a direct methemoglobin level can be obtained.{{cite journal |last1=Da-Silva |first1=Shonola S. |last2=Sajan |first2=Imran S. |last3=Underwood |first3=Joseph P. |title=Congenital Methemoglobinemia: A Rare Cause of Cyanosis in the Newborn—A Case Report |journal=Pediatrics |date=August 2003 |volume=112 |issue=2 |pages=e158–e161 |doi=10.1542/peds.112.2.e158 |pmid=12897322 |doi-access=free }}

As of 22 May 2007, the United States Environmental Protection Agency has established a maximum contaminant level of 10 mg/L for nitrate and 1 mg/L for nitrite in drinking water due to the potential harmful effects in infants.{{cite web|title=US EPA Archive Document- Nitrates and Nitrites|url=https://archive.epa.gov/region5/teach/web/pdf/nitrates_summary.pdf|url-status=live|access-date=2 March 2023|archive-url=https://web.archive.org/web/20220430221235/https://archive.epa.gov/region5/teach/web/pdf/nitrates_summary.pdf|archive-date=30 April 2022|date=22 May 2007|website=US EPA}}

A screening tool has been developed to screen for critical cardiac defects, which refers to cardiac lesions that require surgery or intervention in the 1st year of life. Screening for critical congenital heart defects should be done on all newborns after 24hours or shortly before discharge. Oxygen saturation is measured in the right hand and either foot.{{Cite web|title=Critical Congenital Heart Defects|url=https://www.cdc.gov/ncbddd/heartdefects/cchd-facts.html#:~:text=Newborn%20screening%20for%20critical%20CHDs%20involves%20a%20simple%20bedside%20test,placed%20on%20the%20baby's%20skin.|url-status=live|website=CDC|archive-url=https://web.archive.org/web/20140911115312/http://www.cdc.gov/ncbddd/heartdefects/cchd-facts.html |archive-date=11 September 2014 }}

A screening is considered positive if:

• Oxygen saturation < 90 % in either extremity,
• Oxygen saturation 90-94 % in both extremities on 3 measurements separated by an hour each,
• Oxygen saturation difference > 3 % between both extremities on 3 measurements separated by an hour each.

Treatment for blue baby syndrome will depend on the underlying cause.

When evaluating a patient for cyanosis or respiratory distress, vital signs should be monitored, especially the patient's heart rate and oxygen saturation. It is beneficial to have vascular access established. In newborns, the pulse oximeter is typically placed on the right hand to determine pre-ductal oxygenation, referring to oxygenation before the ductus arteriosus (connection between aorta and pulmonary artery). This gives the oxygenation level the heart and brain receive. Traditionally, supplemental oxygen is given in an escalating manner beginning with free-flowing oxygen, progressing to positive pressure ventilation or continuous positive airway pressure, and ending with mechanical intubation. The goal oxygen saturation is between 85 and 95 %. If an infant requires supplemental oxygen for a prolonged time it should be heated and humidified to avoid heat loss.{{Cite book|last=American Academy of Pediatrics and American Heart Association|title=Textbook of Neonatal Resuscitation|publisher=American Academy of Pediatrics|year=2016|pages=33–65}}

Some babies born with cyanotic heart disease are treated with prostaglandin E1 after birth to keep the ductus arteriosus open and allow for more oxygenated blood to be pumped to the body. Many also receive oxygen therapy to increase the percentage of oxygen in the blood. Most of these babies will require surgery during infancy to correct their structural heart defect.

The first-line treatment for severe methemoglobinemia is methylene blue, a medication that will reduce methemoglobin in the blood. This is possible because methylene blue oxidizes NADPH, which in turn can convert methemoglobin back to hemoglobin.

Out of all the babies born with congenital heart defects, about 25 % have cyanosis as a result. Tetralogy of Fallot is the most common cyanotic cardiac heart defect.{{cite book |last1=Ossa Galvis |first1=Maria M. |last2=Bhakta |first2=Rupal T. |last3=Tarmahomed |first3=Abdulla |last4=Mendez |first4=Magda D. |title=StatPearls |date=2024 |publisher=StatPearls Publishing |chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK500001/ |chapter=Cyanotic Heart Disease |pmid=29763177 }}

Methemoglobinemia is considered to be rare, with acquired methemoglobinemia encountered more than the congenital form.{{cite book |last1=Ludlow |first1=John T. |last2=Wilkerson |first2=Richard G. |last3=Nappe |first3=Thomas M. |title=StatPearls |date=2024 |publisher=StatPearls Publishing |chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK537317/ |chapter=Methemoglobinemia |pmid=30726002 }}

In the case of cyanotic causing heart defects, about 75 % of infants survive to 1 year of age and 69 % survive to 18 years of age. These individuals have an increased risk of developmental delay, heart failure, or heart rhythm disorders.

Methemoglobinemia responds well to treatment, its prognosis is associated with the level of methemoglobinemia and the degree of end organ damage it can cause. Death can occur when levels reach 70 %.{{EMedicine|article|204178|Methemoglobinemia}}

The first successful operation to treat blue baby syndrome caused by tetralogy of Fallot occurred at Johns Hopkins University in 1944. Through a collaboration between pediatric cardiologist Helen Taussig, surgeon Alfred Blalock, and surgical technician Vivien Thomas, the Blalock-Thomas-Taussig shunt was created. Dr. Taussig had recognized that children with Tetralogy of Fallot who also had a patent ductus arteriosus (PDA) typically lived longer, so the trio tried to create the same effect as a PDA by joining the subclavian artery to the pulmonary artery, relieving the child's cyanosis.{{cite book |last1=Thomas |first1=Vivien T. |title=Partners of the Heart: Vivien Thomas and His Work with Alfred Blalock |date=1998 |publisher=University of Pennsylvania Press, Incorporated |isbn=978-0-8122-1634-9 }}{{pn|date=February 2024}} The operation was published in the Journal of the American Medical Association in 1945 and impacted management of blue babies around the world.{{Cite web|url=https://medicalarchives.jhmi.edu:8443/firstor.htm|title=That First Operation|website=Johns Hopkins Medical Institutions|access-date=13 November 2019|archive-date=12 June 2020|archive-url=https://web.archive.org/web/20200612232719/https://medicalarchives.jhmi.edu:8443/firstor.htm|url-status=dead}}

Anna was the name of the dog who was the first survivor of the surgery, considered an experimental procedure at the time. Anna survived the first pulmonary bypass after having been operated on twice. The second operation was required to replace the original stitches with flexible ones. After their success with Anna, Blalock and Thomas had the courage to perform the very first open heart surgery on Eileen Saxon in 1944. In 1950, Anna's story was made into a movie, and the film has been shown to various schools and other groups.{{cite web|url=http://www.hopkinsmedicine.org/mcp/Front_page/anna/index.html|title=Information on Anna|first=Chris|last=Smith|publisher=|accessdate=22 July 2016|archive-url=https://web.archive.org/web/20160331073734/http://www.hopkinsmedicine.org/mcp/Front_page/anna/index.html|archive-date=31 March 2016}}

{{reflist}}

{{Congenital heart defects}}

{{DEFAULTSORT:Blue Baby Syndrome}}

Category:Neonatology

Category:Syndromes affecting the heart