Clinical Resources

Read the well-established and mounting body of evidence recognizing the risks of unmanaged Jaundice and supporting the use of ETCOc testing with newborns.

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Clinical Guidelines
- FOCUS OF GUIDELINE The overall aim of this guideline is to promote an approach that will reduce the frequency of severe neonatal hyperbilirubinemia and bilirubin encephalopathy and minimize the risk of unintended harm such as increased anxiety, decreased breastfeeding, or unnecessary treatment for the general population and excessive cost and waste. Recent reports of kernicterus indicate that this condition, although rare, is still occurring. Analysis of these reported cases of kernicterus suggests that if health care personnel follow the recommendations listed in this guideline, kernicterus would be largely preventable. Identification of Hemolysis Because of their poor specificity and sensitivity, the standard laboratory tests for hemolysis are frequently unhelpful. However, end-tidal carbon monoxide, corrected for ambient carbon monoxide (ETCOc), levels can confirm the presence or absence of hemolysis, and measurement of ETCOc is the only clinical test that provides a direct measurement of the rate of heme catabolism and the rate of bilirubin production. Thus, ETCOc may be helpful in determining the degree of surveillance needed and the timing of intervention. It is not yet known, however, how ETCOc measurements will affect management.
- More than 80% of newborn infants will have some degree of jaundice. Careful monitoring of all newborn infants and the application of appropriate treatments are essential because high bilirubin concentrations can cause acute bilirubin encephalopathy and kernicterus. (…) Central to this guideline is having systems in place including policies in hospitals and other types of birthing locations to provide the care necessary to minimize the risk of kernicterus. Evidence Leading to Changes Since the publication of the previous guideline, the evidence base regarding the monitoring and treatment of hyperbilirubinemia has expanded. Key new research findings appear in the evidence tables included in Appendix B and in the accompanying technical report. In addition, the committee reviewed guidelines from the Northern California Neonatal Consortium and the Academy of Breastfeeding Medicine. (…) Because the new evidence is insufficient to derive specific treatment thresholds by quantitatively estimating the risks and benefits of different approaches to care, the committee began with the previous AAP guidelines. Based on an evaluation of evidence published since 2004, the committee raised the phototherapy thresholds by a narrow range that the committee considered to be safe. The committee also used new research assessment approach based on the hour-specific bilirubin concentration and the approach to rapidly address elevated bilirubin concentrations, defined as “escalation of care.”
  1. Identifying Risk Factors for Hyperbilirubinemia
  Infants with risk factors for hyperbilirubinemia (Table 1) require closer monitoring than infants without risk factors. Determining the presence of these risk factors requires examining the infant, assessing laboratory data, and obtaining a family history of blood disorders or neonatal jaundice. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked recessive enzymopathy that decreases protection against oxidative stress, is now recognized as one of the most important causes of hazardous hyperbilirubinemia leading to kernicterus in the United States and across the globe. Identifying neonates with G6PD deficiency is a challenge. Most affected infants will not have a positive family history. Genetic ancestry from a population in which this condition is prevalent (e.g., Sub-Saharan Africa, Middle East, Mediterranean, Arabian Peninsula, and Southeast Asia) can be helpful in predicting risk. This is an example of how the delivery of race-conscious medicine can lead to improved health outcomes. Knowing information about genetic ancestry can help inform the assessment of G6PD risk. Overall, 13% of African American males and about 4% of African American females have G6PD deficiency. There are clinical events that should raise suspicion about the presence of G6PD deficiency. Newborn infants with G6PD deficiency are more likely to receive phototherapy before hospital discharge, probably because of both increased bilirubin production and decreased conjugation, and have a greater risk of readmission and retreatment. Severe hyperbilirubinemia or atypical development of hyperbilirubinemia, such as elevated TSB in a formula-fed infant or late-onset jaundice, should raise the possibility of G6PD deficiency. An infant with G6PD deficiency can develop a sudden and extreme increase in TSB that may be hard to anticipate or prevent. Even after an acute hemolytic event, there may be little or no laboratory evidence of hemolysis. It is important for clinicians to recognize that measuring the G6PD activity during or soon after the hemolytic event or after an exchange transfusion can lead to a falsely normal result. If G6PD deficiency is strongly suspected but the measurement of G6PD activity is normal or close to normal, the G6PD activity should be measured at least 3 months later. KAS 3: Use TSB as the definitive test to guide phototherapy and escalation-of-care decisions, including exchange transfusion. (Aggregate Evidence Quality Grade X, Recommendation) “Decisions to initiate phototherapy or escalate care are guided by the gestational age, the hour-specific TSB, and the presence of risk factors for bilirubin neurotoxicity (Table 2). The presence of hyperbilirubinemia neurotoxicity risk factors lowers the threshold for treatment with phototherapy and the level at which care should be escalated.” Lower gestational age and isoimmune hemolytic disease are risk factors both for developing significant hyperbilirubinemia and for bilirubin neurotoxicity. Although it is not clear if hemolysis attributable to causes other than isoimmunization also increases the risk of bilirubin neurotoxicity, it is prudent to assume that it does. Other important neurotoxicity risk factors are related to serious illness in the newborn infant (e.g., sepsis). Low serum albumin can increase the risk of neurotoxicity because of the greater availability of unbound bilirubin (i.e., bilirubin not bound to albumin). KAS 7: If more than 1 TcB or TSB measure is available, the rate of increase may be used to identify infants at higher risk of subsequent hyperbilirubinemia. A rapid rate of increase (0.3 mg/dL per hour in the first 24 hours or 0.2 mg/dL per hour thereafter) is exceptional and suggests hemolysis. In this case, perform a DAT if not previously done. (Aggregate Evidence Quality Grade D, Option) If available, measurement of end tidal carbon monoxide production, corrected for ambient carbon monoxide (ETCOc), is a potentially useful method for quantifying hemolysis. Carbon monoxide is produced in equimolar amounts with bilirubin when heme is catabolized to bilirubin. KAS 10: Intensive phototherapy is recommended at the total serum bilirubin thresholds in Fig 2 or Fig 3 on the basis of gestational age, hyperbilirubinemia neurotoxicity risk factors, and age of the infant in hours. (Aggregate Evidence Quality Grade X, Recommendation) [The phototherapy treatment] thresholds, like those in the 2004 guidelines, are based on expert opinion rather than strong evidence that they distinguish between infants in whom the benefits of phototherapy do or do not exceed its risks.
ETCO – THE GOLD STANDARD FOR DIAGNOSING AND QUANTIFYING HEMOLYSIS IN NEONATES AND INFANTS, evidence-based CLINICAL USEs and benefits
- - The study evaluated the value of an end-tidal carbon monoxide corrected for inhaled carbon monoxide concentration (ETCOc) at the early neonatal period to determine if the value is useful for predicting subsequent hyperbilirubinemia (HB) in non-hemolytic full-term infants.
  - Seven of the 51 infants enrolled in the study developed HB.
  - The ETCOc levels in the hyperbilirubinemic infants did not decrease significantly in the first 72 h after birth and were higher than those in non-hyperbilirubinemic infants at 42, 48, 54 and 66 h of age. The ETCOc level at 42 h of age was the most predictive of subsequent HB by ROC analysis. At the cut-off level of 1.8 μL/L (p.p.m.)
  - Researchers concluded that increased ETCOc level in the early neonatal period is associated with subsequent HB, even in infants without hemolytic disease. The ETCOc measurement may be useful as a screening test for predicting non-hemolytic HB.
- - In this prospective study the researchers used the CoSense monitor to study 56 neonates with Significant Hyperbilirubinemia (SHB) to detect hemolysis.
  - CoSense provided similar information as invasive blood tests (DAT, retic count, hematocrit, and bilirubin), confirming feasibility of detecting hemolysis using a simple breath test.
- - In this prospective, controlled study, researchers used the CoSense ETCO monitor to analyze 33 pediatric patients with Sickle Cell Anemia (SCA) to detect hemolysis in patients with a known hemolytic condition.
  - ETCO values 5-fold higher in SCA subjects than controls and the ETCO values correlated with reticulocytes and bilirubin.
- - The authors tested end tidal carbon monoxide (ETCO) as a marker of the rate of heme metabolism to bilirubin.
  - They found that ETCO values of 20 neonates and children with known hemolytic disorders were higher than 20 age-matched healthy controls, indicating that this instrumentation recognizes hemolysis in neonates and children.
  - ETCO reference intervals were also higher in healthy neonates during the first three days after birth (5th to 95th percentile reference range, 1.4 to 1.7 ppm) than after 1 month of age.
  - The data suggests that hemolysis is physiological during the first days after birth.
- - The study assessed the relative contributions of increased bilirubin production (indexed by end-tidal carbon monoxide (CO) concentrations, corrected for ambient CO (ETCOc)) to hour-specific total bilirubin (TB) levels in healthy late preterm and term newborns.
  - Post hoc analyses of concurrent ETCOc and TB (at 30±6 h of age) and follow-up TB levels at age 96±12 h and up to 168 h after birth were performed on 641 term and late preterm infants.
  - Increased bilirubin production (hour-specific ETCOc ≥1.7 p.p.m. at age 30±6 h) was noted in ~80%, 42% and 32% of infants in the high-, intermediate- and low-risk TB zones, respectively. One infant with TB <40th percentile and ETCOc <1.7 p.p.m. developed TB ≥95th percentile at age 168 h, probably due to decreased bilirubin elimination.
  - Infants in the high-risk quartile of the hour-specific bilirubin nomogram have a higher mean bilirubin production. Infants with TB levels ≥95th percentile without increased bilirubin production have impaired bilirubin elimination.
- - This study supports the clinical accuracy of CoSense ETCO values in newborns at Stanford University.
  - Carboxyhemoglobin (COHb) levels in blood are used for experimental measurements of hemolysis.
  - Strong linear correlation between CoSense ETCO and COHb indicates accurate detection of hemolysis by CoSense.
- - This study defines the use of ETCO in the clinical management of hyperbilirubinemia (HB).
  - For the 79 infants who met the study criteria, End-tidal CO concentrations measurements were performed using a CoSense Monitor. Up to 4 ETCOc measurements were taken once per day (~24 hours) for up to four days of life (≤96 hours of age) in conjunction with routine TB levels. Subjects readmitted to the neonatal intensive care unit were also eligible to have the ETCOc measurements collected in the same way after readmission until the subject was ≤144 hours of age.
  - An elevated ETCOc level (>1.5 ppm) and/or an excessive rate of TB rise may identify those infants who are most at risk and should be aggressively treated with phototherapy. In the absence of clinical risk factors, these at-risk newborns could be observed and provided lactation support to enhance enteral milk intake such that phototherapy could be deferred.
  - Researchers concluded that near-simultaneous ETCOc and TB measurements in infants with TB >75th percentile accurately identify hemolytic HB. Hour-specific bilirubin load, consequent to bilirubin production, coupled with knowledge about bilirubin elimination disorders, can help predict an infant’s post-discharge TB risk zone. In addition, identification of hemolytic disorders can help guide clinicians in their treatment of HB to deduce when patients lack adequate bilirubin elimination mechanisms.
- - This study explores the efficacy of using CoSense to measure hemolysis in newborns via ETCO levels.
  - A prospective, multihospital, test‐of‐concept study measured ETCO of hospitalized neonates with a total bilirubin (TB) value >75th percentile on the Bhutani bilirubin nomogram.
  - 37 neonates with an elevated ETCOc were labeled as having ‘hemolytic jaundice’. It was recommended that a follow‐up TB check occurred <24 h after hospital discharge.
  - By means of a direct antiglobulin test (DAT/Coombs), 11 of the 37 infants were found positive for ABO hemolytic disease.
  - Thirty‐six of the 37 with an elevated ETCOc had repeat TB monitoring <24 h after discharge home.
  - None of the 100 were re-hospitalized for jaundice treatment compared with a rate of 2.99 rehospitalizations per 100 control neonates who had a TB value >75th percentile. [zero readmission using ETCO vs 2.99% readmission for neonates who had a TB value >75th percentile.]
  - Researchers concluded that ETCOc measurement is a feasible means of assessing hemolysis in jaundiced neonates during the birth hospitalization. When hemolysis is identified, parents are likely to bring the infant for a TB checkup <24 h after discharge.
- - The aim of this review was to address the importance of hemolysis and its clinical detection in neonates with hyperbilirubinemia (HB).
  - The determination of a newborn’s bilirubin production rate is critical to the assessment of a newborn’s risk for developing unpredictable extreme HB and preventing BIND.
- - In this multi-facility study of 283 newborns, researchers compared the value of 2 methods to identify neonates at risk of hemolytic hyperbilirubinemia (HB): total serum/plasma bilirubin (TB) or transcutaneous bilirubin (TcB) and end-tidal breath carbon monoxide (CO), corrected for ambient CO (ETCOc).
  - Of interest, TB/TcB levels in infants differed significantly from one facility to another, while no differences in ETCOc levels were found across sites.
  - Total bilirubin (TB) or transcutaneous bilirubin (TcB) percentile risk assessments combined with end-tidal carbon monoxide (ETCOc) measurements and TB rate of rise (ROR) calculations can identify hemolytic HB.
  - Thus, by combining measures, four clinical conditions can be identified:
  - (i) infants with elevated bilirubin (TB/TcB), who have normal bilirubin production (ETCOc) and adequate bilirubin elimination (TB ROR);
  - (ii) infants with elevated bilirubin, who have increased bilirubin production but efficient bilirubin elimination;
  - (iii) infants with elevated bilirubin, who have normal bilirubin production but inadequate bilirubin elimination;
  - (iv) infants with elevated bilirubin, who have increased bilirubin production and insufficient bilirubin elimination – a group at high risk for bilirubin neurotoxicity.
  - The authors suggest that since unconjugated (or unbound) bilirubin increases in the presence of hemolysis, there is an association between increased bilirubin production and total body bilirubin which helps to explain the association between hemolytic jaundice and bilirubin neurotoxicity.
  - To comply with the 2004 AAP Practice Guideline, which suggests that some infants with hemolysis need to be treated at lower thresholds for initiation of phototherapy, the authors state that “ETCOc measurements are the best method currently available to identify increased heme turnover and bilirubin production. ETCOc measurements together with TB/TcB percentiles and serial measurements of TB/TcB should provide additional diagnostic accuracy.”
ETCOc Testing
- - The study evaluated the value of an end-tidal carbon monoxide corrected for inhaled carbon monoxide concentration (ETCOc) at the early neonatal period to determine if the value is useful for predicting subsequent hyperbilirubinemia (HB) in non-hemolytic full-term infants.
  - Seven of the 51 infants enrolled in the study developed HB.
  - The ETCOc levels in the hyperbilirubinemic infants did not decrease significantly in the first 72 h after birth and were higher than those in non-hyperbilirubinemic infants at 42, 48, 54 and 66 h of age. The ETCOc level at 42 h of age was the most predictive of subsequent HB by ROC analysis. At the cut-off level of 1.8 μL/L (p.p.m.)
  - Researchers concluded that increased ETCOc level in the early neonatal period is associated with subsequent HB, even in infants without hemolytic disease. The ETCOc measurement may be useful as a screening test for predicting non-hemolytic HB.
Hemolysis And Risk
- - It is apparent that a linear relationship does not exist between neonatal TB and the risk of BIND; rather, other measures of hyperbilirubinemia (such as unbound bilirubin or bilirubin-albumin binding capacity) may be more relevant.
  - The overall TB level may not be as important in determining neurotoxicity as is the free or unbound bilirubin level, or the bilirubine-albumin binding capacity.
  - American Academy of Pediatrics Subcommittee on Hyperbilirubinemia, “it is apparent that the use of a single total serum bilirubin level to predict long-term outcomes is inadequate and will lead to conflicting results.”
  - Newman et al., ’s 2006 study found no difference in cognitive outcomes between neonates with or without hyperbilirubinemia, it was noted that, within the group of neonates with hyperbilirubinemia, those with a positive direct antiglobulin test (DAT) had lower cognitive scores.
- - In this prospective controlled study of 272 newborns, the authors clarified the contribution of an increase in bilirubin production in hyperbilirubinemia (HB).
  - Hemolysis is an important mechanism responsible for HB in the first 4 days of life.
- - This retrospective review analyzed data from the CPP to investigate whether bilirubin is more neurotoxic in newborns with a positive DAT (used as a surrogate for hemolysis) in 54,795 newborns ≥ 36 weeks GA.
  - The association between TSB levels ≥ 25 mg/dL, a positive DAT, and lower IQ scores supports AAP recommendation to treat at a lower level of jaundice with a positive DAT which reinforces findings of Newman et al. NEJM. 2006;354(18).
- - This prospective observational study of 105 preterm infants ≤ 32 weeks GA evaluated the predictive value of ETCO and cytokine levels for long-term outcome.
  - ETCO <2.0 ppm in the first 24 hours of life is highly predictive of a favorable neurodevelopmental outcome at 3.5 years.
  - Majority of children with an ETCO >2.0 ppm in the first 24 hours of life had adverse neurodevelopmental outcomes.
- - In this Retrospective study of neonates with bilirubin ≥ 25 mg/dL, n=12, the researchers evaluated a quality improvement process to diagnose hemolytic conditions in neonates with hyperbilirubinemia (HB).
  - Many of the cases of extreme HB have an underlying basis involving hemolysis.
  - Inherited conditions such as hereditary spherocytosis and G6PD deficiency can be missed in neonates.
- - This review describes the causes of neonatal hemolysis and the risk of BIND associated with neonates with hemolytic disease.
  - Severe hyperbilirubinemia in newborns can be caused by hemolysis, which results from several different conditions.
  - Infants with hemolytic disease are at greater risk of developing bilirubin-induced neurotoxicity and BIND.
- - Unconjugated (indirect) hyperbilirubinemia (HB) is a ubiquitous transitional phenomenon in newborns attributable to a metabolic imbalance favoring bilirubin production over hepatic–enteric bilirubin clearance.
  - Uncontrolled or rapidly rising HB can reach neurotoxic levels with potentially lethal consequences. Thus, the welfare of jaundiced newborns is dependent on striking an appropriate balance between the protective effects and the risk of bilirubin neurotoxicity.
  - TSB is a poor predictor of neurotoxicity compared to unconjugated (unbound) bilirubin, it is still the diagnostic tool of choice and the measure for instituting and monitoring treatment efficacy, as tools for evaluating unconjugated bilirubin are not yet routinely available.
  - The authors conclude that community-oriented interventions to curtail the incidence of hemolytic jaundice, ensure timely access to effective treatment and provide appropriate follow-up for all newborns with or at risk of severe HB, must be regarded as global health imperatives.
- - The guidelines of the American Academy of Pediatrics (AAP) for monitoring neonatal jaundice recommend universal postnatal screening for hyperbilirubinemia within 48 h from discharge.
  - An observational case-control study was performed on 100 consecutive neonates with jaundice who were readmitted to hospital for phototherapy treatment and were compared to 100 neonates with jaundice during hospitalization who were not readmitted after discharge. Data from the patients` medical record was analyzed to identify additional factors that increase the risk for jaundice-related readmission.
  - The risk of readmission decreased by 48% with every day added to the original hospitalization stay, and by 71% if phototherapy had been administered during postnatal hospitalization. In contrast, the risk increased by 28% with every elevation by 1% in hematocrit, and by 2.78 time when the delta in infant weight was > 5% (the difference between birth weight and weight at discharge during the postnatal hospitalization).
  - We observed that neonate with low-risk jaundice were more likely to be readmitted to hospital for phototherapy compared to neonate with high-risk jaundice.
  - The authors concluded none of the neonates in the readmission group were assessed as having major risk factors for developing hyperbilirubinemia and as being in the low-risk zone according to the AAP guidelines and therefore discharged early. We suggest that while the AAP guidelines are appropriate for the management of high-risk neonates presenting with jaundice, they are less suitable to low-risk neonates presenting with physiological jaundice. The criteria for hospital discharge of the latter neonates need to be more stringent.