Can laboratory tests that are routinely used in adult patients also be used in pediatric patients? Does the current literature support the routine use of troponin, brain natriuretic peptide, D-dimer, and lactate in children? Adult problems such as acute coronary syndrome and pulmonary embolism are rare in pediatrics, and there is a paucity of literature on how blood tests commonly used to help diagnose these conditions in adults play a role in the diagnosis and management of children. This article presents the literature about 4 common blood tests and examines the clinical applications of each.
Key points
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Troponin in children can be used reliably for acute coronary syndrome, cardiac contusion, and myocarditis.
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Both brain natriuretic peptide (BNP) and proBNP can be used in monitoring for progression of heart failure in congenital heart disease.
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D-dimer is not validated in pediatrics for the evaluation of pulmonary embolism.
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The Surviving Sepsis Campaign cannot make a recommendation on the use of lactate in pediatric patients with septic shock based on the available literature.
Introduction
Careful consideration goes into the ordering of blood work on pediatric patients. Laboratory tests are common for adult patients, but in children there may be hesitancy when subjecting children to a potentially painful procedure. When blood tests are ordered, the clinician needs to be aware of how to interpret the results and whether the results are even applicable in children. Providers can more readily interpret a troponin level on an 80-year-old patient with chest pain, but what if that patient was only 8 years old? Laboratory tests such as troponin, brain natriuretic peptide (BNP), D-dimer, and lactate are all examples of widely used tests where the interpretation is more routine and validated in adults. However, the question remains whether these results can be interpreted in the same manner in children.
Troponin
Troponin is a protein complex found in both skeletal and cardiac muscle thin muscle filaments consisting of 3 subunits: troponin I, T, and C. Genes expressed in adult cardiac muscle produce cardiac-specific troponins I and T (cTnI, cTnT). cTnI and cTnT therefore have utility as cardiac biomarkers for the diagnosis of disorders causing cardiac injury. , Troponin C is also produced in skeletal muscles and is not helpful as a cardiac marker. cTns are extremely specific to myocardial cell injury and their utility is well established in the adult population in the work-up for possible myocardial injury. ,
The expression of cTns is different between embryonic and adult hearts. During fetal development, cTnT is transiently expressed by skeletal tissue. , cTnT has also been shown to be transiently increased following delivery, with 1 study of healthy full-term infants showing a statistically significant increase in the level of a high-sensitivity cTnT (hs-cTnT) in the first few days of life. By 2 to 5 days of life, all patients had a hs-cTnT level greater than the upper limit of normal for older children and adults. A wide range of hs-cTnT values was seen in this group, which highlights the need for caution when using cTnT to evaluate cardiac injury in newborn infants. It is hypothesized that the changes in expression of the troponin proteins may make cardiac myocytes more resistant to the transient hypoxia present during fetal development and labor. ,
cTn release from cardiomyocytes has been shown to occur as a result of irreversible cell injury, from cell necrosis or activation of the apoptosis pathway. In the incidence of cardiomyocyte necrosis, the systemic troponin increase is relative to the extent of necrosis. It remains unclear whether reversible injuries to cardiomyocytes lead to clinically significant increases in cTn level. The level of circulating cTn decreases as it is catabolized in other tissues; however, impaired clearance caused by underlying conditions such as renal failure may lead to prolonged increases of cTn level or even increased baseline cTn level.
Clinical Applications
Previous studies have shown that serum troponin is used rarely in the pediatric population, even among those patients presenting with chest pain. One study showed that 26% of children presenting with chest pain had serum laboratory studies done, but only 2.6% had serum troponins.
Acute Coronary Syndromes
Acute myocardial infarctions (AMIs) are rare in the pediatric population compared with the adult population, but they do occur. Troponins have emerged as the biomarker of choice in evaluation for AMI because of both the high sensitivity and specificity for myocardial damage in adult studies. , After myonecrosis, troponin increases are detectable in the bloodstream within 3 to 4 hours of injury. In the adult emergency department (ED) population, increased cTn is associated with an increase in inpatient mortality. A 10-fold increase in troponin level has been shown to double the risk of death. CTn levels correlate with the size of infarct in ST-elevation myocardial infarctions (STEMIs). Although rare, ACS should be considered in pediatric patients with consistent histories, particularly if risk factors such as congenital heart disease [CHD] or acquired heart disease (eg, Kawasaki disease [KD], hyperlipidemia, autoimmune vasculitis), and supporting electrocardiogram (ECG) changes are present. , Given the low incidence of AMI, there is little research on this condition in the pediatric population; however, if suspicion exists for AMI, troponins should be considered because of the clear utility in both acute and ongoing evaluation of the condition.
Drug Use–induced Myocardial Injury
Recreational drugs, including cocaine, amphetamine, cannabis, spice, and K2 (cannabis derivatives), have been shown to result in myocardial injury, including AMI. , , Coronary vasospasm secondary to drug use is well documented in the pediatric population. Although cocaine use is a known risk factor for coronary vasospasm, the same condition has been reported in pediatric patients after marijuana use. , Coronary vasospasm can present similarly to AMI and can show focal ECG changes, including ST elevations and other ischemic changes. In 1 study, all 7 patients diagnosed with myocardial injury related to drug use presented with chest pain. The median troponin level on presentation in this group was 17.2 ng/mL (range, 8.6–33.7 ng/mL). Urine drug screen should be considered for pediatric patients with chest pain and a positive troponin test, particularly in adolescents.
Intentional or accidental ingestions of other nonrecreational drugs have also been shown to cause increased troponin levels. Cardiac drugs (β-blockers, calcium channel blockers), noncardiac drugs (antidepressants, colchicum), as well as carbon monoxide poisoning can cause myocardial damage and increased troponin levels. Myocardial damage from drugs can be either reversible or irreversible. Troponin should be considered in symptomatic or hemodynamically unstable children with history of ingestion or possible ingestion.
Cardiac Contusion
Mechanical trauma, both accidental and iatrogenic, can damage the myocardium. Multiple studies have shown that cTnI and cTnT are more sensitive and specific to cardiac injury than creatine kinase–myocardial band, which is also found in skeletal muscle. , One study in adults showed that all 6 patients with echocardiographic evidence of wall motion abnormalities after trauma had an increased cTnI level. One other patient with an increased cTnI level had no wall motion abnormalities but did have a pericardial effusion. In a study of pediatric patients with blunt chest trauma, 3 of 4 patients with electrocardiographic or echocardiographic evidence of cardiac injury had increases in the cTnI level of more than 2.0 ng/mL. CTn levels should be considered in symptomatic patients with blunt trauma with an abnormal ECG or chest radiograph, arrhythmia, unexplained hypotension, physical signs of chest trauma, signs of heart failure, or abnormal cardiac motion on ultrasonography.
Myocarditis
Myocarditis is inflammation of the myocardium resulting in myocardial dysfunction and has been shown in multiple studies to be a common cause of pediatric sudden death. , Presentations can be notoriously nonspecific, but myocarditis should be considered in patients presenting with chest pain in the setting of an antecedent viral illness, unexplained tachycardia, hepatomegaly, new gallop rhythm, respiratory distress, or signs of shock. CTn tests are useful in the evaluation for myocarditis. In 1 study, myocarditis was the most common diagnosis (27%) in pediatric ED patients presenting with chest pain and an increased troponin level. Eisenberg and colleagues showed a 100% sensitivity and an 85% specificity for myocarditis using a cTnT value of 0.01 ng/mL or greater as a cutoff. A normal troponin test using this cutoff can be used exclude myocarditis. Abnormal troponin level in the first 72 hours of hospitalization in pediatric patients with viral myocarditis is associated with subsequent need for extracorporeal membrane oxygenation (25.6% vs 7.1%) and intravenous immunoglobulin.
Kawasaki Disease
KD is a condition defined by acute inflammation that involves both arterial walls as well as the myocardium. cTn is not found in the vessel walls; however, endomyocardial biopsies of patients with KD have shown a range of diffuse myocardial inflammation. , Studies have shown conflicting utility of troponin in KD, with between 30% and 40% of patient in the acute stage having an increased cTnI level. , Sato and colleagues showed that all patients with KD and increased troponin level had normalization of their cTnI level by repeat testing more than 12 months later. Among patients with KD in this group with coronary artery aneurysms, only 3 out of 9 had increased levels of cTnI, suggesting that troponin levels do not exclude aneurysms. Based on the current data, cTnI level is not sensitive enough to rule out KD. However, it may provide some useful clinical information and raise suspicion of cardiac involvement if positive.
Congenital Heart Disease
Increases in cTn levels are uncommon in pediatric patients with stable CHD. Troponin I and T levels have been shown to be chronically increased in pediatric patients with atrial septal defects (ASDs) and ventricular septal defects (VSDs) with left to right shunting, with VSDs showing a greater increase than ASDs. The ventricular volume overload caused by these conditions is thought to cause damage to the myocardium resulting in the increases. Both cTnI and cTnT levels also show correlation with pulmonary to systemic pressure ratios, suggesting that increased right ventricular pressures also lead to myocardial damage. Variations from a known baseline can be a useful tool to evaluate clinical status in patients with known CHD.
Secondary Cardiac Ischemia
There are many other possible causes of secondary cardiac ischemia and myocardial damage, including severe anemia, tachyarrhythmias, sepsis, and shock. Increased troponin level has been observed in patients with status asthmaticus, thought to be secondary to prolonged tachycardia and the use of high-dose β-2 agonists resulting in diastolic hypotension. Sepsis and shock states can result in demand ischemia caused by the mismatch where the oxygen supply cannot keep up with the increased myocardium oxygen demand even in normal coronary arteries. If there is suspicion for cardiac ischemia based on the clinical presentation as in the conditions discussed earlier, it is reasonable to order troponin levels; however, management should be directed toward treating the underlying cause of the ischemia.
Brain natriuretic peptide
BNP is secreted primarily from the ventricles in the heart in response to increases in pressure and volume from myocyte stretch. , , The precursor to BNP, proBNP, is split into its biologically active form of BNP and the inactive N-terminal (NT) proBNP in the cardiac myocytes. , Both cleavage products can be detected in the circulation. The half-life of NT proBNP is 60 to 120 minutes, whereas the half-life of BNP is shorter at approximately 20 minutes. NT proBNP is also more stable than BNP at room temperature, and NT proBNP is less affected by kidney function. Pediatric studies have compared BNP and NT proBNP values and have shown good correlation, suggesting that the patient can be followed clinically with either BNP or NT proBNP depending on laboratory availability.
BNP concentrations are highest during the first 4 days of life, decrease rapidly during the first week, and decline slower through the first month. Between 1 month and 12 years, the BNP levels remain steady without any gender differences noted until adolescence. , , Standard values based on age have been established.
Clinical Applications
Congenital heart disease and heart failure
Both BNP and NT proBNP are well-known markers for cardiac dysfunction in adults. , These laboratory tests have been studied best in the setting of pediatric CHD. , Children with CHD can have volume and pressure overload along with cyanosis and pulmonary hypertension leading to direct pressure and stretching of the myocardium. BNP is released into the bloodstream causing diuresis, vasodilatation, and inhibition of myocardial remodeling. , BNP levels are higher in those children with clinical signs of heart failure compared with those without signs of heart failure. , , There was a small study of 34 children where BNP levels were evaluated and followed by echocardiography. All patients with left ventricular dysfunction had increased BNP levels.
Prognostication
BNP and NT proBNP can serve as a prognostic indicator. , After surgery for CHD, there has been an association between BNP levels and the duration of mechanical ventilation, intensive care unit (ICU) stay, and the need for ionotropic support. In children with dilated cardiomyopathy, increased BNP levels were associated with future cardiac death, hospitalization, and need for transplant. In pediatric patients admitted to the ICU with decompensated heart failure, increased BNP levels at discharge were associated with adverse outcomes in the subsequent 2 months. In post–cardiac transplant patients, increasing BNP level may be an early indication of transplant rejection. ,
Respiratory distress
The utility of BNP in differentiating a cardiac from pulmonary disorder in patients with respiratory distress has also been addressed in pediatrics. In 1 study involving 49 infants with respiratory distress, the patients with a final diagnosis of heart failure had a higher mean BNP concentration than those patients with other causes. , Other studies have suggested that, if the BNP value is in the normal range for the assay, then the patient is less likely to have congestive heart failure. There is a suggestion that the relative change in NT proBNP levels may be useful in pulmonary hypertension, but currently there is insufficient literature to support the routine use of BNP or NT proBNP in acute management. Overall, BNP may be useful in differentiating pulmonary from cardiac-related respiratory distress, but additional studies are needed.
Inflammatory Processes
Inflammation of the myocardium can also increase the production of BNP. BNP and NT proBNP levels are increased in patients during the acute phase of KD, whereas levels are only mildly increased in patients with other febrile illnesses. Further studies are needed to address the usefulness of BNP as a diagnostic aid in KD. In children with myocarditis, a higher BNP level was independently related to worse outcomes and increased risk of death. In children with concern for inflammation of the myocardium, a BNP level may aid in prognostication.
D-dimer Testing in Children
D-dimer is an indirect marker of fibrin turnover and fibrinolysis. D-dimer molecules are produced after the formation of thrombin and following the degradation of cross-linked fibrin. Because D-dimer marks the activation of the coagulation and fibrinolytic systems, the test serves as an indirect marker for thrombotic and thrombolytic activity.
D-dimer level increase has been reported in patients with liver disease, coronary artery disease, cancer, trauma, pregnancy, infection, renal disease, recent surgery, and advanced age. , There have been attempts to determine age-adjusted values and cutoffs related to specific conditions, but there is much variability, even in the adult literature.
Clinical Applications
Pulmonary embolism
D-dimers are often sent during the evaluation for pulmonary embolism (PE) despite the lack of literature on the topic in pediatrics. In a retrospective analysis conducted by Kanis and colleagues of D-dimer in PE, D-dimer was ordered in 45% of children tested for PE. Children do not necessarily present with PE the same as adults. A small study showed that the most common presenting signs of PE in the pediatric ED were tachypnea and tachycardia (70% of patients). Hypoxia was not present in any of the children. The most common symptoms for performing D-dimer testing were shortness of breath, chest pain, and cough.
D-dimer sensitivities range between 79% and 100% for detecting PE, but specificities range from 13% to 69% depending on the study. , Out of 526 children who had a D-dimer sent, only 34 of the children had a PE and all of those had an increased D-dimer level. There were only 17 patients who had a PE that did not have a D-dimer sent. The sensitivity in this study was 100%, but the specificity was only 58%. In a study by Biss and colleagues, the D-dimer level was increased in 23 patients with PE and normal in 4 patients with PE (15%). The D-dimer level was increased in 9 out of 12 who were suspected of having a PE but did not. There was slightly better performance of D-dimer when only considering adolescents. , ,
Larger studies are needed before D-dimer can be widely used to aid in the diagnosis of PE. Development and validation of a clinical prediction rule similar to the Wells score and PERC (pulmonary embolism rule-out criteria) rule in adults will further help to refine those pediatric patients who have a higher pretest probability and will thereby improve the utility of D-dimer testing. During the development and validation of the Wells criteria, patients younger than 18 years were excluded, and follow-up studies have shown that the Wells score did not perform as well in children as it does in adults and should be used cautiously. , , If the clinician sends D-dimer testing, the test will likely perform better if the patient has pathophysiology more similar to adults or has known risk factors for PE. The incidence of PE in children has a bimodal distribution: infancy and adolescence. Infants are more at risk if they are premature, have major surgery, or have cardiac defects. , Adolescents have risk factors including malignancy, recent surgery, central venous access, limb immobility, or hormonal contraception. , , There are currently no guidelines to recommend the routine use of D-dimer testing in children younger than 18 years for the evaluation of PE.
Infection
Using D-dimer to risk stratify patients with concern for infection has been studied in pediatrics. In sepsis, fibrinolysis can be impaired by increased levels of plasminogen activator inhibitor-1, which increases fibrin, thereby increasing D-dimer levels. Sharma and colleagues prospectively studied 50 children aged 1 to 10 years with suspected sepsis and measured D-dimer levels. The D-dimer level was increased in 72% of patients with sepsis and in none of the controls. Given the evidence from the adult literature suggesting that higher D-dimer levels are present in more severe infection and the information from this small study, there may be consideration of measurement of D-dimer in children with sepsis because it may predict later development of disseminated intravascular coagulation (DIC). There is no evidence to suggest the timing of this measurement or whether this needs to be done in the ED.
Lee and colleagues performed a retrospective analysis of 177 infants younger than 2 years with a febrile urinary tract infection. The D-dimer levels were statistically higher in patients with acute pyelonephritis compared with a simple urinary tract infection. This test could be used to risk stratify patients who are at greater risk of renal scaring ; however, larger studies are needed before routine use is advised.
Lactate
Historically, lactate has been a surrogate marker for tissue perfusion. Lactate is a byproduct of glucose metabolism and formed by the reduction of pyruvate during anaerobic metabolism. , Lactate is continually produced in the body, with baseline levels between 0.5 and 1.8 mmol/L in healthy adults. , Increased levels can be seen with increased production, administration of lactate-containing fluids, or decreased clearance. Pediatric production and clearance of lactate may differ from adults. One study by Aono and colleagues even identified crying as a factor for increased lactate levels in children 1 to 3 years old. Exercise studies in children have been shown to have a poor correlation between aerobic metabolism and lactate production. Children have higher oxygen transport capacity compared with adults, which can cause children to respond differently to anaerobic metabolism. Children may also have an improved buffering system compared with adults that can compensate for anaerobic metabolism before lactate is produced.
Clinical Applications
Sepsis
Early sepsis in children can be difficult to recognize, and having objective tools could be beneficial. Despite a lack of formal guidelines and evidence, lactate measurement has become a component of many pediatric emergency sepsis quality programs, with 1 survey showing that up to 68% of responding pediatric emergency medicine providers routinely measured it. The Surviving Sepsis Campaign, last updated in February 2020, could not make a recommendation on the use of lactate in pediatric patients with suspected shock. The investigators did state that lactate levels are often measured during the evaluation of septic shock if the test can be obtained rapidly. However, lactate levels alone are not an appropriate screening test. Increased lactate levels may be more suggestive of sepsis in patients in whom there is already clinical suspicion.
The link between lactate and mortality in pediatrics is inconsistent in the literature. Scott and colleagues examined children treated in the ED for sepsis. Lactate levels measured within 30 minutes of ED arrival that were more than 36 mg/dL (2 mmol/L) were associated with an increased 30-day mortality, but with a sensitivity of only 20%. Another study, by Miescier and colleagues, included 864 pediatric patients with septic shock. The median lactate level in the pediatric ED was 2.1 mmol/L. In this study, there was no association of lactate level and mortality. Lactate levels of 3.1 mmol/L or higher in the ED were associated with pediatric ICU (PICU) admission and the use of vasoactive medications within 24 hours. , Other studies have shown that, with a lactate level greater than 4 mmol/L, there is an increased risk of organ dysfunction, positive blood culture, and hospital and PICU admission. , Lactate may be an early biomarker of disease severity, but the literature is inconsistent and more data are needed to assess early measurements.
Trauma
In adult patients with trauma, initial serum lactate level has been an indicator of patient outcome and correlates with a higher mortality, need for massive blood transfusion, and injury severity. A study by Ramanathan and colleagues of 277 children more than 2 years old who met trauma alert criteria had initial lactate levels drawn. Patients with an increased lactate level had a higher injury severity score and increased need for intubation, procedures, and ICU admission. Overall, a lactate level of greater than 2 mmol/L had a poor sensitivity and specificity as a screening test and was a poor predictor of injury severity, injury patterns, and patient outcomes. As an isolated measurement, the lactate level carries little clinical significance. The investigators suggested that a lactate of less than 2 mmol/L may be reassuring in the presence of a reassuring examination, normal liver function tests, and an absence of hematuria.
Asthma
Obtaining a lactate level in patients with status asthmaticus may cause unnecessary interventions. Laboratory work performed on patients receiving continuous albuterol may show an anion gap metabolic acidosis and increased lactate levels. Lactic acid levels in severe asthma exacerbations can be increased related to impaired oxygen delivery or medication-induced excessive β-adrenergic stimulation. , Lactic acidosis–related hyperventilation may be mistaken for worsening airway compromise, resulting in escalation of albuterol or increasing respiratory support, which may be unnecessary. Lactate testing should be avoided in these patients.
Mitochondrial disease
Lactic acidosis is a presenting feature of inborn errors of metabolism that involve defective mitochondrial metabolism. Lactate is produced in the inner mitochondrial membrane so, when mitochondrial DNA is defective, patients can have chronically increased lactate levels or, depending on the condition, can have increased lactate level only when precipitated by infection, stress, or trauma. , In patients with a known mitochondrial disorder or a critically ill, undifferentiated infant where a genetic metabolic condition is on the differential, a lactate level may be beneficial to guide management.
Intussusception
Intussusception decreases blood flow to the bowels, causing decreased tissue perfusion and increasing lactic acid level. In a study by Lee and colleagues involving 249 patients with ileocolic intussusception, there was a trend toward a higher lactate level in the 50 patients with poor outcomes. Patients with lactic acid levels of 2.5 mmol/L or higher had a greater risk of failed nonsurgical reduction or recurrence. When the cutoff value for lactic acid was increased from 2.5 mmol/L to 3.0 mmol/L, the positive predictive value for poor outcomes, including failure of nonoperative reduction or recurrence within 48 hours, increased from 50% to 88.9%. More research is needed before recommending a routine lactic acid level in all patients with intussusception.
Summary
Some laboratory tests, such as troponin, have been proved in the literature to be reliably used in pediatric patients; however, laboratory tests should not be used in isolation. The differential diagnosis should first come from the clinical history and physical examination before determining whether a laboratory test will further contribute to the diagnosis. Troponin has been validated in the pediatric literature for conditions such as acute coronary syndrome and myocarditis. A BNP test may be useful in patients with CHD or heart failure. If PE is in the differential, a D-dimer test may not be as useful as in the adult population because of a lack of a clinical validation rule in order to risk stratify the patient. The literature on the use of lactate and sepsis is conflicting. There is no formal recommendation for the routine use of lactate in sepsis. With all of these laboratory tests, additional research is needed to further refine the current recommendations.
Clinics care points
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Do not rely on a single laboratory test for patient diagnosis; laboratory tests should be integrated as a part of the complete picture.
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Troponin:
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Use in patients with clinical concern for cardiac ischemia, cardiac contusion, and myocarditis.
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Not sensitive enough to rule out KD.
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Troponin level is not routinely increased in stable CHD.
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BNP and NT proBNP:
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Levels are higher in patients with heart failure compared with patients without.
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May help differentiate cardiac and pulmonary causes of respiratory distress, but more research is needed.
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Increased levels in patients with myocarditis portend a worse outcome.
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D-Dimer:
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There is no validated clinical decision rule to apply before the decision to obtain a D-dimer level.
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The D-dimer level performs better in adolescents than in younger children, but there is insufficient literature to support its routine use.
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May predict later development of DIC in septic patients, but more research is needed before routine use is recommended.
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Lactate:
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There is no defined cutoff value.
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Lactate levels are often measured during the evaluation of septic shock if the test can be obtained rapidly. However, the Surviving Sepsis Campaign could not make a recommendation on the use of lactate in pediatric patients with suspected shock.
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A lactate level greater than 2 mmol/L was a poor predictor of injury severity or patient outcomes in trauma.
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Can be used in patients with mitochondrial disease or undifferentiated critically ill neonates.
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