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Point of care testing: Transcutaneous bilirubinometry in neonates
Available online at www.sciencedirect.com
Clinical Biochemistry 42 (2009) 143 – 149
Review
Point of care testing: Transcutaneous bilirubinometry in neonates A. Carceller-Blanchard a,⁎, J. Cousineau b , E.E. Delvin b a
b
Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montréal, Québec, Canada Department of Clinical Biochemistry, CHU Sainte-Justine, Université de Montréal, Montréal, Québec, Canada Received 18 April 2008; received in revised form 19 September 2008; accepted 19 September 2008 Available online 2 October 2008
Abstract Physicians taking care of infants in the first days of life are often faced with neonatal jaundice, especially in an era where post-partum discharge occurs earlier and assessment of newborn bilirubinemia status is required prior to discharge. The Canadian Pediatric Society and the American Academy of Pediatrics have developed and published guidelines for the diagnosis and management of hyperbilirubinemia in newborns. Point of care testing refers to any test performed outside of laboratory by clinical personnel and close to the site of patient care. Based on a summary of multiple reports during the last twenty years, we realize that devices which provide a non-invasive transcutaneous bilirubin (TcB) measurement have proven to be very useful as screening tools and provide a valid estimate of the total serum bilirubin level (TSB). Published data suggest that these devices provide measurements within 30–50 μmol/L of the TSB levels and can replace laboratory measurement particularly when TSB levels are less than 260 μmol/L. At the present time, in the literature, evidence is insufficient to abandon neonatal serum bilirubin testing and replace it with TcB. Any measurement, TSB or TcB, has potential for error. However, we have evidence that TcB, can help avoiding potential errors associated with even visual assessment of jaundice and may be useful as screening device to detect significant jaundice and decrease a large number of unnecessary skin punctures. The current manuscript is based on a careful comprehensive literature review concerning neonatal hyperbilirubinemia. We consider that this manuscript will help clinicians and laboratory professionals in the management of neonatal jaundice. © 2008 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. Keywords: Neonates; Transcutaneous bilirubin; Jaundice
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Invasive methods for the measurement of bilirubin. . . . . . . . . . . . . . . . . . . . Non-invasive methods for the measurement of bilirubin . . . . . . . . . . . . . . . . . Quality assurance issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . American Academy of Pediatrics recommendations . . . . . . . . . . . . . . . . . . . Clinical, technical and financial considerations of transcutaneous bilirubin measurement References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction
⁎ Corresponding author. Département de Pédiatrie, CHU Sainte-Justine, 3175 Chemin Côte Ste-Catherine, Montréal, Québec, Canada H3T 1C5. E-mail address: [email protected] (A. Carceller-Blanchard).
Neonatal jaundice, commonly found in 60% of normal newborns, is normally a self-resolving episode ending 72 to 96 h after birth [1,2]. Transient elevation of blood bilirubin occurs by combination of an increase in red blood cell
0009-9120/$ - see front matter © 2008 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.clinbiochem.2008.09.106
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destruction and concomitant decrease in hepatic bilirubin conjugation [2]. As early as 1941, Davidson and Weech [3] have recognized that these two processes were related to the degree of jaundice and the serum bilirubin. Six years later, King [4] devised a colorimetric micro-method base on the van den Bergh diazo method to quantitatively measure the bile pigment. Billing et al. [5] in 1954, showed increased bilirubin in newborn infants in relation to birth weight. Invasive methods for the measurement of bilirubin For the past 60 years, and as shown by the College of American Pathologists proficiency surveys, advances in analytical methods have progressively allowed the automated measurement of bilirubin to become more reliable [6,7]. The most recent of these surveys [8] revealed a variation in the bilirubin measurement ranging between 3.7% for the Jendrassik–Groff method and 10.7% for the diazo-alcohol or DMSO methods. Imprecision is increased when using patient blood samples, given pre-analytical and analytical errors, as well as interferences. Pre-analytical errors are related to blood procurement procedure, rapidity and conditions of transportation to the laboratory. Analytical errors may be due to haemolysis, a relatively frequent event when collecting blood from a heel prick in newborns, and the ensuing release of haemoglobin and other intracellular compounds that can interfere with chemical-based measurement of bilirubin [9].
Non-invasive methods for the measurement of bilirubin The first attempt at non-invasive measurement of bilirubin goes back to the 1960's when the icterometer was introduced [10]. This device, based on reflectance, had poor analytical specificity and sensitivity, and poor reproducibility with coefficient of variations ranging between 20 and 40%. In the past years, bilirubinometers have gradually been improved and are now based on simultaneous multiple wavelength analysis. Table 1 shows comparisons between serum/plasma bilirubin measurements and non-invasive transcutaneous bilirubinometry published in the literature during the past thirty years [11–26]. Transcutaneous devices are now able to better discriminate haeme and melanin pigments from bilirubin by differential spectral analysis, thus being less subject to bias [27,28]. As factors such as race or weight do not affect accuracy; they show much better correlation with serum bilirubin [23,25,28,29]. Accuracy and precision of TcB measurement was said to be comparable to the standard of care laboratory test, even when phototherapy and/or exchange transfusion were considered [30,31]. However, for the National Academy of Clinical Biochemistry (NACB), the published data does not allow clear recommendations as the use of TcB during phototherapy [32,33]. Table 2 shows results for different transcutaneous bilirubinometers as predictors of jaundice published in the literature. As can be seen, the sensitivity, specificity and, positive and negative predictive values varied among the
Table 1 Comparison between serum/plasma bilirubin determinations and non-invasive transcutaneous bilirubinometry in the literature Author [Ref.]
Year
N
Comparisons
Bland–Altman bias plot
Correlation
Mean [95% CI] Chaibva et al. [11] Yamanouchi et al. [12] Schumacher et al. [13]
1974 1980 1985
55 66 106
Yamauchi and Yamanouchi [14] Gupta et al. [15] Linder et al. [16] Knudsen and Ebbesen [17] Tan et al. [18] Tayaba et al. [19]
1988 1991 1994 1996 1996 1998
336 161 123 150 542 900
Rubaltelli et al. [20] Wong et al. [21]
2001 2002
210 64
Robertson et al. [22] Engle et al. [23] Kazmierczak et al. [24] Maisels et al. [25]
2002 2002 2004 2004
101 304 95 849 146 178 53 35
Carceller et al. [26]
2006
Units are expressed as μmol/L. Year: year of publication. N: number of subjects included in the study. BC: BiliCheck.
Serum/icterometer Serum/Minolta Serum/icterometer Serum/Minolta Serum/Minolta Serum/icterometer Plasma/Minolta 101 Plasma/Minolta 101 Plasma/Minolta Serum/Chromatics Colormate III HPLC/BC Serum/BC Minolta 102/BC Serum/BC Serum/BC HPLC/BC Serum/Minolta 103 Minolta 103/BC Total blood/BC Plasma/BC Total blood/plasma
17.8 [− 77.0 to 4 [− 67.9 to 0 [− 66.7 to 6.84 [− 32.5 to
+77.0] +67.9] +66.7] +42.8]
Regression line y = ax + b (p value)
0.96 0.93 0.63 0.74 0.93 0.99 0.96 0.78 0.80 0.96
(b0.01) (0.001) 0.04x + 167.8 (0.0001) 0.9862x − 0.86
0.89
1.07x + 2.85
1.11x + 136 (b0.001) 0.12x + 29.8 0.19x + 158.2
0.87 0.84
1.01x+18.6
0.91
0.8716x + 15.6
0.78 0.77 0.76
0.9197x + 12.1 (b0.001) 0.9733x + 9.0 (b0.001) 0.9426x + 10.4 (b0.001)
0.26 [− 54.5 to +54.5] 6.84 [51.3 to +31.6] 1.5 [− 50.4 to +47.5] 5.3 [− 35.8 to +46.5] 3.1 [− 34.6 to +40.7]
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Table 2 Sensitivity, specificity, positive and negative predictive values of non-invasive transcutaneous bilirubinometry in the literature Author [Ref.]
Year
N
Gestational age
Device
Serum cut-off
Sensitivity %
Specificity %
PPV %
Minolta Icterometer Minolta 101 HPLC BC Minolta BC BC BC Minolta
≥220 N171 N220 N220 N220 ≥170 ≥150 N170 N260 ≥260
94 97 86 76 66 100 100 73 33 100
78 71 98 96 89 32 21 97 96 68
44 78 86 94 84 35 32 99 82 27
Weeks N36 37 to 42 N37 ≤ 36 and N36
Schumacher et al. [13] Gupta et al. [15] Linder et al. [16] Rubaltelli et al. [20]
1985 1991 1994 2001
106 77 123 210
Wong et al. [21]
2002
64
Engle et al. [23]
2002
304
N35
Dai et al. [27]
1997
45
N37
31 to 42
NPV % 99 96 98 82 75
50 75 100
Units are expressed as μmol/L. Year: year of publication. N: number of subjects included in the study. BC: BiliCheck. PPV: positive predictive value. NPV: negative predictive value.
studies. This could be due to the heterogeneity of the study populations and the age of the newborns at the time of the measurements [13,15,16,20,21,23,27]. Bertini and Rubaltelli [29] and Rubaltelli et al. [20] give sensitivity, specificity, positive and negative predictive values of BiliCheck compared to the HPLC measurement of serum bilirubin at various clinically relevant cut-off points (Table 3). Carceller et al. [26] concluded that BiliCheck may be used to monitor bilirubin in term neonates at 48 h of life and they recommended that clinicians be conscious of the limit of precision for both BiliCheck and laboratory measures (Table 1). Quality assurance issues When measuring TcB, it is important that the nursing and medical staff register the test results in the patient's chart.
However, newer generations of bilirubinometers will need to have connectivity features, so that results are automatically registered in the Laboratory Information System, as well as in the patient's chart, in order to improve quality assurance. Maisels and King [34] recommended a daily calibration of the instrument as well as every three months, TcB measurements should be compared with 5 to 10 laboratory bilirubin determinations. Yamanouchi et al. [12] reported that the intra-observer and inter-observer imprecision coefficients of variation ranged between 2.6–4.9%, and 2.1–5.0% respectively. However, Bertini and Rubatelli [29] reported interobserver and inter-device coefficients of variation ranging between 4–11% and 7–18% (Table 4). This imprecision is however similar to that reported for serum bilirubin in laboratories surveys [35,36]. It must be stressed that, in 2006, the NACB recommended the adoption of the BiliCheck
Table 3 The sensitivity, specificity, positive and negative predictive values of HPLC and BiliCheck HPLC
≥222.3 ≥256.5 ≥290.7
BC
≥171.0 ≥188.1 ≥205.2 ≥205.2 ≥222.3 ≥239.4 ≥239.4 ≥256.5 ≥273.6
Bertini and Rubaltelli. [29] a
Rubaltelli et al. [20] b
Sensitivity %
Specificity %
Sensitivity %
Specificity %
PPV %
NPV %
100 100 95.3 100 72 68 57 43 43
52 63 85 56 62 89 71 86 87
97 93 86 92 81 63 90 77 63
64 73 85 71 82 92 87 91 96
70 75 83 57 66 76 53 59 73
96 92 87 95 91 86 98 96 94
Units are expressed as μmol/L. Adapted from Bertini and Rubaltelli [29] and Rubaltelli et al. [20]. BC: BiliCheck. PPV: positive predictive value. NPV: negative predictive value. a Gestational age was N30 weeks. b Gestational age was ≤36 and N36.
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Table 4 Inter-operator and inter-device coefficient of variations Inter-operator variability
Clinical, technical and financial considerations of transcutaneous bilirubin measurement
Inter-device variability
TcB
CV %
TcB
CV %
≤137 N137 ≤220 N220 All values
11 5 4 5.7
≤ 137 N137 ≤220 N220 All values
17.6 7.8 7.2 9.3
Units are expressed as μmol/L. Adapted from Bertini and Rubaltelli [29]. TcB: transcutaneous bilirubin (BiliCheck). CV: coefficient of variation.
and the Air-Shield devices for TcB measurement in the management and follow-up of neonatal jaundice, as they provided similar accuracy when compared with laboratory bilirubin measurements [32,33]. American Academy of Pediatrics recommendations Recognizing that kernicterus, a condition with associated morbidity, is a public health concern [37–39], the Subcommittee on hyperbilirubinemia Management of the American Academy of Pediatrics (AAP), has developed and published, in 1994 and 2004, detailed consensus-based practice parameters for diagnosis and management of hyperbilirubinemia in healthy term newborns [40,41]. The AAP recommends that TcB and/or blood bilirubin measurements be performed on every infant who is jaundiced within the first 24 h of life; the need to repeat this measurement depends on postnatal age and bilirubin concentration [42–44]. Guidelines have also been established recommending that prior to discharge, all newborns be assessed for the risk of developing severe hyperbilirubinemia. In fact, in 1999, Buthani et al. [45] published a nomogram for well newborns at 35 or more weeks' gestational age based on the hour-specific serum bilirubin values before discharge and for designation of risk of hyperbilirubinemia. Bilirubin concentrations were divided into 4 risk zones, with high-risk being the adjusted 95th percentile track. This concentration had a high predictive value for subsequent bilirubin levels being consistent with kernicterus [37]. A list of high risk factors for severe hyperbilirubinemia identified in epidemiologic studies has been published [46,47]. Keren et al. [48] found that gestational age was the strongest predictor for significant hyperbilirubinemia and could be used in combination with the pre-discharge risk zone to stratify infants into distinct risk categories. Future research is needed to develop evidencebased recommendations and determine the incidence of hyperbilirubinemia for late preterm infants, optimal discharge timing, counselling and post discharge follow-up of jaundice, particularly for those who are breastfed [49]. Petrova's survey [50] shows that paediatricians' practices regarding low utilization of laboratory diagnosis for quantification of jaundice after discharge and underestimation of risk factors contribute to progression of severe hyperbilirubinemia and is an important public health concern.
Jaundice continues to be a problematic clinical challenge, due to factors as breastfeeding and early hospital discharge. Early visual identification of jaundice does not give an accurate estimation of hyperbilirubinemia severity. Tayaba et al. [19] reported that the correlation (r) between the visual estimate and laboratory measurements was 0.75 and that of TcB and laboratory measurement was 0.96. Measuring bilirubin transcutaneously on a device available on point-of-care basis seems a tempting option, since it is totally non-invasive and that turnaround time, for attending physicians to access results, is potentially reduced. The balance between cost and benefit remains a preoccupation. Few studies evaluating the cost associated with the implementation of TcB measurement are available. In 2005, Petersen et al. [51] reported a decrease in hospitalization charges as a result of fewer readmissions of newborns due to hyperbilirubinemia. However this decrease in cost was counterbalanced by increased TcB measurements and an increased number of newborns treated with phototherapy prior to discharge. For NACB [32,33], further evidence is needed to evaluate whether TcB measurements improve clinical outcome, shorten length of stay or decrease the readmission rate for newborns with hyperbilirubinemia. Although TcB measurements may result in increased operational costs, the primary aim is the patient's comfort, which implies reducing the number of skin punctures performed on neonates. Indeed, serum bilirubin measurements is one of the most frequent causes for collection of blood from newborn, a procedure that has been documented to involve pain and stress [9,52]. TcB may be useful as a screening device to detect clinically significant jaundice and decrease the need for serum bilirubin measurements [53]. However, for NACB, there is insufficient evidence available to judge on the impact of TcB measurements on number of blood samples collected from newborns [32,33]. Jaundice measurement sites, using TcB, have been standardized. When measured on the forehead and sternum, TcB is similar to blood sample values [14,54]. Although Maisels et al. [25] found better correlation between TcB and serum concentrations when TcB measurements were performed on the sternum (r = 0.953) as compared to the forehead (r = 0.914). NACB [32,33] has recommended the TcB measurements either on the forehead or the sternum and the use of nomograms based upon the postnatal age and bilirubin concentration to assess the need for and timing of repeat TcB measurements. There are some factors that may affect TcB measurements as gestational age, birth weight, phototherapy, exchange transfusion, skin pigmentation and postnatal age. Since the 80's, studies have been carried out with different models of bilirubinometers and in different conditions [34,55–60]. Rubaltelli et al. [20] comparing the BiliCheck meter versus serum bilirubin measured using HPLC found that gestational age did not affect the correlation between these two methods. Carceller et al. [26] observed that weight loss seen in neonates had little influence and did not affect the agreement between
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BiliCheck and measurements of bilirubin in blood. BiliCheck has been used as a screening device in preterm infants [31,61,62]. Authors recommend being cautious when skin measurements are performed in the presence of peripheral oedema and/or a poor peripheral circulation; its application in the Neonatal Intensive Care Units reduced the number of blood samples by 40%. Other studies found that the severity of illness (hypoxia, hypoglycaemia, infection, respiratory distress syndrome, bleeding or abdominal problems) did not adversely impact the TcB measurements [63,64]. Phototherapy has been reported by numerous studies to adversely affect the correlation between TcB and blood measurement [30,63,65–68]. For NACB [32,33], the effect of gestational age on TcB measurement is not clear. Some reports suggest limiting the use of TcB measurements to newborns less than 30, 32 or 34 weeks of gestation, while others suggest no effect of gestational age. There are too few studies available that address the effect of underlying illnesses in newborns and their effects on the use of TcB measurements. Several authors showed that BiliCheck could be used not only as a screening device but also as a reliable substitute of blood determination [20,24,29,43,69,70]. Frequently, studies give data when jaundiced was clinically obvious in neonates and was measured with the TcB. These studies are contradictory; some reported a reduction, no change or an increase in the total number of bilirubin tests in the laboratory [19,34,51,64,71–74]. Dai et al. [71] have evaluated the use of a TcB as a screening device, giving a cut-off value of 260 μmol/L (sensitivity and specificity: 100% and 67.7%; predictive values of positive and negative cut-off: 27% and 100%). For clinical purposes, 100% sensitivity is needed. Briscoe et al. [72] have published that 18 mg/dL of TcB (conversion from mg/dL × 17.1 = 308 μmol/L) gives a 100% sensitivity and 45% specificity, with 34% reduction of blood tests. Bilirubin concentration from nonchemical photometric devices that exceed 250 μmol/L should be confirmed with standard laboratory methods [69]. In fact, some authors estimate that approximately 60–80% of skin punctures could be prevented by use of this device [64,75]. TcB has been shown to be a good device to screen for neonatal hyperbilirubinemia in neonates that are discharged within 48 h of birth [76–79] and also could be very useful in outpatient's population for home follow-up. Maisels et al. [25] recommended TcB measurements from the sternum after infants have been discharged, to eliminate ambient light influence. Many investigators speculated that TcB measurements could influence length of hospitalization and readmission rates; it is not clear whether the time saving had any impact on length of stay, however, there is a significant reduction in the number of hospital readmissions [19,51]. Maisels and Newman [80] state the importance to provide a follow-up or at least perform bilirubin check within 24 to 48 h of discharge to children who replace in the upper intermediate or high-risk zones in the nomogram [45,81]. Conclusion: Published studies suggest that non-invasive transcutaneous bilirubinometry is a precise test and a good way of screening for jaundice, and to identify neonates that require a blood sample for serum bilirubin measurement. We are not sure
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that the effectiveness of this method could reduce costs but it definitively reduces skin punctures. Every hospital needs to consider the implementation of this procedure after assessing reproducibility and accuracy of each device used. References [1] Maisels MJ. What's in a name? Physiologic and pathologic jaundice: the conundrum of defining normal bilirubin levels in the newborn. Pediatrics 2006;118:805–7. [2] Maisels MJ, McDonagh AF. Phototherapy for neonatal jaundice. N Engl J Med 2008;358:920–8. [3] Davidson LT, Merritt KK, Weech AA. Hyperbilirubinemia in the newborn. Am J Dis Child 1941;61:958–80. [4] King E. Microanalysis in medical biochemistry. 2nd ed. London: Churchill; 1947. [5] Billing BH, Cole PG, Lathe GH. Increased plasma bilirubin in newborn infants in relation to birth weight. Br Med J 1954;2:1263–5. [6] Lo SF, Doumas BT, Ashwood ER. Performance of bilirubin determinations in US laboratories—revisited. Clin Chem 2004;50:190–4. [7] Lo SF, Doumas BT, Ashwood ER. Bilirubin proficiency testing using specimens containing unconjugated bilirubin and human serum: results of a College of American Pathologists study. Arch Pathol Lab Med 2004;128: 1219–23. [8] College of American Pathologists: Chemistry/Therapeutic Drug Monitoring Participant Summary. Surveys 2008. Accessed September 17th, 2008. [9] Shah V, Taddio A, Kulasekaran K, O'Brien L, Perkins E, Kelly E. Evaluation of a new lancet device (BD QuikHeel) on pain response and success of procedure in term neonates. Arch Pediatr Adolesc Med 2003; 157:1075–8. [10] Gosset IH. A perspex icterometer for neonates. Lancet 1960;1:87–8. [11] Chaibva NT, Fenner A, Wolfsdorf J. Reliability of an icterometer in Black neonates with hyperbilirubinaemia. S Afr Med J 1974;48:1533–4. [12] Yamanouchi I, Yamauchi Y, Igarashi I. Transcutaneous bilirubinometry: preliminary studies of noninvasive transcutaneous bilirubin meter in the Okayama National Hospital. Pediatrics 1980;65:195–202. [13] Schumacher RE, Thornbery JM, Gutcher GR. Transcutaneous bilirubinometry: a comparison of old and new methods. Pediatrics 1985;76:10–4. [14] Yamauchi Y, Yamanouchi I. Transcutaneous bilirubinometry. Evaluation of accuracy and reliability in a large population. Acta Paediatr Scand 1988; 77:791–5. [15] Gupta PC, Kumari S, Mullick DN, Lal UB. Icterometer: a useful screening tool for neonatal jaundice. Indian Pediatr 1991;28:473–6. [16] Linder N, Regev A, Gazit G, et al. Noninvasive determination of neonatal hyperbilirubinemia: standardization for variation in skin color. Am J Perinatol 1994;11:223–5. [17] Knudsen A, Ebbesen F. Transcutaneous bilirubinometry in neonatal intensive care units. Arch Dis Child Fetal Neonatal Ed 1996;75:F53–6. [18] Tan KL, Chia HP, Koh BC. Transcutaneous bilirubinometry in Chinese, Malay and Indian infants. Acta Paediatr 1996;85:986–90. [19] Tayaba R, Gribetz D, Gribetz I, Holzman IR. Noninvasive estimation of serum bilirubin. Pediatrics 1998;102:E28. [20] Rubaltelli FF, Gourley GR, Loskamp N, et al. Transcutaneous bilirubin measurement: a multicenter evaluation of a new device. Pediatrics 2001; 107:1264–71. [21] Wong CM, van Dijk PJ, Laing IA. A comparison of transcutaneous bilirubinometers: SpectRx BiliCheck versus Minolta AirShields. Arch Dis Child Fetal Neonatal Ed 2002;87:F137–40. [22] Robertson A, Kazmierczak S, Vos P. Improved transcutaneous bilirubinometry: comparison of SpectRx BiliCheck and Minolta Jaundice Meter JM-102 for estimating total serum bilirubin in a normal newborn population. J Perinatol 2002;22:12–4. [23] Engle WD, Jackson GL, Sendelbach D, Manning D, Frawley WH. Assessment of a transcutaneous device in the evaluation of neonatal hyperbilirubinemia in a primarily Hispanic population. Pediatrics 2002; 110:61–7.
148
A. Carceller-Blanchard et al. / Clinical Biochemistry 42 (2009) 143–149
[24] Kazmierczak SC, Robertson AF, Briley KP, Kreamer B, Gourley GR. Transcutaneous measurement of bilirubin in newborns: comparison with an automated Jendrassik–Grof procedure and HPLC. Clin Chem 2004;50: 433–5. [25] Maisels MJ, Ostrea Jr EM, Touch S, et al. Evaluation of a new transcutaneous bilirubinometer. Pediatrics 2004;113:1628–35. [26] Carceller AM, Delvin E, Gonthier M, Gregoire MC, Cousineau J, Alexandrov L. [Evaluation of transcutaneous bilirubin measurement and agreement with bilirubinemia]. Ann Biol Clin (Paris) 2006;64:575–9. [27] Dai J, Parry DM, Krahn J. Transcutaneous bilirubinometry: its role in the assessment of neonatal jaundice. Clin Biochem 1997;30:1–9. [28] Onks D, Silverman L, Robertson A. Effect of melanin, oxyhemoglobin and bilirubin on transcutaneous bilirubinometry. Acta Paediatr 1993;82:19–21. [29] Bertini G, Rubaltelli FF. Non-invasive bilirubinometry in neonatal jaundice. Semin Neonatol 2002;7:129–33. [30] Tan KL, Dong F. Transcutaneous bilirubinometry during and after phototherapy. Acta Paediatr 2003;92:327–31. [31] Nanjundaswamy S, Petrova A, Mehta R, Hegyi T. Transcutaneous bilirubinometry in preterm infants receiving phototherapy. Am J Perinatol 2005;22:127–31. [32] Kazmierczak S, Bhutani VK, Gourley GR, et al. Transcutaneous bilirubin testing. In: Laboratory medicine practice guidelines: evidence-based practice for point-of-care testing. Washington (DC): National Academy of Clinical Biochemistry (NACB); 2006. p. 5–12. [33] Nichols JH, Christenson RH, Clarke W, et al. Executive summary. The National Academy of Clinical Biochemistry Laboratory Medicine Practice Guideline: evidence-based practice for point-of-care testing. Clin Chim Acta 2007;379:14–28 [discussion 9–30]. [34] Maisels MJ, Kring E. Transcutaneous bilirubinometry decreases the need for serum bilirubin measurements and saves money. Pediatrics 1997;99: 599–601. [35] Vreman HJ, Verter J, Oh W, et al. Interlaboratory variability of bilirubin measurements. Clin Chem 1996;42:869–73. [36] Doumas BT, Eckfeldt JH. Errors in measurement of total bilirubin: a perennial problem. Clin Chem 1996;42:845–8. [37] Bhutani VK, Johnson LH, Jeffrey Maisels M, et al. Kernicterus: epidemiological strategies for its prevention through systems-based approaches. J Perinatol 2004;24:650–62. [38] Hansen TW. Kernicterus in a full-term infant: the need for increased vigilance. Pediatrics 1995;95:798–9. [39] Penn AA, Enzmann DR, Hahn JS, Stevenson DK. Kernicterus in a full term infant. Pediatrics 1994;93:1003–6. [40] American Academy of Pediatrics Provisional Committee for Quality Improvement and Subcommittee on Hyperbilirubinemia. Practice parameter: management of hyperbilirubinemia in the healthy term newborn. Pediatrics 1994;94:558–65. [41] Bhutani VK, Johnson LH. Urgent clinical need for accurate and precise bilirubin measurements in the United States to prevent kernicterus. Clin Chem 2004;50:477–80. [42] American Academy of Pediatrics. Subcommittee of Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297–316. [43] Bhutani VK, Gourley GR, Adler S, Kreamer B, Dalin C, Johnson LH. Noninvasive measurement of total serum bilirubin in a multiracial predischarge newborn population to assess the risk of severe hyperbilirubinemia. Pediatrics 2000;106:E17. [44] Bhutani VK, Johnson LH. Jaundice technologies: prediction of hyperbilirubinemia in term and near-term newborns. J Perinatol 2001;21(Suppl 1): S76–82 [discussion S3–S7]. [45] Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics 1999;103:6–14. [46] American Academy of Pediatrics Subcommittee of Hyperbilirubinemia. Neonatal jaundice and kernicterus. Pediatrics 2001;108:763–5. [47] Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction and prevention of extreme neonatal hyperbilirubinemia in a mature health maintenance organization. Arch Pediatr Adolesc Med 2000;154:1140–7.
[48] Keren R, Luan X, Friedman S, Saddlemire S, Cnaan A, Bhutani VK. A comparison of alternative risk-assessment strategies for predicting significant neonatal hyperbilirubinemia in term and near-term infants. Pediatrics 2008;121:e170–9. [49] Smith JR, Donze A, Schuller L. An evidence-based review of hyperbilirubinemia in the late preterm infant, with implications for practice: management, follow-up, and breastfeeding support. Neonatal Netw 2007;26:395–405. [50] Petrova A, Mehta R, Birchwood G, Ostfeld B, Hegyi T. Management of neonatal hyperbilirubinemia: pediatricians' practices and educational needs. BMC Pediatr 2006;6:6. [51] Petersen JR, Okorodudu AO, Mohammad AA, Fernando A, Shattuck KE. Association of transcutaneous bilirubin testing in hospital with decreased readmission rate for hyperbilirubinemia. Clin Chem 2005;51: 540–4. [52] Owens ME, Todt EH. Pain in infancy: neonatal reaction to a heel lance. Pain 1984;20:77–86. [53] Ip S, Chung M, Kulig J, O'Brien R, Sege R, Glicken S, et al. An evidencebased review of important issues concerning neonatal hyperbilirubinemia. Pediatrics 2004;114:e130–53. [54] Maisels MJ, Conrad S. Transcutaneous bilirubin measurements in full-term infants. Pediatrics 1982;70:464–7. [55] Goldman SL, Penalver A, Penaranda R. Jaundice meter: evaluation of new guidelines. J Pediatr 1982;101:253–6. [56] Hannemann RE, Schreiner RL, DeWitt DP, Norris SA, Glick MR. Evaluation of the Minolta bilirubin meter as a screening device in white and black infants. Pediatrics 1982;69:107–9. [57] Tan KL. Transcutaneous bilirubinometry in Chinese and Malay neonates. Ann Acad Med Singapore 1985;14:591–4. [58] Tan KL, Mylvaganam A. Transcutaneous bilirubinometry in preterm very low birthweight infants. Acta Paediatr Scand 1988;77:796–801. [59] Nanjundaswamy S, Petrova A, Mehta R, Bernstein W, Hegyi T. The accuracy of transcutaneous bilirubin measurements in neonates: a correlation study. Biol Neonate 2004;85:21–5. [60] Slusher TM, Angyo IA, Bode-Thomas F, et al. Transcutaneous bilirubin measurements and serum total bilirubin levels in indigenous African infants. Pediatrics 2004;113:1636–41. [61] Willems WA, van den Berg LM, de Wit H, Molendijk A. Transcutaneous bilirubinometry with the Bilicheck in very premature newborns. J Matern Fetal Neonatal Med 2004;16:209–14. [62] Donzelli G, Pratesi S. Transcutaneous bilirubinometry in healthy preterm newborns. Clin Biochem 2000;33:505–8. [63] Knupfer M, Pulzer F, Braun L, Heilmann A, Robel-Tillig E, Vogtmann C. Transcutaneous bilirubinometry in preterm infants. Acta Paediatr 2001;90: 899–903. [64] Ebbesen F, Rasmussen LM, Wimberley PD. A new transcutaneous bilirubinometer, BiliCheck, used in the neonatal intensive care unit and the maternity ward. Acta Paediatr 2002;91:203–11. [65] Yamauchi Y, Yamanouchi I. Transcutaneous bilirubinometry. Effect of irradiation on the skin bilirubin index. Biol Neonate 1988;54:314–9. [66] Hegyi T, Hiatt IM, Indyk L. Transcutaneous bilirubinometry. I. Correlations in term infants. J Pediatr 1981;98:454–7. [67] Yamauchi Y, Yamanouchi I. Transcutaneous bilirubinometry: bilirubin kinetics of the skin and serum during and after phototherapy. Biol Neonate 1989;56:263–9. [68] Jangaard KA, Curtis H, Goldbloom RB. Estimation of bilirubin using BiliChek, a transcutaneous bilirubin measurement device: effects of gestational age and use of phototherapy. Paediatr Child Health 2006;11: 79–83. [69] Samanta S, Tan M, Kissack C, Nayak S, Chittick R, Yoxall CW. The value of Bilicheck as a screening tool for neonatal jaundice in term and near-term babies. Acta Paediatr 2004;93:1486–90. [70] Grohmann K, Roser M, Rolinski B, et al. Bilirubin measurement for neonates: comparison of 9 frequently used methods. Pediatrics 2006;117: 1174–83. [71] Dai J, Krahn J, Parry DM. Clinical impact of transcutaneous bilirubinometry as an adjunctive screen for hyperbilirubinemia. Clin Biochem 1996; 29:581–6.
A. Carceller-Blanchard et al. / Clinical Biochemistry 42 (2009) 143–149 [72] Briscoe L, Clark S, Yoxall CW. Can transcutaneous bilirubinometry reduce the need for blood tests in jaundiced full term babies? Arch Dis Child Fetal Neonatal Ed 2002;86:F190–2. [73] Stevenson DK, Wong RJ, Vreman HJ, McDonagh AF, Maisels MJ, Lightner DA. National Institute of Child Health and Human Development Conference on kernicterus: research on prevention of bilirubin-induced brain injury and kernicterus: bench-to-bedside—diagnostic methods and prevention and treatment strategies. J Perinatol 2004;24:521–5. [74] Bourchier D, Cull AB, Oettli PE. Transcutaneous bilirubinometry: 22 months experience at Waikato Women's Hospital. N Z Med J 1987; 100:599–600. [75] Maisels MJ. Transcutaneous bilirubinometry. NeoReviews 2006;7: e217–25. [76] Yamauchi Y, Yamanouchi I. Clinical application of transcutaneous bilirubin measurement. Early prediction of hyperbilirubinemia. Acta Paediatr Scand 1990;79:385–90.
149
[77] Knudsen A, Ebbesen F, Hansen H, Brodersen R. The increase of yellow skin colour beyond that of serum bilirubin: a proposed indicator of risk for bilirubin encephalopathy in the newborn. Acta Paediatr Jpn 1993;35: 418–22. [78] Knudsen A. Predicting the need for phototherapy in healthy mature neonates using transcutaneous bilirubinometry on the first postnatal day. Biol Neonate 1995;68:398–403. [79] Carbonell X, Botet F, Figueras J, Riu-Godo A. Prediction of hyperbilirubinaemia in the healthy term newborn. Acta Paediatr 2001;90: 166–70. [80] Maisels MJ, Newman TB. Predicting hyperbilirubinemia in newborns: the importance of timing. Pediatrics 1999;103:493–5. [81] Alpay F, Sarici SU, Tosuncuk HD, Serdar MA, Inanc N, Gokcay E. The value of first-day bilirubin measurement in predicting the development of significant hyperbilirubinemia in healthy term newborns. Pediatrics 2000;106:E16.
Clinical Biochemistry 42 (2009) 143 – 149
Review
Point of care testing: Transcutaneous bilirubinometry in neonates A. Carceller-Blanchard a,⁎, J. Cousineau b , E.E. Delvin b a
b
Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montréal, Québec, Canada Department of Clinical Biochemistry, CHU Sainte-Justine, Université de Montréal, Montréal, Québec, Canada Received 18 April 2008; received in revised form 19 September 2008; accepted 19 September 2008 Available online 2 October 2008
Abstract Physicians taking care of infants in the first days of life are often faced with neonatal jaundice, especially in an era where post-partum discharge occurs earlier and assessment of newborn bilirubinemia status is required prior to discharge. The Canadian Pediatric Society and the American Academy of Pediatrics have developed and published guidelines for the diagnosis and management of hyperbilirubinemia in newborns. Point of care testing refers to any test performed outside of laboratory by clinical personnel and close to the site of patient care. Based on a summary of multiple reports during the last twenty years, we realize that devices which provide a non-invasive transcutaneous bilirubin (TcB) measurement have proven to be very useful as screening tools and provide a valid estimate of the total serum bilirubin level (TSB). Published data suggest that these devices provide measurements within 30–50 μmol/L of the TSB levels and can replace laboratory measurement particularly when TSB levels are less than 260 μmol/L. At the present time, in the literature, evidence is insufficient to abandon neonatal serum bilirubin testing and replace it with TcB. Any measurement, TSB or TcB, has potential for error. However, we have evidence that TcB, can help avoiding potential errors associated with even visual assessment of jaundice and may be useful as screening device to detect significant jaundice and decrease a large number of unnecessary skin punctures. The current manuscript is based on a careful comprehensive literature review concerning neonatal hyperbilirubinemia. We consider that this manuscript will help clinicians and laboratory professionals in the management of neonatal jaundice. © 2008 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. Keywords: Neonates; Transcutaneous bilirubin; Jaundice
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Invasive methods for the measurement of bilirubin. . . . . . . . . . . . . . . . . . . . Non-invasive methods for the measurement of bilirubin . . . . . . . . . . . . . . . . . Quality assurance issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . American Academy of Pediatrics recommendations . . . . . . . . . . . . . . . . . . . Clinical, technical and financial considerations of transcutaneous bilirubin measurement References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction
⁎ Corresponding author. Département de Pédiatrie, CHU Sainte-Justine, 3175 Chemin Côte Ste-Catherine, Montréal, Québec, Canada H3T 1C5. E-mail address: [email protected] (A. Carceller-Blanchard).
Neonatal jaundice, commonly found in 60% of normal newborns, is normally a self-resolving episode ending 72 to 96 h after birth [1,2]. Transient elevation of blood bilirubin occurs by combination of an increase in red blood cell
0009-9120/$ - see front matter © 2008 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.clinbiochem.2008.09.106
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destruction and concomitant decrease in hepatic bilirubin conjugation [2]. As early as 1941, Davidson and Weech [3] have recognized that these two processes were related to the degree of jaundice and the serum bilirubin. Six years later, King [4] devised a colorimetric micro-method base on the van den Bergh diazo method to quantitatively measure the bile pigment. Billing et al. [5] in 1954, showed increased bilirubin in newborn infants in relation to birth weight. Invasive methods for the measurement of bilirubin For the past 60 years, and as shown by the College of American Pathologists proficiency surveys, advances in analytical methods have progressively allowed the automated measurement of bilirubin to become more reliable [6,7]. The most recent of these surveys [8] revealed a variation in the bilirubin measurement ranging between 3.7% for the Jendrassik–Groff method and 10.7% for the diazo-alcohol or DMSO methods. Imprecision is increased when using patient blood samples, given pre-analytical and analytical errors, as well as interferences. Pre-analytical errors are related to blood procurement procedure, rapidity and conditions of transportation to the laboratory. Analytical errors may be due to haemolysis, a relatively frequent event when collecting blood from a heel prick in newborns, and the ensuing release of haemoglobin and other intracellular compounds that can interfere with chemical-based measurement of bilirubin [9].
Non-invasive methods for the measurement of bilirubin The first attempt at non-invasive measurement of bilirubin goes back to the 1960's when the icterometer was introduced [10]. This device, based on reflectance, had poor analytical specificity and sensitivity, and poor reproducibility with coefficient of variations ranging between 20 and 40%. In the past years, bilirubinometers have gradually been improved and are now based on simultaneous multiple wavelength analysis. Table 1 shows comparisons between serum/plasma bilirubin measurements and non-invasive transcutaneous bilirubinometry published in the literature during the past thirty years [11–26]. Transcutaneous devices are now able to better discriminate haeme and melanin pigments from bilirubin by differential spectral analysis, thus being less subject to bias [27,28]. As factors such as race or weight do not affect accuracy; they show much better correlation with serum bilirubin [23,25,28,29]. Accuracy and precision of TcB measurement was said to be comparable to the standard of care laboratory test, even when phototherapy and/or exchange transfusion were considered [30,31]. However, for the National Academy of Clinical Biochemistry (NACB), the published data does not allow clear recommendations as the use of TcB during phototherapy [32,33]. Table 2 shows results for different transcutaneous bilirubinometers as predictors of jaundice published in the literature. As can be seen, the sensitivity, specificity and, positive and negative predictive values varied among the
Table 1 Comparison between serum/plasma bilirubin determinations and non-invasive transcutaneous bilirubinometry in the literature Author [Ref.]
Year
N
Comparisons
Bland–Altman bias plot
Correlation
Mean [95% CI] Chaibva et al. [11] Yamanouchi et al. [12] Schumacher et al. [13]
1974 1980 1985
55 66 106
Yamauchi and Yamanouchi [14] Gupta et al. [15] Linder et al. [16] Knudsen and Ebbesen [17] Tan et al. [18] Tayaba et al. [19]
1988 1991 1994 1996 1996 1998
336 161 123 150 542 900
Rubaltelli et al. [20] Wong et al. [21]
2001 2002
210 64
Robertson et al. [22] Engle et al. [23] Kazmierczak et al. [24] Maisels et al. [25]
2002 2002 2004 2004
101 304 95 849 146 178 53 35
Carceller et al. [26]
2006
Units are expressed as μmol/L. Year: year of publication. N: number of subjects included in the study. BC: BiliCheck.
Serum/icterometer Serum/Minolta Serum/icterometer Serum/Minolta Serum/Minolta Serum/icterometer Plasma/Minolta 101 Plasma/Minolta 101 Plasma/Minolta Serum/Chromatics Colormate III HPLC/BC Serum/BC Minolta 102/BC Serum/BC Serum/BC HPLC/BC Serum/Minolta 103 Minolta 103/BC Total blood/BC Plasma/BC Total blood/plasma
17.8 [− 77.0 to 4 [− 67.9 to 0 [− 66.7 to 6.84 [− 32.5 to
+77.0] +67.9] +66.7] +42.8]
Regression line y = ax + b (p value)
0.96 0.93 0.63 0.74 0.93 0.99 0.96 0.78 0.80 0.96
(b0.01) (0.001) 0.04x + 167.8 (0.0001) 0.9862x − 0.86
0.89
1.07x + 2.85
1.11x + 136 (b0.001) 0.12x + 29.8 0.19x + 158.2
0.87 0.84
1.01x+18.6
0.91
0.8716x + 15.6
0.78 0.77 0.76
0.9197x + 12.1 (b0.001) 0.9733x + 9.0 (b0.001) 0.9426x + 10.4 (b0.001)
0.26 [− 54.5 to +54.5] 6.84 [51.3 to +31.6] 1.5 [− 50.4 to +47.5] 5.3 [− 35.8 to +46.5] 3.1 [− 34.6 to +40.7]
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Table 2 Sensitivity, specificity, positive and negative predictive values of non-invasive transcutaneous bilirubinometry in the literature Author [Ref.]
Year
N
Gestational age
Device
Serum cut-off
Sensitivity %
Specificity %
PPV %
Minolta Icterometer Minolta 101 HPLC BC Minolta BC BC BC Minolta
≥220 N171 N220 N220 N220 ≥170 ≥150 N170 N260 ≥260
94 97 86 76 66 100 100 73 33 100
78 71 98 96 89 32 21 97 96 68
44 78 86 94 84 35 32 99 82 27
Weeks N36 37 to 42 N37 ≤ 36 and N36
Schumacher et al. [13] Gupta et al. [15] Linder et al. [16] Rubaltelli et al. [20]
1985 1991 1994 2001
106 77 123 210
Wong et al. [21]
2002
64
Engle et al. [23]
2002
304
N35
Dai et al. [27]
1997
45
N37
31 to 42
NPV % 99 96 98 82 75
50 75 100
Units are expressed as μmol/L. Year: year of publication. N: number of subjects included in the study. BC: BiliCheck. PPV: positive predictive value. NPV: negative predictive value.
studies. This could be due to the heterogeneity of the study populations and the age of the newborns at the time of the measurements [13,15,16,20,21,23,27]. Bertini and Rubaltelli [29] and Rubaltelli et al. [20] give sensitivity, specificity, positive and negative predictive values of BiliCheck compared to the HPLC measurement of serum bilirubin at various clinically relevant cut-off points (Table 3). Carceller et al. [26] concluded that BiliCheck may be used to monitor bilirubin in term neonates at 48 h of life and they recommended that clinicians be conscious of the limit of precision for both BiliCheck and laboratory measures (Table 1). Quality assurance issues When measuring TcB, it is important that the nursing and medical staff register the test results in the patient's chart.
However, newer generations of bilirubinometers will need to have connectivity features, so that results are automatically registered in the Laboratory Information System, as well as in the patient's chart, in order to improve quality assurance. Maisels and King [34] recommended a daily calibration of the instrument as well as every three months, TcB measurements should be compared with 5 to 10 laboratory bilirubin determinations. Yamanouchi et al. [12] reported that the intra-observer and inter-observer imprecision coefficients of variation ranged between 2.6–4.9%, and 2.1–5.0% respectively. However, Bertini and Rubatelli [29] reported interobserver and inter-device coefficients of variation ranging between 4–11% and 7–18% (Table 4). This imprecision is however similar to that reported for serum bilirubin in laboratories surveys [35,36]. It must be stressed that, in 2006, the NACB recommended the adoption of the BiliCheck
Table 3 The sensitivity, specificity, positive and negative predictive values of HPLC and BiliCheck HPLC
≥222.3 ≥256.5 ≥290.7
BC
≥171.0 ≥188.1 ≥205.2 ≥205.2 ≥222.3 ≥239.4 ≥239.4 ≥256.5 ≥273.6
Bertini and Rubaltelli. [29] a
Rubaltelli et al. [20] b
Sensitivity %
Specificity %
Sensitivity %
Specificity %
PPV %
NPV %
100 100 95.3 100 72 68 57 43 43
52 63 85 56 62 89 71 86 87
97 93 86 92 81 63 90 77 63
64 73 85 71 82 92 87 91 96
70 75 83 57 66 76 53 59 73
96 92 87 95 91 86 98 96 94
Units are expressed as μmol/L. Adapted from Bertini and Rubaltelli [29] and Rubaltelli et al. [20]. BC: BiliCheck. PPV: positive predictive value. NPV: negative predictive value. a Gestational age was N30 weeks. b Gestational age was ≤36 and N36.
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Table 4 Inter-operator and inter-device coefficient of variations Inter-operator variability
Clinical, technical and financial considerations of transcutaneous bilirubin measurement
Inter-device variability
TcB
CV %
TcB
CV %
≤137 N137 ≤220 N220 All values
11 5 4 5.7
≤ 137 N137 ≤220 N220 All values
17.6 7.8 7.2 9.3
Units are expressed as μmol/L. Adapted from Bertini and Rubaltelli [29]. TcB: transcutaneous bilirubin (BiliCheck). CV: coefficient of variation.
and the Air-Shield devices for TcB measurement in the management and follow-up of neonatal jaundice, as they provided similar accuracy when compared with laboratory bilirubin measurements [32,33]. American Academy of Pediatrics recommendations Recognizing that kernicterus, a condition with associated morbidity, is a public health concern [37–39], the Subcommittee on hyperbilirubinemia Management of the American Academy of Pediatrics (AAP), has developed and published, in 1994 and 2004, detailed consensus-based practice parameters for diagnosis and management of hyperbilirubinemia in healthy term newborns [40,41]. The AAP recommends that TcB and/or blood bilirubin measurements be performed on every infant who is jaundiced within the first 24 h of life; the need to repeat this measurement depends on postnatal age and bilirubin concentration [42–44]. Guidelines have also been established recommending that prior to discharge, all newborns be assessed for the risk of developing severe hyperbilirubinemia. In fact, in 1999, Buthani et al. [45] published a nomogram for well newborns at 35 or more weeks' gestational age based on the hour-specific serum bilirubin values before discharge and for designation of risk of hyperbilirubinemia. Bilirubin concentrations were divided into 4 risk zones, with high-risk being the adjusted 95th percentile track. This concentration had a high predictive value for subsequent bilirubin levels being consistent with kernicterus [37]. A list of high risk factors for severe hyperbilirubinemia identified in epidemiologic studies has been published [46,47]. Keren et al. [48] found that gestational age was the strongest predictor for significant hyperbilirubinemia and could be used in combination with the pre-discharge risk zone to stratify infants into distinct risk categories. Future research is needed to develop evidencebased recommendations and determine the incidence of hyperbilirubinemia for late preterm infants, optimal discharge timing, counselling and post discharge follow-up of jaundice, particularly for those who are breastfed [49]. Petrova's survey [50] shows that paediatricians' practices regarding low utilization of laboratory diagnosis for quantification of jaundice after discharge and underestimation of risk factors contribute to progression of severe hyperbilirubinemia and is an important public health concern.
Jaundice continues to be a problematic clinical challenge, due to factors as breastfeeding and early hospital discharge. Early visual identification of jaundice does not give an accurate estimation of hyperbilirubinemia severity. Tayaba et al. [19] reported that the correlation (r) between the visual estimate and laboratory measurements was 0.75 and that of TcB and laboratory measurement was 0.96. Measuring bilirubin transcutaneously on a device available on point-of-care basis seems a tempting option, since it is totally non-invasive and that turnaround time, for attending physicians to access results, is potentially reduced. The balance between cost and benefit remains a preoccupation. Few studies evaluating the cost associated with the implementation of TcB measurement are available. In 2005, Petersen et al. [51] reported a decrease in hospitalization charges as a result of fewer readmissions of newborns due to hyperbilirubinemia. However this decrease in cost was counterbalanced by increased TcB measurements and an increased number of newborns treated with phototherapy prior to discharge. For NACB [32,33], further evidence is needed to evaluate whether TcB measurements improve clinical outcome, shorten length of stay or decrease the readmission rate for newborns with hyperbilirubinemia. Although TcB measurements may result in increased operational costs, the primary aim is the patient's comfort, which implies reducing the number of skin punctures performed on neonates. Indeed, serum bilirubin measurements is one of the most frequent causes for collection of blood from newborn, a procedure that has been documented to involve pain and stress [9,52]. TcB may be useful as a screening device to detect clinically significant jaundice and decrease the need for serum bilirubin measurements [53]. However, for NACB, there is insufficient evidence available to judge on the impact of TcB measurements on number of blood samples collected from newborns [32,33]. Jaundice measurement sites, using TcB, have been standardized. When measured on the forehead and sternum, TcB is similar to blood sample values [14,54]. Although Maisels et al. [25] found better correlation between TcB and serum concentrations when TcB measurements were performed on the sternum (r = 0.953) as compared to the forehead (r = 0.914). NACB [32,33] has recommended the TcB measurements either on the forehead or the sternum and the use of nomograms based upon the postnatal age and bilirubin concentration to assess the need for and timing of repeat TcB measurements. There are some factors that may affect TcB measurements as gestational age, birth weight, phototherapy, exchange transfusion, skin pigmentation and postnatal age. Since the 80's, studies have been carried out with different models of bilirubinometers and in different conditions [34,55–60]. Rubaltelli et al. [20] comparing the BiliCheck meter versus serum bilirubin measured using HPLC found that gestational age did not affect the correlation between these two methods. Carceller et al. [26] observed that weight loss seen in neonates had little influence and did not affect the agreement between
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BiliCheck and measurements of bilirubin in blood. BiliCheck has been used as a screening device in preterm infants [31,61,62]. Authors recommend being cautious when skin measurements are performed in the presence of peripheral oedema and/or a poor peripheral circulation; its application in the Neonatal Intensive Care Units reduced the number of blood samples by 40%. Other studies found that the severity of illness (hypoxia, hypoglycaemia, infection, respiratory distress syndrome, bleeding or abdominal problems) did not adversely impact the TcB measurements [63,64]. Phototherapy has been reported by numerous studies to adversely affect the correlation between TcB and blood measurement [30,63,65–68]. For NACB [32,33], the effect of gestational age on TcB measurement is not clear. Some reports suggest limiting the use of TcB measurements to newborns less than 30, 32 or 34 weeks of gestation, while others suggest no effect of gestational age. There are too few studies available that address the effect of underlying illnesses in newborns and their effects on the use of TcB measurements. Several authors showed that BiliCheck could be used not only as a screening device but also as a reliable substitute of blood determination [20,24,29,43,69,70]. Frequently, studies give data when jaundiced was clinically obvious in neonates and was measured with the TcB. These studies are contradictory; some reported a reduction, no change or an increase in the total number of bilirubin tests in the laboratory [19,34,51,64,71–74]. Dai et al. [71] have evaluated the use of a TcB as a screening device, giving a cut-off value of 260 μmol/L (sensitivity and specificity: 100% and 67.7%; predictive values of positive and negative cut-off: 27% and 100%). For clinical purposes, 100% sensitivity is needed. Briscoe et al. [72] have published that 18 mg/dL of TcB (conversion from mg/dL × 17.1 = 308 μmol/L) gives a 100% sensitivity and 45% specificity, with 34% reduction of blood tests. Bilirubin concentration from nonchemical photometric devices that exceed 250 μmol/L should be confirmed with standard laboratory methods [69]. In fact, some authors estimate that approximately 60–80% of skin punctures could be prevented by use of this device [64,75]. TcB has been shown to be a good device to screen for neonatal hyperbilirubinemia in neonates that are discharged within 48 h of birth [76–79] and also could be very useful in outpatient's population for home follow-up. Maisels et al. [25] recommended TcB measurements from the sternum after infants have been discharged, to eliminate ambient light influence. Many investigators speculated that TcB measurements could influence length of hospitalization and readmission rates; it is not clear whether the time saving had any impact on length of stay, however, there is a significant reduction in the number of hospital readmissions [19,51]. Maisels and Newman [80] state the importance to provide a follow-up or at least perform bilirubin check within 24 to 48 h of discharge to children who replace in the upper intermediate or high-risk zones in the nomogram [45,81]. Conclusion: Published studies suggest that non-invasive transcutaneous bilirubinometry is a precise test and a good way of screening for jaundice, and to identify neonates that require a blood sample for serum bilirubin measurement. We are not sure
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that the effectiveness of this method could reduce costs but it definitively reduces skin punctures. Every hospital needs to consider the implementation of this procedure after assessing reproducibility and accuracy of each device used. References [1] Maisels MJ. What's in a name? Physiologic and pathologic jaundice: the conundrum of defining normal bilirubin levels in the newborn. Pediatrics 2006;118:805–7. [2] Maisels MJ, McDonagh AF. Phototherapy for neonatal jaundice. N Engl J Med 2008;358:920–8. [3] Davidson LT, Merritt KK, Weech AA. Hyperbilirubinemia in the newborn. Am J Dis Child 1941;61:958–80. [4] King E. Microanalysis in medical biochemistry. 2nd ed. London: Churchill; 1947. [5] Billing BH, Cole PG, Lathe GH. Increased plasma bilirubin in newborn infants in relation to birth weight. Br Med J 1954;2:1263–5. [6] Lo SF, Doumas BT, Ashwood ER. Performance of bilirubin determinations in US laboratories—revisited. Clin Chem 2004;50:190–4. [7] Lo SF, Doumas BT, Ashwood ER. Bilirubin proficiency testing using specimens containing unconjugated bilirubin and human serum: results of a College of American Pathologists study. Arch Pathol Lab Med 2004;128: 1219–23. [8] College of American Pathologists: Chemistry/Therapeutic Drug Monitoring Participant Summary. Surveys 2008. Accessed September 17th, 2008. [9] Shah V, Taddio A, Kulasekaran K, O'Brien L, Perkins E, Kelly E. Evaluation of a new lancet device (BD QuikHeel) on pain response and success of procedure in term neonates. Arch Pediatr Adolesc Med 2003; 157:1075–8. [10] Gosset IH. A perspex icterometer for neonates. Lancet 1960;1:87–8. [11] Chaibva NT, Fenner A, Wolfsdorf J. Reliability of an icterometer in Black neonates with hyperbilirubinaemia. S Afr Med J 1974;48:1533–4. [12] Yamanouchi I, Yamauchi Y, Igarashi I. Transcutaneous bilirubinometry: preliminary studies of noninvasive transcutaneous bilirubin meter in the Okayama National Hospital. Pediatrics 1980;65:195–202. [13] Schumacher RE, Thornbery JM, Gutcher GR. Transcutaneous bilirubinometry: a comparison of old and new methods. Pediatrics 1985;76:10–4. [14] Yamauchi Y, Yamanouchi I. Transcutaneous bilirubinometry. Evaluation of accuracy and reliability in a large population. Acta Paediatr Scand 1988; 77:791–5. [15] Gupta PC, Kumari S, Mullick DN, Lal UB. Icterometer: a useful screening tool for neonatal jaundice. Indian Pediatr 1991;28:473–6. [16] Linder N, Regev A, Gazit G, et al. Noninvasive determination of neonatal hyperbilirubinemia: standardization for variation in skin color. Am J Perinatol 1994;11:223–5. [17] Knudsen A, Ebbesen F. Transcutaneous bilirubinometry in neonatal intensive care units. Arch Dis Child Fetal Neonatal Ed 1996;75:F53–6. [18] Tan KL, Chia HP, Koh BC. Transcutaneous bilirubinometry in Chinese, Malay and Indian infants. Acta Paediatr 1996;85:986–90. [19] Tayaba R, Gribetz D, Gribetz I, Holzman IR. Noninvasive estimation of serum bilirubin. Pediatrics 1998;102:E28. [20] Rubaltelli FF, Gourley GR, Loskamp N, et al. Transcutaneous bilirubin measurement: a multicenter evaluation of a new device. Pediatrics 2001; 107:1264–71. [21] Wong CM, van Dijk PJ, Laing IA. A comparison of transcutaneous bilirubinometers: SpectRx BiliCheck versus Minolta AirShields. Arch Dis Child Fetal Neonatal Ed 2002;87:F137–40. [22] Robertson A, Kazmierczak S, Vos P. Improved transcutaneous bilirubinometry: comparison of SpectRx BiliCheck and Minolta Jaundice Meter JM-102 for estimating total serum bilirubin in a normal newborn population. J Perinatol 2002;22:12–4. [23] Engle WD, Jackson GL, Sendelbach D, Manning D, Frawley WH. Assessment of a transcutaneous device in the evaluation of neonatal hyperbilirubinemia in a primarily Hispanic population. Pediatrics 2002; 110:61–7.
148
A. Carceller-Blanchard et al. / Clinical Biochemistry 42 (2009) 143–149
[24] Kazmierczak SC, Robertson AF, Briley KP, Kreamer B, Gourley GR. Transcutaneous measurement of bilirubin in newborns: comparison with an automated Jendrassik–Grof procedure and HPLC. Clin Chem 2004;50: 433–5. [25] Maisels MJ, Ostrea Jr EM, Touch S, et al. Evaluation of a new transcutaneous bilirubinometer. Pediatrics 2004;113:1628–35. [26] Carceller AM, Delvin E, Gonthier M, Gregoire MC, Cousineau J, Alexandrov L. [Evaluation of transcutaneous bilirubin measurement and agreement with bilirubinemia]. Ann Biol Clin (Paris) 2006;64:575–9. [27] Dai J, Parry DM, Krahn J. Transcutaneous bilirubinometry: its role in the assessment of neonatal jaundice. Clin Biochem 1997;30:1–9. [28] Onks D, Silverman L, Robertson A. Effect of melanin, oxyhemoglobin and bilirubin on transcutaneous bilirubinometry. Acta Paediatr 1993;82:19–21. [29] Bertini G, Rubaltelli FF. Non-invasive bilirubinometry in neonatal jaundice. Semin Neonatol 2002;7:129–33. [30] Tan KL, Dong F. Transcutaneous bilirubinometry during and after phototherapy. Acta Paediatr 2003;92:327–31. [31] Nanjundaswamy S, Petrova A, Mehta R, Hegyi T. Transcutaneous bilirubinometry in preterm infants receiving phototherapy. Am J Perinatol 2005;22:127–31. [32] Kazmierczak S, Bhutani VK, Gourley GR, et al. Transcutaneous bilirubin testing. In: Laboratory medicine practice guidelines: evidence-based practice for point-of-care testing. Washington (DC): National Academy of Clinical Biochemistry (NACB); 2006. p. 5–12. [33] Nichols JH, Christenson RH, Clarke W, et al. Executive summary. The National Academy of Clinical Biochemistry Laboratory Medicine Practice Guideline: evidence-based practice for point-of-care testing. Clin Chim Acta 2007;379:14–28 [discussion 9–30]. [34] Maisels MJ, Kring E. Transcutaneous bilirubinometry decreases the need for serum bilirubin measurements and saves money. Pediatrics 1997;99: 599–601. [35] Vreman HJ, Verter J, Oh W, et al. Interlaboratory variability of bilirubin measurements. Clin Chem 1996;42:869–73. [36] Doumas BT, Eckfeldt JH. Errors in measurement of total bilirubin: a perennial problem. Clin Chem 1996;42:845–8. [37] Bhutani VK, Johnson LH, Jeffrey Maisels M, et al. Kernicterus: epidemiological strategies for its prevention through systems-based approaches. J Perinatol 2004;24:650–62. [38] Hansen TW. Kernicterus in a full-term infant: the need for increased vigilance. Pediatrics 1995;95:798–9. [39] Penn AA, Enzmann DR, Hahn JS, Stevenson DK. Kernicterus in a full term infant. Pediatrics 1994;93:1003–6. [40] American Academy of Pediatrics Provisional Committee for Quality Improvement and Subcommittee on Hyperbilirubinemia. Practice parameter: management of hyperbilirubinemia in the healthy term newborn. Pediatrics 1994;94:558–65. [41] Bhutani VK, Johnson LH. Urgent clinical need for accurate and precise bilirubin measurements in the United States to prevent kernicterus. Clin Chem 2004;50:477–80. [42] American Academy of Pediatrics. Subcommittee of Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297–316. [43] Bhutani VK, Gourley GR, Adler S, Kreamer B, Dalin C, Johnson LH. Noninvasive measurement of total serum bilirubin in a multiracial predischarge newborn population to assess the risk of severe hyperbilirubinemia. Pediatrics 2000;106:E17. [44] Bhutani VK, Johnson LH. Jaundice technologies: prediction of hyperbilirubinemia in term and near-term newborns. J Perinatol 2001;21(Suppl 1): S76–82 [discussion S3–S7]. [45] Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics 1999;103:6–14. [46] American Academy of Pediatrics Subcommittee of Hyperbilirubinemia. Neonatal jaundice and kernicterus. Pediatrics 2001;108:763–5. [47] Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction and prevention of extreme neonatal hyperbilirubinemia in a mature health maintenance organization. Arch Pediatr Adolesc Med 2000;154:1140–7.
[48] Keren R, Luan X, Friedman S, Saddlemire S, Cnaan A, Bhutani VK. A comparison of alternative risk-assessment strategies for predicting significant neonatal hyperbilirubinemia in term and near-term infants. Pediatrics 2008;121:e170–9. [49] Smith JR, Donze A, Schuller L. An evidence-based review of hyperbilirubinemia in the late preterm infant, with implications for practice: management, follow-up, and breastfeeding support. Neonatal Netw 2007;26:395–405. [50] Petrova A, Mehta R, Birchwood G, Ostfeld B, Hegyi T. Management of neonatal hyperbilirubinemia: pediatricians' practices and educational needs. BMC Pediatr 2006;6:6. [51] Petersen JR, Okorodudu AO, Mohammad AA, Fernando A, Shattuck KE. Association of transcutaneous bilirubin testing in hospital with decreased readmission rate for hyperbilirubinemia. Clin Chem 2005;51: 540–4. [52] Owens ME, Todt EH. Pain in infancy: neonatal reaction to a heel lance. Pain 1984;20:77–86. [53] Ip S, Chung M, Kulig J, O'Brien R, Sege R, Glicken S, et al. An evidencebased review of important issues concerning neonatal hyperbilirubinemia. Pediatrics 2004;114:e130–53. [54] Maisels MJ, Conrad S. Transcutaneous bilirubin measurements in full-term infants. Pediatrics 1982;70:464–7. [55] Goldman SL, Penalver A, Penaranda R. Jaundice meter: evaluation of new guidelines. J Pediatr 1982;101:253–6. [56] Hannemann RE, Schreiner RL, DeWitt DP, Norris SA, Glick MR. Evaluation of the Minolta bilirubin meter as a screening device in white and black infants. Pediatrics 1982;69:107–9. [57] Tan KL. Transcutaneous bilirubinometry in Chinese and Malay neonates. Ann Acad Med Singapore 1985;14:591–4. [58] Tan KL, Mylvaganam A. Transcutaneous bilirubinometry in preterm very low birthweight infants. Acta Paediatr Scand 1988;77:796–801. [59] Nanjundaswamy S, Petrova A, Mehta R, Bernstein W, Hegyi T. The accuracy of transcutaneous bilirubin measurements in neonates: a correlation study. Biol Neonate 2004;85:21–5. [60] Slusher TM, Angyo IA, Bode-Thomas F, et al. Transcutaneous bilirubin measurements and serum total bilirubin levels in indigenous African infants. Pediatrics 2004;113:1636–41. [61] Willems WA, van den Berg LM, de Wit H, Molendijk A. Transcutaneous bilirubinometry with the Bilicheck in very premature newborns. J Matern Fetal Neonatal Med 2004;16:209–14. [62] Donzelli G, Pratesi S. Transcutaneous bilirubinometry in healthy preterm newborns. Clin Biochem 2000;33:505–8. [63] Knupfer M, Pulzer F, Braun L, Heilmann A, Robel-Tillig E, Vogtmann C. Transcutaneous bilirubinometry in preterm infants. Acta Paediatr 2001;90: 899–903. [64] Ebbesen F, Rasmussen LM, Wimberley PD. A new transcutaneous bilirubinometer, BiliCheck, used in the neonatal intensive care unit and the maternity ward. Acta Paediatr 2002;91:203–11. [65] Yamauchi Y, Yamanouchi I. Transcutaneous bilirubinometry. Effect of irradiation on the skin bilirubin index. Biol Neonate 1988;54:314–9. [66] Hegyi T, Hiatt IM, Indyk L. Transcutaneous bilirubinometry. I. Correlations in term infants. J Pediatr 1981;98:454–7. [67] Yamauchi Y, Yamanouchi I. Transcutaneous bilirubinometry: bilirubin kinetics of the skin and serum during and after phototherapy. Biol Neonate 1989;56:263–9. [68] Jangaard KA, Curtis H, Goldbloom RB. Estimation of bilirubin using BiliChek, a transcutaneous bilirubin measurement device: effects of gestational age and use of phototherapy. Paediatr Child Health 2006;11: 79–83. [69] Samanta S, Tan M, Kissack C, Nayak S, Chittick R, Yoxall CW. The value of Bilicheck as a screening tool for neonatal jaundice in term and near-term babies. Acta Paediatr 2004;93:1486–90. [70] Grohmann K, Roser M, Rolinski B, et al. Bilirubin measurement for neonates: comparison of 9 frequently used methods. Pediatrics 2006;117: 1174–83. [71] Dai J, Krahn J, Parry DM. Clinical impact of transcutaneous bilirubinometry as an adjunctive screen for hyperbilirubinemia. Clin Biochem 1996; 29:581–6.
A. Carceller-Blanchard et al. / Clinical Biochemistry 42 (2009) 143–149 [72] Briscoe L, Clark S, Yoxall CW. Can transcutaneous bilirubinometry reduce the need for blood tests in jaundiced full term babies? Arch Dis Child Fetal Neonatal Ed 2002;86:F190–2. [73] Stevenson DK, Wong RJ, Vreman HJ, McDonagh AF, Maisels MJ, Lightner DA. National Institute of Child Health and Human Development Conference on kernicterus: research on prevention of bilirubin-induced brain injury and kernicterus: bench-to-bedside—diagnostic methods and prevention and treatment strategies. J Perinatol 2004;24:521–5. [74] Bourchier D, Cull AB, Oettli PE. Transcutaneous bilirubinometry: 22 months experience at Waikato Women's Hospital. N Z Med J 1987; 100:599–600. [75] Maisels MJ. Transcutaneous bilirubinometry. NeoReviews 2006;7: e217–25. [76] Yamauchi Y, Yamanouchi I. Clinical application of transcutaneous bilirubin measurement. Early prediction of hyperbilirubinemia. Acta Paediatr Scand 1990;79:385–90.
149
[77] Knudsen A, Ebbesen F, Hansen H, Brodersen R. The increase of yellow skin colour beyond that of serum bilirubin: a proposed indicator of risk for bilirubin encephalopathy in the newborn. Acta Paediatr Jpn 1993;35: 418–22. [78] Knudsen A. Predicting the need for phototherapy in healthy mature neonates using transcutaneous bilirubinometry on the first postnatal day. Biol Neonate 1995;68:398–403. [79] Carbonell X, Botet F, Figueras J, Riu-Godo A. Prediction of hyperbilirubinaemia in the healthy term newborn. Acta Paediatr 2001;90: 166–70. [80] Maisels MJ, Newman TB. Predicting hyperbilirubinemia in newborns: the importance of timing. Pediatrics 1999;103:493–5. [81] Alpay F, Sarici SU, Tosuncuk HD, Serdar MA, Inanc N, Gokcay E. The value of first-day bilirubin measurement in predicting the development of significant hyperbilirubinemia in healthy term newborns. Pediatrics 2000;106:E16.