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Preterm Small for Gestational Age Infants Are Not at Higher Risk for Parenteral Nutrition–Associated Cholestasis
Preterm Small for Gestational Age Infants Are Not at Higher Risk for Parenteral Nutrition–Associated Cholestasis Simonetta Costa, MD, PhD, Luca Maggio, MD, Paola Sindico, MD, Francesco Cota, MD, PhD, Maria Pia De Carolis, MD, and Costantino Romagnoli, MD Objective To assess if being small for gestational age impacts parenteral nutrition–associated cholestasis (PNAC) development. Study design We reviewed all the very low–birth weight infants exposed to parenteral nutrition for >14 days from 1996 to 2006, comparing auxological and clinical data, as well as nutritional history, during the first 4 weeks of life of infants with cholestasis and control subjects. Results Of 445 very low–birth weight infants, 55 had development of PNAC. Infants with cholestasis had lower birth weight and gestational age but similar birth weight z-score compared with infants without cholestasis, and they received a lower amount of enteral feeds (25.8 20.7 vs 67.9 33.0mL/kg, P < .001), a greater amount of intravenous glucose (10.6 1.3 vs 7.5 2.5g/kg, P < .0001), lipids (1.8 0.4 vs 1.3 0.5, P < .0001) and proteins (2.7 0.5 vs 1.9 0.7, P < .0001), and needed a higher number of days of fasting (13.2 6.7 vs 6.5 4.8, P < .001). Enteral intake between 0 and 21 days of life (OR 0.66; 95% CI 0.53, 0.81, P < .0001) and oxygen therapy (OR 1.05; 95% CI 1.01, 1.09; P = .030) were identified as the best independent predictors of PNAC. Conclusions Enteral feeding remains the main factor for the prevention of PNAC, whereas small for gestational age infants do not have a higher risk of PNAC. (J Pediatr 2010;156:575-9). See related article, p 580
P
arenteral nutrition (PN) plays an important role in the neonatal intensive care unit, and it can be life saving for critically ill newborn babies who are unable to receive adequate enteral nourishment. However, exposure to PN is demonstrated as the main factor in the development of cholestasis in preterm infants. Several risk factors related to intravenous hyperalimentation have been implicated in the development of parenteral nutrition–associated cholestasis (PNAC), such as the total caloric overload, the quality of amino acid solutions, the cumulative amount of lipid infusion, the presence of excessive aluminium in the PN solution, and the high manganese intake with PN.1-5 Moreover, sepsis, necrotizing enterocolitis (NEC), bowel surgery, and lack of enteral feeding were suggested as potential contributors to the development of PNAC.6-10 It has recently been suggested that being small for gestational age (SGA) is an independent risk factor for PNAC.11 The aim of our study was to assess in our population of very low–birth weight (VLBW) infants, whether being SGA is one of the independent risk factors for PNAC.
Methods We performed a retrospective review of all infants with birth weight # 1500 g assisted in our neonatal intensive care unit (NICU) from January 1, 1996, to December 31, 2006, who received PN for more than 14 days and who were still alive at 28 days of life. PNAC was defined as direct bilirubin greater than 2.0 mg/dL persistent for at least 2 consecutive tests during the administration of PN, not associated with other known causes of cholestasis.1,12-14 Infants with cholestasis caused by genetic or metabolic disorders, congenital infections, extrahepatic obstructions, or congenital gastrointestinal disorders requiring surgery were excluded from the study. In all infants who received PN, direct bilirubin level was tested weekly. Auxological and clinical data, as well as a complete and detailed nutritional hisAGA Appropriate for gestational age tory, were collected in all infants during BPD Bronchopulmonary dysplasia the first 28 days of life. Gestational age BW Birth weight GA IUGR NEC NICU PN PNAC SGA VLBW
Gestational age Intrauterine growth restriction Necrotizing enterocolitis Neonatal intensive care unit Parenteral nutrition Parenteral nutrition associated cholestasis Small for gestational age Very low birth weight
From the Division of Neonatology, Department of Paediatrics, Catholic University Sacred Heart (S.C., L.M. P.S., F.C., M.C., C.R.), Rome, Italy The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright Ó 2010 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.10.038
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was determined by the best obstetric estimate on the basis of the first day of the last menstrual period, prenatal ultrasound, and postnatal physical examination. SGA infants were defined with the Italian intrauterine reference values as those whose birth weight z-score was below 1.28.15 Among the main morbidities, bronchopulmonary dysplasia (BPD) was defined according to the most recent definitions16; necrotizing enterocolitis (NEC) was diagnosed according to the criteria of Bell, and only infants with a grade above IIa were considered as affected17; sepsis was defined by positive blood or cerebrospinal fluid cultures and typical clinical signs. Duration of oxygen therapy, mechanical ventilation, antibiotic treatment, as well as mortality rate and length of hospital stay were also considered. The nutritional history included the number of days without any enteral intake during the first 28 days of life, as well as the amount of enteral and intravenous daily intakes. Two separate NICU databases were used as information sources: a nutrition database recording details about parenteral and enteral feeding, and a neonatal database containing demographic details, antenatal and perinatal history, postdelivery status, neonatal diagnosis, procedures, therapies, complications, and main outcomes at discharge. Data from the 2 databases and a review of the single medical records were entered into a single study database for the retrospective analysis. PN was started for all VLBW infants within the first 24 hours of life; progression of nutrient intakes was regulated with an electronic decision-support program developed by our unit. Nutritional guidelines provided that infants were started at 1 to 2 g/kg/d of protein (Trophamine 6%), and increased to achieve a maximum of 3.5 -4.0 g/kg/day within the first week of life. Intravenous lipids (Intralipid 20%) were started at 0.5 g/kg/d and increased to a maximum of 3.0 g/ kg/d at day 7 of life. Glucose administration was started with an infusion of 6 g/kg/day and advanced to a maximum of 12 to 14 g/kg/d, according to the daily infant’s glycemic tolerance. Caregivers, using a computer in the NICU, could confirm or modify the recommended dosages looking at the individual infant. PN was stopped when infants were able to tolerate approximately 120 mL/kg/day of enteral feeding and showed sustained growth, defined by at least 15 g/kg/ day, during the last 72 hours. Enteral feeding was planned to start within the first 24 to 120 hours of life with mother’s milk, or with pasteurized pooled premature human milk; subsequently, infants were fed their own mother’s milk fortified with Eoprotin (Milupa, Milan, Italy) when an intake of 100 mL/kg was well tolerated, and never before day 14 of life. When there were difficulties in obtaining sufficient quantities of human milk, or a mother was not able to supply her own milk, infants were fed, partially or totally, with a preterm formula. Statistical Analysis Results are showed as mean standard deviation (SD) for the continuous variables, and as percentages for the categorical variables. The groups were compared by use of the Student t test for parametric data, and the Wilcoxon rank-sum 576
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Table I. Data at birth, morbidity rates, and therapies of infants with and without PNAC, during hospital stay PNAC (n = 55) Gestational age (w) Birth weight (g) Male/Female BW z-score BW z-score < 1.28 (%) NEC (%) BPD (%) Sepsis (%) Antibiotic therapy (n of cycles) Mechanical ventilation (days) Oxygen therapy (days) Length of stay (days) Mortality rate (%)
27.4 2.5 850 274 32/23 0.82 1.17 17 (30.9) 8 (14.5) 10 (18.2) 31 (56.4) 5.3 3.3 30.1 43.4 59.4 69.6 111 55 11 (20)
No PNAC (n = 390)
P
28.7 2.3 1052 238 175/215 0.60 1.11 112 (28.7) 13 (3.3) 19 (4.9) 98 (25.1) 2.4 2.1 11.2 18.5 21.6 36.3 69 36 5 (1.3)
<.001 <.001 .083 .175 .752 .002 .001 <.001 <.001 <.001 <.001 .002 <.001
test (Mann Whitney U test) for nonparametric data. Categorical variables were compared by use of the Fisher exact test. Multivariate analysis was conducted by logistic regression to define the role of specific factors that may affect PNAC. All the variables significantly associated to PNAC after the univariate analysis were entered into the initial model. Backward stepwise selection was used to select the variables to enter in the final model with a significance level for the removal and the addition, respectively, of 0.3 and 0.2. A 2-tailed value of P < .05 was considered significant. Statistical analysis was performed with the Stata Statistical Software: Release 10 (Stata Corp LP, College Station, Texas).
Results During the study period 445 VLBW infants who met the inclusion criteria were identified, and 55 of them (12.3%) had development of PNAC. The mean day of life at which cholestasis was detected was 27.3 10.8. The diagnosis of PNAC was made in 6 (11%) infants during the fourth week of life, in 16 infants (29%) during the fifth week of life, and in 33 infants (60%) after the fifth week of life. The mean maximum value of direct bilirubin was 5.1 1.7 mg/dL. The mean duration of PNAC was 28.3 12.9 days. Infants who had development of PNAC were significantly more immature and smaller than those without PNAC; the mean birth weight (BW) z-score was similar between the 2 groups, as well as the percentage of infants with a BW z-score below –1.28 (Table I). Infants with PNAC had a higher incidence of main morbidities, required a longer duration of mechanical ventilation and supplemental oxygen, and showed a longer hospital stay and a higher mortality rate than infants without PNAC (Table I). Infants with PNAC received a significantly lower amount of enteral nutrition from 0 to 14, 0 to 21, and 0 to 28 days of life and needed a longer period of fasting as compared with infants who did not have development of PNAC (Table II). The mean amount of intravenous protein, glucose, and lipids from 0 to 14, 0 to 21, and 0 to Costa et al
ORIGINAL ARTICLES
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Table II. Nutritional data of infants with and without PNAC PNAC (n = 55) Enteral feeds (mL/kg/d) 0-14 days 12.2 19.0 0-21 days 17.6 20.7 0-28 days 25.8 20.7 NPO (days) 0-14 days 8.1 4.3 0-21 days 10.5 6.0 0-28 days 13.2 6.7 Intravenous protein (g/kg/d) 0-14 days 2.7 0.6 0-21 days 2.7 0.5 0-28 days 2.7 0.5 Intravenous glucose (g/kg/d) 0-14 days 10.4 1.1 0-21 days 10.7 1.3 0-28 days 10.6 1.3 Intravenous lipids (g/kg/d) 0-14 days 1.8 0.4 0-21 days 1.9 0.4 0-28 days 1.8 0.4
No PNAC (n = 390)
P
31.9 23.7 51.8 30.0 67.9 33.0
<.001 <.001 <.001
5.3 3.4 6.1 4.3 6.5 4.8
<.001 <.001 <.001
2.4 0.6 2.2 0.7 1.9 0.7
.001 <.001 <.001
9.4 1.6 8.5 2.2 7.5 2.5
<.001 <.001 <.001
1.6 0.4 1.4 0.5 1.3 0.5
.001 <.001 <.001
28 days of life was significantly higher in infants with PNAC (Table II). Among infants with PNAC, SGA infants had significantly lower BW, and they were more mature than appropriate for gestational age (AGA) infants (Table III). The morbidity rate was similar in the 2 groups, except for the NEC prevalence, more frequent among AGA infants. Duration of mechanical ventilation and of oxygen therapy, length of hospital stay, and mortality rate were similar between the 2 groups. The mean day of life at which PNAC was detected did not differ significantly between SGA and AGA infants; no differences resulted in the mean maximum value of direct bilirubin detected, as well as in the duration of PNAC. SGA infants received similar amount of enteral and parenteral intakes and showed similar days of fasting than AGA infants (Table III). Table III. Patient characteristics and nutritional data for infants with PNAC SGA (n = 17) Gestational age (w) Birth weight (g) BW z-score NEC (%) BPD (%) Bacterial sepsis (%) Mechanical ventilation (d) Oxygen therapy (d) Length of stay (d) Mortality (%) PNAC diagnosis (day of life) Max. direct bilirubin (mg/dL) PNAC duration (d) Enteral feed 0-28 days (mL/kg/d) NPO 0-28 days (d) IV protein 0-28 days (g/kg/d) IV glucose 0-28 days (g/kg/d) IV lipids 0-28 days (g/kg/d) IV, Intravenous.
28.5 3.0 680 204 2.15 0.74 0 6 (35.3) 10 (58.8) 30.9 38.3 63.6 67.6 114 55 4 (23.5) 25.3 10.6 4.9 1.6 30.0 12.5 24.8 17.8 12.7 6.5 2.7 0.4 10.9 1.2 1.9 0.4
AGA (n = 38)
P
27.0 2.1 .003 926 270 .001 0.23 0.77 <.0001 8 (21.0) .040 4 (10.5) .076 21 (55.3) .897 29.6 45.9 .919 61.9 73.9 .935 110 56 .806 7 (18.4) .661 28.5 10.3 .296 5.2 1.8 .557 28.4 11.6 .646 26.2 22.1 .819 13.5 6.8 .684 2.6 0.5 .471 10.5 1.3 .285 1.9 0.4 1
Among those variables significantly associated with PNAC in the univariate analysis, the stepwise regression analysis retained four variables, but only enteral feeding and oxygen therapy were independently associated with PNAC (Table IV). No association between BW z-score and PNAC was found.
Discussion In our study being SGA was not an independent risk factor for PNAC among VLBW infants treated with PN for at least 14 days, whereas early enteral feeding and oxygen therapy were found to be independent predictors. Mean enteral feeding intake from 0 to 21 days of life was negatively associated with PNAC; every 10 mL/kg enteral feeding increase during the first 21 days of life, there was a 34% risk reduction of PNAC. This finding is in agreement with several observations that identify the early lack of enteral feeding as the main positive predictor of PNAC.18 It has been shown that fasting has several metabolic and endocrine consequences on both gastrointestinal and liver function. The levels of gastrointestinal hormones, such as gastrin, motilin, glucose-dependent insulinotropic polypeptide, secretin, pancreatic polypeptide, glucagon, and vasoactive intestinal peptide are reduced in infants on PN not receiving enteral feeding.19,20 This may lead to reduced gall bladder contractility, and development of intestinal stasis. Intestinal stasis is associated with bacterial overgrowth, bacterial translocation, and sepsis.21 Sepsis, finally, could exacerbate cholestasis, as well as the production of lithocholic acid, which has been shown to be toxic to the liver.22,23 In our study oxygen therapy was the second independent predictor for PNAC; each additional week of oxygen therapy was associated to a 5% increased risk for PNAC. However, oxygen should not be considered toxic for the liver but rather as a proxy of the illness severity and therefore to the difficulty to receive and to sustain enteral feeding. The main results of our study are not in agreement with those of Robinson et al,11 who reported that SGA preterm infants, exposed to PN for at least 7 days, showed an increased risk for PNAC. This discrepancy could be due to several reasons. First, in our study we have carefully detailed the nutritional history in the first 28 days of life to focus on the role of PN before the onset of PNAC, whereas Robinson et al11 reported the total duration of PN exposure, precluding the possibility of identifying nutritional factors as independent predictors of PNAC. Second, we have chosen to include in
Table IV. Logistic regression analysis of factors influencing PNAC IV protein 0-21 days (g/kg/d) Enteral intake 0-21 days (10 mL/kg) Oxygen therapy (w) NEC
OR
95% CI
P
1.69 0.66 1.05 2.25
0.74, 3.50 0.53, 0.81 1.01, 1.09 0.79, 6.40
.210 <.001 .030 .127
IV, Intravenous.
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our series only those infants who received PN for more than 14 days rather than the 7 days in the series by Robinson et al11; this decision resulted from some histopathologic data showing that patients with a total PN duration less than 2 weeks have no or only mild degrees of fibrosis, and patients with more than 6 weeks of total PN develop moderate-to-severe fibrosis.24 Third, in both studies, information about the prevalence of intrauterine growth restriction (IUGR) among the SGA infants is missing. Robinson et al11 reported maternal conditions that may have contributed to uteroplacental insufficiency, but they were not able to indicate if their infants were really intrauterine growth retarded. IUGR condition is defined as an impaired growth and development of the embryo/fetus during pregnancy and is ideally detected by a diminished growth velocity of the fetus on serial ultrasonographic scans25; therefore not all IUGR infants are SGA infants, and not all SGA infants have IUGR. Baserga et al26 reported a higher incidence of PNAC in extremely low-birth weight-SGA infants with an obstetric history of IUGR. They suggested that IUGR, because of uteroplacental insufficiency, is the main condition that predisposes preterm infants to development of PNAC. In their study SGA infants who had a higher incidence of PNAC also had a higher number of feeding intolerance episodes, reached well-sustained feeds significantly later, and received higher intravenous glucose and lipid intake as compared with AGA infants. Moreover, no attempt to adjust for confounders was performed. In our study, among the independent variables not associated with PNAC, there were also intravenous non-protein calories and protein intake. This finding could be related to the exclusive use of parenteral amino-acid solutions appropriate for newborn infants and to intravenous intakes provided during the study, not high enough to significantly impair liver function. Indeed, our infants received a mean daily protein and lipid intake quite lower than the amount usually reported to be associated with PNAC.2,3,27 Moreover, the use of strict nutritional guidelines allowed us to obtain uniform intravenous intakes among all infants. The strength of our study is based on the large number of infants, and on the carefully detailed analysis of the actual nutritional intakes in the first 28 days of life to focus on the role of PN before the onset of PNAC. However, because of the retrospective design of the study, we were unable to obtain details about the prevalence of IUGR infants, and we cannot speculate on its potential role on PNAC development. Our data suggest that early enteral feeding remains the main factor for the prevention of PNAC in VLBW infants and that, in our setting, SGA infants did not show an increased risk of PNAC. Further prospective studies are needed to test the causative role of IUGR on PNAC in AGA infants. n Submitted for publication Feb 23, 2009; last revision received Sep 29, 2009; accepted Oct 28, 2009. Reprint requests: Simonetta Costa, MD, Division of Neonatology, Department of Paediatrics, Largo A. Gemelli 8, 00168 - Rome – Italy. E-mail: simocosta@ yahoo.it.
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References 1. Kubota A, Okada A, Nezu R, Kamata S, Imura K, Takagi Y. Hyperbilirubinemia in neonates associated with total parenteral nutrition. JPEN 1988;12:602-6. 2. Wright K, Ernst KD, Gaylord MS, Dawson JP, Burnette TM. Increased incidence of parenteral nutrition-associated cholestasis with Aminosyn PF compared to Trophamine. J Perinatol 2003;23:444-50. 3. Shin JI, Namgung R, Park MS, Lee C. Could lipid infusion be a risk for parenteral nutrition-associated cholestasis in low birth weight neonates? Eur J Pediatr 2008;167:197-202. 4. Von Stockhausen HB, Schrod L, Bratter P, Rosick U. Aluminium loading in premature infants during intensive care as related to clinical aspects. J Trace Elem Electrolytes Health Dis 1990;4:209-13. 5. Fok TF, Chui KKM, Cheung R, Ng PC, Cheung KL, Hjelm M. Manganese intake and cholestatic jaundice in neonates receiving parenteral nutrition: a randomized controlled study. Acta Pediatr 2001; 90:1009-15. 6. Kaufman SS, Gondolesi GE, Fishbein TM. Parenteral nutrition associated liver disease. Sem Neonatol 2003;8:375-81. 7. Drongowski RA, Coran AG. An analysis of factors contributing to the development of total parenteral nutrition-induced cholestasis. JPEN J Parenter Enteral Nutr 1989;13:586-9. 8. Kelly DA. Liver complications of pediatric parenteral nutrition-epidemiology. Nutrition 1998;14:153-7. 9. Kaufman SS, Gondolesi GE, Fishbein TM. Parenteral nutrition associated liver disease. Semin Neonatol 2003;8:375-81. 10. Moss RL, Das JB, Raffensperger JG. Necrotizing enterocolitis and total parenteral nutrition-associated cholestasis. Nutrition 1996;12: 340-3. 11. Robinson DT, Ehrenkranz RA. Parenteral nutrition-associated cholestasis in small for gestational age infants. J Pediatr 2008;152:59-62. 12. Teitelbaum DH. Parenteral nutrition-associated cholestasis. Curr Opin Pediatr 1997;9:270-5. 13. McLin VA, Balistreri WF. Approach to neonatal cholestasis. In: Walker WA, Goulet O, Kleinman RE, Sherman PM, Shneider BL, Sanderson IR, eds. Pediatric gastrointestinal disease. Volume 2. 4th ed. Ontario, Canada: B. C. Decker; 2004:1079-93. 14. Gura KM, Duggan CP, Collier SB, Jennings RW, Folkman J, Bistrian BR, Puder M. Reversal of parenteral nutrition-associated liver disease in two infants with short bowel syndrome using parenteral fish oil: implications for future management. Pediatrics 2006;118:197-201. 15. Gagliardi L, Macagno F, Pedrotti D, Coraiola M, Furlan R, Agostinis L, et al. Standard antropometrici neonatali prodotti dalla task-force della Societa` Italiana di Neonatologia e basati su una popolazione italiana nord-orientale. Riv Ital Pediatr 1999;25:159-69. 16. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-9. 17. Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based on clinical staging. Ann Surg 1978;187:1-7. 18. Kaufman SS. Prevention of parenteral nutrition-associated liver disease in children. Pediatr Transplant 2002;6:37-42. 19. Greenberg G, Wolman S, Christofides N, Bloom SR, JeeJeedhoy KN. Effect of total parenteral nutrition on gut hormone release in human. Gastroenterology 1981;80:988-93. 20. Teitelbaum DH, Han-Markey T, Schumacher RE. Treatment of parenteral nutrition-associated cholestasis with cholecystokinin-octapeptide. J Pediatr Surg 1995;30:1082-5. 21. Lucas A, Bloom SR, Ainsley-Green A. Metabolic and endocrine consequences of depriving preterm infants of enteral nutrition. Acta Paediatr Scand 1983;72:245-9. 22. Pierro A, van Saene HK, Jones MO, Brown D, Nunn AJ, Lloyd DA. Clinical impact of abnormal gut flora in infants receiving parenteral nutrition. Am Surg 1998;227:547-52. 23. Demircan M, Ergun O, Avanoglu S, Yilmaz F, Ozok G. Determination of serum bile acids routinely may prevent delay in diagnosis
Costa et al
April 2010 of total parenteral nutrition-induced cholestasis. J Pediatr Surg 1999; 34:565-7. 24. Zambrano E, El-Hennawy M, Ehrenkranz RA, Zelterman D, ReyesMu´gica M. Total parenteral nutrition induced liver pathology: an autopsy series of 24 newborn cases. Pediatrs Dev Pathol 2004;7: 425-32. 25. Lee PA, Chernausek SD, Hokken-Koelega ACS, Czernichow P. International small for gestational age board consensus development conference
ORIGINAL ARTICLES statement: management of short children born small for gestational age, April 24-October 1, 2001. Pediatrics 2003;111:1253-61. 26. Baserga MC, Sola A. Intrauterine growth restriction impacts tolerance to total parenteral nutrition in extremely low birth weight infants. J Perinatol 2004;24:476-81. 27. Vileisis RA, Inwood RJ, Hunt CE. Prospective controlled study of parenteral nutrition-associated cholestatic jaundice: effect of protein intake. J Pediatr 1980;96:893-7.
50 Years Ago in THE JOURNAL OF PEDIATRICS Practices and Pitfalls in the Early Detection and Control of Heart Disease in Children Hubbard JP. J Pediatr 1960;56:544-50
I
n 1960, Hubbard summarized all that was then known regarding the causes of heart disease in children. At that time, rheumatic heart disease (RHD) and the cardiac complications of prenatal exposure to maternal Rubella were the only forms of pediatric heart disease with a defined cause. In 2009, of course, congenital heart disease (CHD) is well known to be associated with prenatal exposure to a number of teratogenic agents, both chemical and infectious, and the genetic cause of many defects is well documented. Indeed, it would appear likely that essentially all CHD is caused by the prenatal environment, the genetic makeup of the child, or a combination. Hubbard also commented on primary and secondary prevention, at least of acute rheumatic fever (ARF), documenting the widespread carriage of beta-hemolytic streptococci in asymptomatic children, the rather nonspecific clinical features of streptococcal pharyngitis, and the role of throat cultures in the definitive diagnosis of ‘‘strep throat.’’ Now, of course, the developed world has access to rapid strep screens, which supplement, but do not replace, throat cultures. Hubbard also pointed out the role of penicillin in the primary and secondary prevention of ARF. Fortunately, the incidence of ARF has continued to decrease, at least in the developed world, and antibiotic treatment of streptococcal pharyngitis is indicated only in those with a confirmatory bacteriologic test. One could argue, however, that in areas of the developing world, where the incidence of ARF is dramatically higher and the availability of reliable laboratory evaluation is limited, it may be more efficacious to simply treat all children with symptoms with an appropriate antibiotic without bacteriologic documentation. In 1960, the diagnosis of RHD, as well as CHD, was largely dependent on the auscultatory skills of the examiner, with judicious use of simple radiographic procedures, electrocardiography, and phonocardiography. Although these still play a vital role for screening purposes, echocardiography, computed tomography, and magnetic resonance imaging have become exceptionally important. Indeed, echocardiography has sometimes replaced skilled auscultation in the evaluation of heart murmurs. This practice is to be discouraged because the responsibility of ‘‘skill’’ is then transferred to the sonographer and the interpreting physician, neither of whom may have significant experience in pediatric echocardiography. In addition, it is far too expensive to be used as a screening test. RHD is largely conquered in the developed world. Sadly, CHD hasn’t suffered the same fate. Warren H. Toews, MD The Heart Center Seattle Children’s Hospital Seattle, Washington 10.1016/j.jpeds.2009.11.052
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P
arenteral nutrition (PN) plays an important role in the neonatal intensive care unit, and it can be life saving for critically ill newborn babies who are unable to receive adequate enteral nourishment. However, exposure to PN is demonstrated as the main factor in the development of cholestasis in preterm infants. Several risk factors related to intravenous hyperalimentation have been implicated in the development of parenteral nutrition–associated cholestasis (PNAC), such as the total caloric overload, the quality of amino acid solutions, the cumulative amount of lipid infusion, the presence of excessive aluminium in the PN solution, and the high manganese intake with PN.1-5 Moreover, sepsis, necrotizing enterocolitis (NEC), bowel surgery, and lack of enteral feeding were suggested as potential contributors to the development of PNAC.6-10 It has recently been suggested that being small for gestational age (SGA) is an independent risk factor for PNAC.11 The aim of our study was to assess in our population of very low–birth weight (VLBW) infants, whether being SGA is one of the independent risk factors for PNAC.
Methods We performed a retrospective review of all infants with birth weight # 1500 g assisted in our neonatal intensive care unit (NICU) from January 1, 1996, to December 31, 2006, who received PN for more than 14 days and who were still alive at 28 days of life. PNAC was defined as direct bilirubin greater than 2.0 mg/dL persistent for at least 2 consecutive tests during the administration of PN, not associated with other known causes of cholestasis.1,12-14 Infants with cholestasis caused by genetic or metabolic disorders, congenital infections, extrahepatic obstructions, or congenital gastrointestinal disorders requiring surgery were excluded from the study. In all infants who received PN, direct bilirubin level was tested weekly. Auxological and clinical data, as well as a complete and detailed nutritional hisAGA Appropriate for gestational age tory, were collected in all infants during BPD Bronchopulmonary dysplasia the first 28 days of life. Gestational age BW Birth weight GA IUGR NEC NICU PN PNAC SGA VLBW
Gestational age Intrauterine growth restriction Necrotizing enterocolitis Neonatal intensive care unit Parenteral nutrition Parenteral nutrition associated cholestasis Small for gestational age Very low birth weight
From the Division of Neonatology, Department of Paediatrics, Catholic University Sacred Heart (S.C., L.M. P.S., F.C., M.C., C.R.), Rome, Italy The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright Ó 2010 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.10.038
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was determined by the best obstetric estimate on the basis of the first day of the last menstrual period, prenatal ultrasound, and postnatal physical examination. SGA infants were defined with the Italian intrauterine reference values as those whose birth weight z-score was below 1.28.15 Among the main morbidities, bronchopulmonary dysplasia (BPD) was defined according to the most recent definitions16; necrotizing enterocolitis (NEC) was diagnosed according to the criteria of Bell, and only infants with a grade above IIa were considered as affected17; sepsis was defined by positive blood or cerebrospinal fluid cultures and typical clinical signs. Duration of oxygen therapy, mechanical ventilation, antibiotic treatment, as well as mortality rate and length of hospital stay were also considered. The nutritional history included the number of days without any enteral intake during the first 28 days of life, as well as the amount of enteral and intravenous daily intakes. Two separate NICU databases were used as information sources: a nutrition database recording details about parenteral and enteral feeding, and a neonatal database containing demographic details, antenatal and perinatal history, postdelivery status, neonatal diagnosis, procedures, therapies, complications, and main outcomes at discharge. Data from the 2 databases and a review of the single medical records were entered into a single study database for the retrospective analysis. PN was started for all VLBW infants within the first 24 hours of life; progression of nutrient intakes was regulated with an electronic decision-support program developed by our unit. Nutritional guidelines provided that infants were started at 1 to 2 g/kg/d of protein (Trophamine 6%), and increased to achieve a maximum of 3.5 -4.0 g/kg/day within the first week of life. Intravenous lipids (Intralipid 20%) were started at 0.5 g/kg/d and increased to a maximum of 3.0 g/ kg/d at day 7 of life. Glucose administration was started with an infusion of 6 g/kg/day and advanced to a maximum of 12 to 14 g/kg/d, according to the daily infant’s glycemic tolerance. Caregivers, using a computer in the NICU, could confirm or modify the recommended dosages looking at the individual infant. PN was stopped when infants were able to tolerate approximately 120 mL/kg/day of enteral feeding and showed sustained growth, defined by at least 15 g/kg/ day, during the last 72 hours. Enteral feeding was planned to start within the first 24 to 120 hours of life with mother’s milk, or with pasteurized pooled premature human milk; subsequently, infants were fed their own mother’s milk fortified with Eoprotin (Milupa, Milan, Italy) when an intake of 100 mL/kg was well tolerated, and never before day 14 of life. When there were difficulties in obtaining sufficient quantities of human milk, or a mother was not able to supply her own milk, infants were fed, partially or totally, with a preterm formula. Statistical Analysis Results are showed as mean standard deviation (SD) for the continuous variables, and as percentages for the categorical variables. The groups were compared by use of the Student t test for parametric data, and the Wilcoxon rank-sum 576
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Table I. Data at birth, morbidity rates, and therapies of infants with and without PNAC, during hospital stay PNAC (n = 55) Gestational age (w) Birth weight (g) Male/Female BW z-score BW z-score < 1.28 (%) NEC (%) BPD (%) Sepsis (%) Antibiotic therapy (n of cycles) Mechanical ventilation (days) Oxygen therapy (days) Length of stay (days) Mortality rate (%)
27.4 2.5 850 274 32/23 0.82 1.17 17 (30.9) 8 (14.5) 10 (18.2) 31 (56.4) 5.3 3.3 30.1 43.4 59.4 69.6 111 55 11 (20)
No PNAC (n = 390)
P
28.7 2.3 1052 238 175/215 0.60 1.11 112 (28.7) 13 (3.3) 19 (4.9) 98 (25.1) 2.4 2.1 11.2 18.5 21.6 36.3 69 36 5 (1.3)
<.001 <.001 .083 .175 .752 .002 .001 <.001 <.001 <.001 <.001 .002 <.001
test (Mann Whitney U test) for nonparametric data. Categorical variables were compared by use of the Fisher exact test. Multivariate analysis was conducted by logistic regression to define the role of specific factors that may affect PNAC. All the variables significantly associated to PNAC after the univariate analysis were entered into the initial model. Backward stepwise selection was used to select the variables to enter in the final model with a significance level for the removal and the addition, respectively, of 0.3 and 0.2. A 2-tailed value of P < .05 was considered significant. Statistical analysis was performed with the Stata Statistical Software: Release 10 (Stata Corp LP, College Station, Texas).
Results During the study period 445 VLBW infants who met the inclusion criteria were identified, and 55 of them (12.3%) had development of PNAC. The mean day of life at which cholestasis was detected was 27.3 10.8. The diagnosis of PNAC was made in 6 (11%) infants during the fourth week of life, in 16 infants (29%) during the fifth week of life, and in 33 infants (60%) after the fifth week of life. The mean maximum value of direct bilirubin was 5.1 1.7 mg/dL. The mean duration of PNAC was 28.3 12.9 days. Infants who had development of PNAC were significantly more immature and smaller than those without PNAC; the mean birth weight (BW) z-score was similar between the 2 groups, as well as the percentage of infants with a BW z-score below –1.28 (Table I). Infants with PNAC had a higher incidence of main morbidities, required a longer duration of mechanical ventilation and supplemental oxygen, and showed a longer hospital stay and a higher mortality rate than infants without PNAC (Table I). Infants with PNAC received a significantly lower amount of enteral nutrition from 0 to 14, 0 to 21, and 0 to 28 days of life and needed a longer period of fasting as compared with infants who did not have development of PNAC (Table II). The mean amount of intravenous protein, glucose, and lipids from 0 to 14, 0 to 21, and 0 to Costa et al
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Table II. Nutritional data of infants with and without PNAC PNAC (n = 55) Enteral feeds (mL/kg/d) 0-14 days 12.2 19.0 0-21 days 17.6 20.7 0-28 days 25.8 20.7 NPO (days) 0-14 days 8.1 4.3 0-21 days 10.5 6.0 0-28 days 13.2 6.7 Intravenous protein (g/kg/d) 0-14 days 2.7 0.6 0-21 days 2.7 0.5 0-28 days 2.7 0.5 Intravenous glucose (g/kg/d) 0-14 days 10.4 1.1 0-21 days 10.7 1.3 0-28 days 10.6 1.3 Intravenous lipids (g/kg/d) 0-14 days 1.8 0.4 0-21 days 1.9 0.4 0-28 days 1.8 0.4
No PNAC (n = 390)
P
31.9 23.7 51.8 30.0 67.9 33.0
<.001 <.001 <.001
5.3 3.4 6.1 4.3 6.5 4.8
<.001 <.001 <.001
2.4 0.6 2.2 0.7 1.9 0.7
.001 <.001 <.001
9.4 1.6 8.5 2.2 7.5 2.5
<.001 <.001 <.001
1.6 0.4 1.4 0.5 1.3 0.5
.001 <.001 <.001
28 days of life was significantly higher in infants with PNAC (Table II). Among infants with PNAC, SGA infants had significantly lower BW, and they were more mature than appropriate for gestational age (AGA) infants (Table III). The morbidity rate was similar in the 2 groups, except for the NEC prevalence, more frequent among AGA infants. Duration of mechanical ventilation and of oxygen therapy, length of hospital stay, and mortality rate were similar between the 2 groups. The mean day of life at which PNAC was detected did not differ significantly between SGA and AGA infants; no differences resulted in the mean maximum value of direct bilirubin detected, as well as in the duration of PNAC. SGA infants received similar amount of enteral and parenteral intakes and showed similar days of fasting than AGA infants (Table III). Table III. Patient characteristics and nutritional data for infants with PNAC SGA (n = 17) Gestational age (w) Birth weight (g) BW z-score NEC (%) BPD (%) Bacterial sepsis (%) Mechanical ventilation (d) Oxygen therapy (d) Length of stay (d) Mortality (%) PNAC diagnosis (day of life) Max. direct bilirubin (mg/dL) PNAC duration (d) Enteral feed 0-28 days (mL/kg/d) NPO 0-28 days (d) IV protein 0-28 days (g/kg/d) IV glucose 0-28 days (g/kg/d) IV lipids 0-28 days (g/kg/d) IV, Intravenous.
28.5 3.0 680 204 2.15 0.74 0 6 (35.3) 10 (58.8) 30.9 38.3 63.6 67.6 114 55 4 (23.5) 25.3 10.6 4.9 1.6 30.0 12.5 24.8 17.8 12.7 6.5 2.7 0.4 10.9 1.2 1.9 0.4
AGA (n = 38)
P
27.0 2.1 .003 926 270 .001 0.23 0.77 <.0001 8 (21.0) .040 4 (10.5) .076 21 (55.3) .897 29.6 45.9 .919 61.9 73.9 .935 110 56 .806 7 (18.4) .661 28.5 10.3 .296 5.2 1.8 .557 28.4 11.6 .646 26.2 22.1 .819 13.5 6.8 .684 2.6 0.5 .471 10.5 1.3 .285 1.9 0.4 1
Among those variables significantly associated with PNAC in the univariate analysis, the stepwise regression analysis retained four variables, but only enteral feeding and oxygen therapy were independently associated with PNAC (Table IV). No association between BW z-score and PNAC was found.
Discussion In our study being SGA was not an independent risk factor for PNAC among VLBW infants treated with PN for at least 14 days, whereas early enteral feeding and oxygen therapy were found to be independent predictors. Mean enteral feeding intake from 0 to 21 days of life was negatively associated with PNAC; every 10 mL/kg enteral feeding increase during the first 21 days of life, there was a 34% risk reduction of PNAC. This finding is in agreement with several observations that identify the early lack of enteral feeding as the main positive predictor of PNAC.18 It has been shown that fasting has several metabolic and endocrine consequences on both gastrointestinal and liver function. The levels of gastrointestinal hormones, such as gastrin, motilin, glucose-dependent insulinotropic polypeptide, secretin, pancreatic polypeptide, glucagon, and vasoactive intestinal peptide are reduced in infants on PN not receiving enteral feeding.19,20 This may lead to reduced gall bladder contractility, and development of intestinal stasis. Intestinal stasis is associated with bacterial overgrowth, bacterial translocation, and sepsis.21 Sepsis, finally, could exacerbate cholestasis, as well as the production of lithocholic acid, which has been shown to be toxic to the liver.22,23 In our study oxygen therapy was the second independent predictor for PNAC; each additional week of oxygen therapy was associated to a 5% increased risk for PNAC. However, oxygen should not be considered toxic for the liver but rather as a proxy of the illness severity and therefore to the difficulty to receive and to sustain enteral feeding. The main results of our study are not in agreement with those of Robinson et al,11 who reported that SGA preterm infants, exposed to PN for at least 7 days, showed an increased risk for PNAC. This discrepancy could be due to several reasons. First, in our study we have carefully detailed the nutritional history in the first 28 days of life to focus on the role of PN before the onset of PNAC, whereas Robinson et al11 reported the total duration of PN exposure, precluding the possibility of identifying nutritional factors as independent predictors of PNAC. Second, we have chosen to include in
Table IV. Logistic regression analysis of factors influencing PNAC IV protein 0-21 days (g/kg/d) Enteral intake 0-21 days (10 mL/kg) Oxygen therapy (w) NEC
OR
95% CI
P
1.69 0.66 1.05 2.25
0.74, 3.50 0.53, 0.81 1.01, 1.09 0.79, 6.40
.210 <.001 .030 .127
IV, Intravenous.
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our series only those infants who received PN for more than 14 days rather than the 7 days in the series by Robinson et al11; this decision resulted from some histopathologic data showing that patients with a total PN duration less than 2 weeks have no or only mild degrees of fibrosis, and patients with more than 6 weeks of total PN develop moderate-to-severe fibrosis.24 Third, in both studies, information about the prevalence of intrauterine growth restriction (IUGR) among the SGA infants is missing. Robinson et al11 reported maternal conditions that may have contributed to uteroplacental insufficiency, but they were not able to indicate if their infants were really intrauterine growth retarded. IUGR condition is defined as an impaired growth and development of the embryo/fetus during pregnancy and is ideally detected by a diminished growth velocity of the fetus on serial ultrasonographic scans25; therefore not all IUGR infants are SGA infants, and not all SGA infants have IUGR. Baserga et al26 reported a higher incidence of PNAC in extremely low-birth weight-SGA infants with an obstetric history of IUGR. They suggested that IUGR, because of uteroplacental insufficiency, is the main condition that predisposes preterm infants to development of PNAC. In their study SGA infants who had a higher incidence of PNAC also had a higher number of feeding intolerance episodes, reached well-sustained feeds significantly later, and received higher intravenous glucose and lipid intake as compared with AGA infants. Moreover, no attempt to adjust for confounders was performed. In our study, among the independent variables not associated with PNAC, there were also intravenous non-protein calories and protein intake. This finding could be related to the exclusive use of parenteral amino-acid solutions appropriate for newborn infants and to intravenous intakes provided during the study, not high enough to significantly impair liver function. Indeed, our infants received a mean daily protein and lipid intake quite lower than the amount usually reported to be associated with PNAC.2,3,27 Moreover, the use of strict nutritional guidelines allowed us to obtain uniform intravenous intakes among all infants. The strength of our study is based on the large number of infants, and on the carefully detailed analysis of the actual nutritional intakes in the first 28 days of life to focus on the role of PN before the onset of PNAC. However, because of the retrospective design of the study, we were unable to obtain details about the prevalence of IUGR infants, and we cannot speculate on its potential role on PNAC development. Our data suggest that early enteral feeding remains the main factor for the prevention of PNAC in VLBW infants and that, in our setting, SGA infants did not show an increased risk of PNAC. Further prospective studies are needed to test the causative role of IUGR on PNAC in AGA infants. n Submitted for publication Feb 23, 2009; last revision received Sep 29, 2009; accepted Oct 28, 2009. Reprint requests: Simonetta Costa, MD, Division of Neonatology, Department of Paediatrics, Largo A. Gemelli 8, 00168 - Rome – Italy. E-mail: simocosta@ yahoo.it.
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References 1. Kubota A, Okada A, Nezu R, Kamata S, Imura K, Takagi Y. Hyperbilirubinemia in neonates associated with total parenteral nutrition. JPEN 1988;12:602-6. 2. Wright K, Ernst KD, Gaylord MS, Dawson JP, Burnette TM. Increased incidence of parenteral nutrition-associated cholestasis with Aminosyn PF compared to Trophamine. J Perinatol 2003;23:444-50. 3. Shin JI, Namgung R, Park MS, Lee C. Could lipid infusion be a risk for parenteral nutrition-associated cholestasis in low birth weight neonates? Eur J Pediatr 2008;167:197-202. 4. Von Stockhausen HB, Schrod L, Bratter P, Rosick U. Aluminium loading in premature infants during intensive care as related to clinical aspects. J Trace Elem Electrolytes Health Dis 1990;4:209-13. 5. Fok TF, Chui KKM, Cheung R, Ng PC, Cheung KL, Hjelm M. Manganese intake and cholestatic jaundice in neonates receiving parenteral nutrition: a randomized controlled study. Acta Pediatr 2001; 90:1009-15. 6. Kaufman SS, Gondolesi GE, Fishbein TM. Parenteral nutrition associated liver disease. Sem Neonatol 2003;8:375-81. 7. Drongowski RA, Coran AG. An analysis of factors contributing to the development of total parenteral nutrition-induced cholestasis. JPEN J Parenter Enteral Nutr 1989;13:586-9. 8. Kelly DA. Liver complications of pediatric parenteral nutrition-epidemiology. Nutrition 1998;14:153-7. 9. Kaufman SS, Gondolesi GE, Fishbein TM. Parenteral nutrition associated liver disease. Semin Neonatol 2003;8:375-81. 10. Moss RL, Das JB, Raffensperger JG. Necrotizing enterocolitis and total parenteral nutrition-associated cholestasis. Nutrition 1996;12: 340-3. 11. Robinson DT, Ehrenkranz RA. Parenteral nutrition-associated cholestasis in small for gestational age infants. J Pediatr 2008;152:59-62. 12. Teitelbaum DH. Parenteral nutrition-associated cholestasis. Curr Opin Pediatr 1997;9:270-5. 13. McLin VA, Balistreri WF. Approach to neonatal cholestasis. In: Walker WA, Goulet O, Kleinman RE, Sherman PM, Shneider BL, Sanderson IR, eds. Pediatric gastrointestinal disease. Volume 2. 4th ed. Ontario, Canada: B. C. Decker; 2004:1079-93. 14. Gura KM, Duggan CP, Collier SB, Jennings RW, Folkman J, Bistrian BR, Puder M. Reversal of parenteral nutrition-associated liver disease in two infants with short bowel syndrome using parenteral fish oil: implications for future management. Pediatrics 2006;118:197-201. 15. Gagliardi L, Macagno F, Pedrotti D, Coraiola M, Furlan R, Agostinis L, et al. Standard antropometrici neonatali prodotti dalla task-force della Societa` Italiana di Neonatologia e basati su una popolazione italiana nord-orientale. Riv Ital Pediatr 1999;25:159-69. 16. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-9. 17. Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based on clinical staging. Ann Surg 1978;187:1-7. 18. Kaufman SS. Prevention of parenteral nutrition-associated liver disease in children. Pediatr Transplant 2002;6:37-42. 19. Greenberg G, Wolman S, Christofides N, Bloom SR, JeeJeedhoy KN. Effect of total parenteral nutrition on gut hormone release in human. Gastroenterology 1981;80:988-93. 20. Teitelbaum DH, Han-Markey T, Schumacher RE. Treatment of parenteral nutrition-associated cholestasis with cholecystokinin-octapeptide. J Pediatr Surg 1995;30:1082-5. 21. Lucas A, Bloom SR, Ainsley-Green A. Metabolic and endocrine consequences of depriving preterm infants of enteral nutrition. Acta Paediatr Scand 1983;72:245-9. 22. Pierro A, van Saene HK, Jones MO, Brown D, Nunn AJ, Lloyd DA. Clinical impact of abnormal gut flora in infants receiving parenteral nutrition. Am Surg 1998;227:547-52. 23. Demircan M, Ergun O, Avanoglu S, Yilmaz F, Ozok G. Determination of serum bile acids routinely may prevent delay in diagnosis
Costa et al
April 2010 of total parenteral nutrition-induced cholestasis. J Pediatr Surg 1999; 34:565-7. 24. Zambrano E, El-Hennawy M, Ehrenkranz RA, Zelterman D, ReyesMu´gica M. Total parenteral nutrition induced liver pathology: an autopsy series of 24 newborn cases. Pediatrs Dev Pathol 2004;7: 425-32. 25. Lee PA, Chernausek SD, Hokken-Koelega ACS, Czernichow P. International small for gestational age board consensus development conference
ORIGINAL ARTICLES statement: management of short children born small for gestational age, April 24-October 1, 2001. Pediatrics 2003;111:1253-61. 26. Baserga MC, Sola A. Intrauterine growth restriction impacts tolerance to total parenteral nutrition in extremely low birth weight infants. J Perinatol 2004;24:476-81. 27. Vileisis RA, Inwood RJ, Hunt CE. Prospective controlled study of parenteral nutrition-associated cholestatic jaundice: effect of protein intake. J Pediatr 1980;96:893-7.
50 Years Ago in THE JOURNAL OF PEDIATRICS Practices and Pitfalls in the Early Detection and Control of Heart Disease in Children Hubbard JP. J Pediatr 1960;56:544-50
I
n 1960, Hubbard summarized all that was then known regarding the causes of heart disease in children. At that time, rheumatic heart disease (RHD) and the cardiac complications of prenatal exposure to maternal Rubella were the only forms of pediatric heart disease with a defined cause. In 2009, of course, congenital heart disease (CHD) is well known to be associated with prenatal exposure to a number of teratogenic agents, both chemical and infectious, and the genetic cause of many defects is well documented. Indeed, it would appear likely that essentially all CHD is caused by the prenatal environment, the genetic makeup of the child, or a combination. Hubbard also commented on primary and secondary prevention, at least of acute rheumatic fever (ARF), documenting the widespread carriage of beta-hemolytic streptococci in asymptomatic children, the rather nonspecific clinical features of streptococcal pharyngitis, and the role of throat cultures in the definitive diagnosis of ‘‘strep throat.’’ Now, of course, the developed world has access to rapid strep screens, which supplement, but do not replace, throat cultures. Hubbard also pointed out the role of penicillin in the primary and secondary prevention of ARF. Fortunately, the incidence of ARF has continued to decrease, at least in the developed world, and antibiotic treatment of streptococcal pharyngitis is indicated only in those with a confirmatory bacteriologic test. One could argue, however, that in areas of the developing world, where the incidence of ARF is dramatically higher and the availability of reliable laboratory evaluation is limited, it may be more efficacious to simply treat all children with symptoms with an appropriate antibiotic without bacteriologic documentation. In 1960, the diagnosis of RHD, as well as CHD, was largely dependent on the auscultatory skills of the examiner, with judicious use of simple radiographic procedures, electrocardiography, and phonocardiography. Although these still play a vital role for screening purposes, echocardiography, computed tomography, and magnetic resonance imaging have become exceptionally important. Indeed, echocardiography has sometimes replaced skilled auscultation in the evaluation of heart murmurs. This practice is to be discouraged because the responsibility of ‘‘skill’’ is then transferred to the sonographer and the interpreting physician, neither of whom may have significant experience in pediatric echocardiography. In addition, it is far too expensive to be used as a screening test. RHD is largely conquered in the developed world. Sadly, CHD hasn’t suffered the same fate. Warren H. Toews, MD The Heart Center Seattle Children’s Hospital Seattle, Washington 10.1016/j.jpeds.2009.11.052
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