- Email: [email protected]
Thiamine Deficiency and Cardiac Dysfunction in Cambodian Infants
Thiamine Deficiency and Cardiac Dysfunction in Cambodian Infants Samuel G. Porter, BS1, Debra Coats, MSN2, Philip R. Fischer, MD3, Kevanna Ou, MD4, Elizabeth L. Frank, PhD5, Phivan Sreang, BSN6, Soksan Saing, MD6, Mark D. Topazian, MD7, Felicity T. Enders, PhD8, and Allison K. Cabalka, MD9 Objectives To compare blood thiamine concentrations, echocardiography findings, and plasma N-terminal proB-type natriuretic peptide (NT-proBNP) levels in infants with clinically diagnosed beriberi and healthy matched controls, and to evaluate changes after thiamine treatment. Study design Sixty-two Cambodian infants (20 cases and 42 controls), aged 2-47 weeks, were enrolled in this prospective study. Echocardiography and phlebotomy were performed at baseline and after thiamine treatment. Results Both cases and controls were thiamine-deficient, with median blood thiamine diphosphate (TDP) concentrations of 47.6 and 55.1 nmol/L, respectively (P = .23). All subjects had normal left ventricular ejection fraction. The median NT-proBNP concentration in cases (340 pg/mL [40.1 pmol/L]) was higher than previously reported normal ranges, but not statistically significantly different from that in controls (175 pg/mL [20.7 pmol/L]) (P = .10), and was not correlated with TDP concentration (P = .13). Two cases with the lowest baseline TDP concentrations (24 and 21 nmol/L) had right ventricular enlargement and elevated NT-proBNP levels that improved dramatically by 48 hours after thiamine administration. Conclusion Only a minority of thiamine-deficient Cambodian infants demonstrate abnormal echocardiography findings. Thiamine deficiency produces echocardiographic evidence of right ventricular dysfunction, but this evidence is not apparent until deficiency is severe. NT-proBNP concentrations are mildly elevated in sick infants with normal echocardiography findings, indicating possible physiological changes not yet associated with echocardiographic abnormalities. (J Pediatr 2014;164:1456-61).
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et beriberi, a disease caused by thiamine deficiency, is a common diagnosis in parts of Southeast Asia.1,2 Thiamine deficiency is widespread among nursing mothers and their breast-fed infants in Prey Veng Province, Cambodia. Mothers in this region efficiently absorb oral thiamine and secrete it in breast milk, but they consume only approximately one-half of the recommended daily intake of thiamine, implicating maternal dietary inadequacy as the cause of infant thiamine deficiency.3-5 Further studies in this area of Cambodia found that up to one-half of deaths during the first year of life may be attributable to beriberi, but that both infants with a clinical diagnosis of beriberi and apparently healthy matched control infants have low thiamine diphosphate (TDP) concentrations.4,6 This implies that thiamine deficiency, as defined by reference ranges for US children with thiamine deficiency, is not necessarily sufficient to cause wet beriberi. The clinical diagnosis of wet beriberi is made when signs of congestive heart failure are present (tachypnea, tachycardia, wheezing, hepatomegaly), often with dysphonia, and the child improves after receiving thiamine.7 Autopsy data from infants with wet beriberi show right ventricular (RV) dilation and hypertrophy, with relative sparing of the left ventricle.8,9 The few available reports on echocardiography in infants with wet beriberi describe tricuspid regurgitation, right heart From the Mayo Medical School, College of Medicine, dilation, and pulmonary hypertension that resolved after thiamine therapy.10,11 Rochester, MN; Eastern Mennonite Missions, Prey Veng, Cambodia; Department of Pediatric and No previous studies have correlated echocardiographic assessment with blood Adolescent Medicine, Mayo Clinic, Rochester, MN; National Maternal and Child Health Center, University of thiamine or plasma N-terminal pro-B type natriuretic peptide (NT-proBNP) Health Science, Phnom Penh, Cambodia; Department of Pathology, University of Utah Health Sciences Center, concentrations in children with beriberi. Salt Lake City, UT; Department of Family Medicine, The specific aims of the present study were: (1) to use portable echocardiogInternational University, Phnom Penh, Cambodia; and Division of Gastroenterology and Hepatology, raphy to compare cardiac function in infants with clinical signs of wet beriberi Department of Medicine, Department of Biomedical Statistics and Informatics, and Division of Pediatric and apparently healthy control infants; (2) to evaluate cardiac changes in infants Cardiology, Department of Pediatric and Adolescent with clinically diagnosed beriberi over the first 48 hours of treatment; and (3) to Medicine, Mayo Clinic, Rochester, MN Supported by ARUP Laboratories, Salt Lake City, UT correlate echocardiographic findings and NT-proBNP levels with case-control (subsidized blood assays); Sonosite Corporation (loaned status and blood thiamine concentrations. ultrasound equipment); and Center for Translational 1
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ETK LV LVEF NT-proBNP RV TDP
Erythrocyte transketolase Left ventricular Left ventricular ejection fraction N-terminal pro-B type natriuretic peptide Right ventricular Thiamine diphosphate
Science Activities, Department of Pediatric and Adolescent Medicine and Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN (additional study expenses). These entities did not play a role in the study design, data collection, data analysis, writing of the manuscript, or decision to submit the paper for publication. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.01.049
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Methods Infants aged 2-47 weeks (n = 62) were enrolled in this prospective, observational study at the Svay Chrum clinic in the Mesang District of Prey Veng Province, Cambodia, between July 10, 2012, and August 3, 2012. All infants presenting to the clinic were screened for clinical findings of beriberi, and 20 met the study criteria. In addition, 42 control infants deemed healthy by their mothers were recruited from surrounding villages. Informed consent was obtained from all mothers. A survey was administered to mothers of all enrolled infants to elicit information on environmental and dietary exposures, as described previously.4 All infants underwent echocardiography and phlebotomy at enrollment. Infants with clinical beriberi received thiamine and underwent repeat echocardiography at 24 and 48 hours after presentation, as well as repeat phlebotomy at 48 hours, before the third daily thiamine administration. Ethics approval was obtained from the Mayo Clinic’s Institutional Review Board and from the Cambodian National Ethics Committee for Health Research. Infants were defined as having clinical beriberi who met all of the following criteria: hepatomegaly (liver edge $2 cm below the costal margin), respiratory rate $40/min, heart rate $140/min, and temperature <37.5 C. Infants with a heart rate >170/min or respiratory rate >70/min (necessitating immediate intervention), and those who had received thiamine treatment at any time since birth, were excluded from the study. This clinical definition was used in a previous study of infant beriberi in Cambodia and is a more specific derivation of the major criteria cited in the literature.1,2,4,7,8,11 Healthy control infants with tachypnea (>50 breaths/min), tachycardia (>150 beats/min), or a temperature >37.5 C were excluded. Enrolled healthy control infants were matched to infants with beriberi by sex and age (2 weeks for infants aged <2 months and 1 month for older infants). More control infants than sick infants were enrolled, because controls were enrolled synchronously and matched to cases at the conclusion of the study. All cases had at least 1 match by the foregoing criteria, and a second match was added when possible. Echocardiography was performed using a portable SonoSite M-Turbo ultrasound machine (SonoSite, Bothell, Washington). Standard parasternal long-axis, parasternal short-axis, apical 4-chamber, and subcostal images were obtained and stored digitally for later analysis. A total of 3 mL of blood was collected at each phlebotomy. Hematocrit was measured immediately. Because of logistical factors, samples from sick infants were frozen to 20 C within 20 minutes, whereas samples from healthy control infants were placed on ice within 2 minutes and frozen to 20 C within 4 hours. All specimens were transferred on dry ice to a 70 C freezer at the National Institute of Public Health in Phnom Penh, Cambodia within 2 weeks of collection. Frozen specimens were batch-shipped to ARUP Laboratories, Salt Lake City, Utah, in a Cryoport Dry Vapor Shipper (www.cryoport.com) at 70 C and were
thawed immediately before the thiamine assay, performed within 3 months of collection. Given this study’s observational nature, treatment of sick infants was determined by the local health practitioners. Immediately after the initial echocardiographic examination, all patients with clinical beriberi received 100 mg of thiamine intramuscularly, divided into 3 doses delivered over 90 minutes. This treatment was repeated at 24 and 48 hours after presentation, in accordance with local protocol. Plasma thiamine, thiamine monophosphate, and whole blood TDP assays were performed by high-performance liquid chromatography as described previously.12 The adult reference interval (derived from self-reported healthy US adults) is 8-30 nmol/L for total plasma thiamine (plasma thiamine + thiamine monophosphate) and 70-180 nmol/L for whole blood TDP. Pediatric thiamine reference ranges have not been formally established, but published TDP concentrations for healthy US infants fall within or above the adult reference range.4,13 NT-proBNP measurements were performed on a Roche Cobas e411 unit (Roche, Basel, Switzerland) as described previously.14 NT-proBNP reference ranges remain ill-defined in the normal pediatric population, but an upper limit of normal has been reported as 299-348.6 pg/mL (35.3-41.1 pmol/L) for infants aged 4 months to 1 year.15,16 Sahin et al17 and Nevo et al18 have proposed cutoff values for cardiac dysfunction screening of 514 pg/mL (60.7 pmol/L) and 415 pg/mL (49 pmol/L), respectively. A subset analysis of healthy neonates aged 1-5 days found a mean NT-proBNP of 1937 pg/mL (228.6 pmol/L), implying an age-related drop after the first few days of life.19 Digital echocardiography clips were stored electronically and subsequently analyzed by 2 independent reviewers (R.L. and A.C.) blinded to patient status. The following measures were assessed: left ventricular (LV) end-diastolic diameter, LV end-systolic diameter, degree of tricuspid regurgitation (trivial, mild, moderate, or severe), visual assessment of RV size (normal, borderline, mild, moderate, or severely increased), and the presence/absence of pericardial effusion. Visual assessment of RV systolic function (normal, mild, moderate, or severe reduction) was performed using qualitative data from all acoustic windows, as specified by the American Society of Echocardiography.20 LV ejection fraction (LVEF) was calculated according to standard methods (normal range), and LV dimensions were indexed to body surface area. Data were recorded as mean SD, median (range), or number (%) per group, as appropriate. To account for matching by age and sex, statistical comparisons between study groups were made with conditional logistic regression. Baseline variables were presented as median and range for each study group and were compared between study groups with conditional logistic regression. The impact of thiamine on cardiac function and vital signs in sick infants was assessed by measurements obtained at baseline and after 2 days, using the Wilcoxon signed-rank test or McNemar test as appropriate. Both LVEF and NT-proBNP were compared with 1457
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total plasma thiamine and TDP separately for cases and controls. These analyses are presented graphically with scatterplots and regression lines; the corresponding regression equations include study group and an interaction term to stratify the effect of thiamine by study group.
Results Twenty infants (12 males, 8 females) presenting to the Svay Chrum Health Clinic at a median age of 8 weeks (range, 3-31 weeks) met our clinical criteria for beriberi. Fortytwo healthy controls (22 males, 20 females), median age 14.5 weeks (range, 2-47 weeks), were enrolled from the surrounding community. Antibiotics were administered concurrently with thiamine in 6 of the 20 sick infants enrolled, at the discretion of local health care providers. All 62 subjects had normal LV size and normal calculated LVEF. There was no significant difference in LVEF, RV function, or presence of tricuspid regurgitation between beriberi cases and controls (Table I). RV size was normal in 17 of the 20 sick infants and in 41 of the 42 healthy controls. Two cases and 1 healthy control had mild RV enlargement at presentation, and 1 case had severe RV enlargement and severely diminished RV function. No subject had pericardial effusion. There was a trend toward higher NT-proBNP concentrations in sick infants compared with matched controls Table I. Baseline cardiac function, NT-proBNP, and thiamine: sick infants versus healthy matched controls Variable
Sick infants (n = 20)
Matched healthy control infants (n = 27)* P value
LVEF, %, median (range) 64.5 (58-72) 65 (58-72) Plasma NT-proBNP, pg/mL, 340 (79-45 246) 175 (56-1262) median (range) Total plasma thiamine, 2.6 (0-34.7) 4.4 (0-17.0) nmol/L, median (range) Whole blood TDP, nmol/L, 47.6 (21.3-114.9) 55.1 (32.7-176.3) median (range) RV size, n (%) Normal 17 (85.0) 27 (100.0) Mild 2 (10.0) 0 Moderate 0 0 Severe 1 (5.0) 0 Visual assessment of RV function, n (%) Normal 19 (95.0) 27 (100.0) Mildly reduced 0 0 Moderately reduced 0 0 Severely reduced 1 (5.0) 0 Tricuspid regurgitation, n (%) None/trivial 17 (85.0) 24 (88.9) Mild 2 (10.0) 3 (11.1) Moderate 1 (5.0) 0
.863 .099† .011z .346 .234
NCx
NCx
.676{
NC, not calculated. *Thirteen cases were matched to 1 control and 7 cases were matched to 2 controls, for a total of 27 case-control pairs. †Regression with outlier (sick infant with NT-proBNP 45 246 pg/mL) was excluded from the regression calculation because it was highly influential. zRegression with outlier included. xP values could not be calculated owing to lack of variability in the subjects. {P value for comparison of mild/moderate versus none/trivial.
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Vol. 164, No. 6 (P = .099), with a statistically significant difference when the outlier was included in the analysis (P = .011) (Table I). The median NT-proBNP concentration in sick infants of 340 pg/mL (40.1 pmol/L) was above the upper limit of normal as defined by Rauh et al16 (299 pg/mL [35.3 pmol/L]). There were no statistically significant differences in total plasma thiamine or whole blood TDP between cases and controls (Table I). However, mean TDP concentrations (cases, 54.9 nmol/L; all controls, 61.9 nmol/L) were substantially lower in the Cambodian infants compared with reported values of 132-177 nmol/L in healthy US infants.4,13 Baseline T and TDP concentrations were not correlated with child age or reported maternal environmental exposures. There was a significant positive correlation between LVEF and both total plasma thiamine (P < .001) and TDP (P = .004) concentrations in cases, but not in controls (P = .221 for T; P = .738 for TDP) (Figure 1). There was no significant correlation between NT-proBNP level and either total plasma thiamine or TDP level among cases or controls (Figure 1). Changes in cardiac function after thiamine administration were assessed in 19 of the 20 sick infants (1 sick infant did not undergo follow-up echocardiography). No statistically significant change in LVEF or NT-proBNP was noted after 48 hours (total thiamine dose, 300 mg), but statistically significant decreases in heart rate, respiratory rate, and liver size were recorded (Table II). After 48 hours, median total plasma thiamine concentrations increased from 2.1 nmol/L to 114.4 nmol/L (P < .001), and median TDP concentrations increased from 45.3 nmol/L to 223.7 nmol/L (P < .001). Of the 3 sick infants with RV enlargement, 2 improved to normal, including 1 infant with baseline severe enlargement and 1 infant with baseline mild enlargement. These 2 infants were considered to have echocardiographic findings consistent with beriberi. Their baseline TDP concentrations of 24 and 21 nmol/L, respectively, were the lowest recorded in this study. Their baseline NT-proBNP concentrations of 45 246 pg/mL (5339 pmol/L) and 882 pg/mL (104.1 pmol/L) improved to 4853 pg/mL (572.7 pmol/L) and 172 pg/mL (20.3 pmol/L), respectively, by 48 hours after treatment. Echocardiography in the infant with severe baseline RV enlargement at presentation showed a compressed, D-shaped left ventricle and tricuspid regurgitation at a velocity of 3.9 m/s (Figure 2, A). At 48 hours, the right ventricle had returned to normal size but remained hypertrophied; RV dysfunction and tricuspid regurgitation had resolved (Figure 2, B). The third infant presenting with mild RV enlargement exhibited no significant changes in echocardiography findings, vital signs, or blood chemistry measurements over 48 hours. None of these 3 infants received antibiotic therapy.
Discussion Endemic in parts of Asia, wet beriberi is characterized primarily by RV dilation, leading to signs and symptoms of heart failure.1,2,8,11 Although the exact mechanism of heart Porter et al
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Figure 1. A, Baseline plasma thiamine and B, whole blood TDP, LVEF, and plasma NT-proBNP levels in 62 Cambodian infants. Red circles and lines: x-axis versus LVEF (%), Blue triangles and lines: x-axis versus NT-proBNP (pg/mL). Open symbols and dashed regression lines represent sick infant cases; filled symbols and solid regression lines, matched healthy control infants. An outlier (NT-proBNP = 45 246 pg/mL) was excluded from the regression calculation because it was highly influential. Th, plasma thiamine; TMP, thiamine monophosphate.
failure in beriberi remains unclear, hemodynamic studies in adults have shown systemic vasodilation, leading to a highoutput state.21 Along with this peripheral vascular dysfunction, intrinsic myocardial dysfunction is likely present, possibly stemming from a combination of abnormal coronary perfusion and altered mitochondrial energy production owing to thiamine’s essential role as a cofactor in the Krebs cycle, though these theories have not yet been clearly proven.22 Thiamine deficiency is common in rural Cambodia, and in this setting afebrile, tachypneic infants are often treated empirically with thiamine.4,6 However, previous studies have shown little difference in the blood thiamine concentrations of Asian infants with clinical beriberi and matched control infants. In those studies, median TDP concentrations of apparently healthy infants ranged from 39 to 56 nmol/L, well below the median TDP concentrations of 132-177 nmol/L reported in healthy US infants.3,4,13 These data suggest that many tachypneic Cambodian infants do not have beriberi, even though they are thiamine-deficient; however, these studies were limited by the absence of independent assessments of cardiac
function. One previous study assessed serum markers of cardiac dysfunction as well as thiamine status in sick Laotian infants, and found higher troponin T (median, 0.07 ng/mL [0.07 mg/L]) and NT-proBNP concentrations (median, 35 000 pg/ mL [4130 pmol/L]) in infants with a clinical diagnosis of beriberi. However, that study assessed thiamine status by means of erythrocyte transketolase (ETK) activity, a functional measure of thiamine deficiency.23 The optimal interpretation of ETK results is uncertain, and conditions other than thiamine deficiency affect ETK activity.24 Our data imply that only very low blood TDP concentrations are associated with overt heart failure in sick Cambodian infants, and that the currently accepted signs and symptoms of beriberi may be nonspecific. Thiamine deficiency does not lead to significant, recognizable echocardiographic changes until the deficiency is severe. Our echocardiographic findings confirm a previous case report of RV dilation and tricuspid regurgitation in wet beriberi, but in contrast to previous reports, we did not find significant LVEF abnormalities in any of our sick infants, whose LVEF was similar to that of healthy control subjects.10,11
Table II. Changes in cardiac function, blood thiamine concentrations, and vital signs after thiamine administration in 19 sick infants Variable LVEF, %, median (range) RV size, n (%) Normal Mild enlargement Severe enlargement Respirations per minute, median (range) Heart rate per minute, median (range) Liver below costal margin, cm, median (range) Plasma NT-proBNP, pg/mL, median (range) Total plasma thiamine, nmol/L, median (range) Whole blood TDP, nmol/L, median (range)
Day 0 (n = 19)
Day 2 (n = 19)
65 (58-72)
65 (58-70)
16 (84.2) 2 (10.5) 1 (5.3) 48 (40-60) 152 (140-170) 3.0 (2.0-4.0) 292 (79-45 246) 2.1 (0-34.7) 45.3 (21.3-114.9)
18 (94.7) 1 (5.3) 0 40 (26-60) 140 (114-176) 2.5 (1.6-3.2) 245 (36-4853) 114.4 (65.1-236.6) 223.7 (110.2-462.6)
Paired difference (day 2-day 0) 0 (9 to 6)
P value .507* .500†
4 (26 to 16) 8 (56 to 22) 0.3 (1.1 to 0.3) 16 (40 393 to 166) 109.7 (46.2-211.4) 188.2 (35.7-391)
.015* .038* <.001* .588* <.001* <.001*
*Wilcoxon signed-rank test. †McNemar test.
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Figure 2. Echocardiography images of an infant with severe RV enlargement at presentation and a matched healthy control infant. All images are at a depth of 7.2 cm. RA, right atrium; LA, left atrium; TV, tricuspid valve; TR, tricuspid regurgitation (refers to blue color Doppler flow); IS, interventricular septum.
Other investigators have reported higher NT-proBNP concentrations in infants and children with cardiac disease (including right-sided heart disease) compared with those with illnesses of other etiologies.15,17,18,25-27 Only a small minority of the sick infants in our study had echocardiographic findings, but there was a difference in median NT-proBNP concentrations between the sick infants and healthy controls, although the statistical significance of this difference depends on inclusion of the outlier (Table I). This difference suggests the possible presence of subtle heart function abnormalities in the majority of the sick infants. However, there was no correlation between plasma NT-proBNP concentration and plasma thiamine or blood TDP concentration either with or without the outlier included in the analysis. Healthy control infants with similar thiamine concentrations had normal plasma NT-proBNP concentrations. Thus, our findings do not link NT-proBNP elevation to thiamine deficiency in this population. This study was limited by the small number of infants enrolled, the even smaller number with echocardiographic abnormalities, and the uncertainty regarding reference ranges for NT-proBNP in infants. We can conclude that thiamine deficiency likely must be severe (blood TDP concentration <25 nmol/L) before cardiac dysfunction is apparent on echocardiography. Further research is needed to confirm the thiamine concentration at which echocardiographic changes become apparent. Because clinical features of beriberi are nonspecific for diagnosis of thiamine deficiency or overt cardiac failure, empiric thiamine treatment continues to be 1460
warranted in sick infants living in areas with a high prevalence of thiamine deficiency. n The authors gratefully acknowledge the assistance of Rothanna Mork, RN, and Somonn Seab, RN, in study implementation and data collection, Rebecca Lindquist, RCCS, for analysis of echocardiographic studies, Jill Killian for her assistance with data analysis, and Jonathan Lowe for his help with the blood assays. Mengkheang Khin assisted with the translations and revisions of the manuscript. Submitted for publication Sep 24, 2013; last revision received Dec 13, 2013; accepted Jan 24, 2014. Reprint requests: Samuel G. Porter, BS, Mayo Medical School, 200 1st St SW, Rochester, MN 55905. E-mail: [email protected]
References 1. Luxemburger C, White NJ, ter Kuile F, Singh HM, Allier-Frachon I, Ohn M, et al. Beri-beri: the major cause of infant mortality in Karen refugees. Trans R Soc Trop Med Hyg 2003;97:251-5. 2. Soukaloun D, Kounnavong S, Pengdy B, Boupha B, Durondej S, Olness K, et al. Dietary and socio-economic factors associated with beriberi in breastfed Lao infants. Ann Trop Paediatr 2003;23:181-6. 3. Coats D, Frank EL, Reid JM, Ou K, Chea M, Khin M, et al. Thiamine pharmacokinetics in Cambodian mothers and their breastfed infants. Am J Clin Nutr 2013;98:839-44. 4. Coats D, Shelton-Dodge K, Ou K, Khun V, Seab S, Sok K, et al. Thiamine deficiency in Cambodian infants with and without beriberi. J Pediatr 2012;161:843-7. 5. Lonsdale D. A review of the biochemistry, metabolism and clinical benefits of thiamin(e) and its derivatives. Evid Based Complement Alternat Med 2006;3:49-59. 6. Kauffman G, Coats D, Seab S, Topazian MD, Fischer PR. Thiamine deficiency in sick children. Am J Clin Nutr 2011;94:616-7.
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June 2014 7. Thanangkul O, Whitaker J. Childhood thiamin deficiency in northern Thailand. Am J Clin Nutr 1966;18:275-7. 8. Wsickiams R. Toward the conquest of beriberi. Cambridge (MA): Harvard University Press; 1961. p. 82-5. 9. Andrews V. Infantile beriberi. Philipp J Sci 1912;7:67. 10. Khowsathit P, Pongpanich B, Layangool T. Cardiac beri-beri: report of a case with an echocardiographic study. Jpn Heart J 1990;31:265-9. 11. Rao SN, Chandak GR. Cardiac beriberi: often a missed diagnosis. J Trop Pediatr 2010;56:284-5. 12. Lu J, Frank EL. Rapid HPLC measurement of thiamine and its phosphate esters in whole blood. Clin Chem 2008;54:901-6. 13. Wyatt DT, Nelson D, Hsickman RE. Age-dependent changes in thiamin concentrations in whole blood and cerebrospinal fluid in infants and children. Am J Clin Nutr 1991;53:530-6. 14. Saunders JT, Nambi V, de Lemos JA, Chambless LE, Virani SS, Boerwinkle E, et al. Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study. Circulation 2011;123: 1367-76. 15. Nir A, Bar-Oz B, Perles Z, Brooks R, Korach A, Rein AJ. N-terminal proB–type natriuretic peptide: reference plasma levels from birth to adolescence: elevated levels at birth and in infants and children with heart diseases. Acta Paediatr 2004;93:603-7. 16. Rauh M, Koch A. Plasma N-terminal pro-B–type natriuretic peptide concentrations in a control population of infants and children. Clin Chem 2003;49:1563-4. 17. Sahin M, Portakal O, Karagoz T, Hascelik G, Ozkutlu S. Diagnostic performance of BNP and NT-ProBNP measurements in children with heart failure based on congenital heart defects and cardiomyopathies. Clin Biochem 2010;43:1278-81. 18. Nevo I, Erlichman M, Algur N, Nir A. N-terminal pro B–type natriuretic peptide levels in infants and children with acute non-cardiac diseases. Isr Med Assoc J 2011;13:420-4.
19. Nir A, Nasser N. Clinical value of NT-ProBNP and BNP in pediatric cardiology. J Card Fail 2005;11:S76-80. 20. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr 2010;23:685-713. 21. Akbarian M, Yankopoulos NA, Abelmann WH. Hemodynamic studies in beriberi heart disease. Am J Med 1966;41:197-212. 22. Attas M, Hanley HG, Stultz D, Jones MR, McAllister RG. Fulminant beriberi heart disease with lactic acidosis: presentation of a case with evaluation of left ventricular function and review of pathophysiologic mechanisms. Circulation 1978;58:566-72. 23. Soukaloun D, Lee SJ, Chamberlain K, Taylor AM, Mayxay M, Sisouk K, et al. Erythrocyte transketolase activity, markers of cardiac dysfunction and the diagnosis of infantile beriberi. PLoS Negl Trop Dis 2011;5:e971. 24. Talwar D, Davidson H, Cooney J, O’Resicky DSJ. Vitamin B(1) status assessed by direct measurement of thiamin pyrophosphate in erythrocytes or whole blood by HPLC: comparison with erythrocyte transketolase activation assay. Clin Chem 2000;46:704-10. 25. Geiger R, Hammerer-Lercher A, Url C, Schweigmann U, Puschendorf B, Sommer R, et al. NT-proBNP concentrations indicate cardiac disease in pediatric patients. Int J Cardiol 2007;123:63-5. 26. Hammerer-Lercher A, Geiger R, Mair J, Url C, Tulzer G, Lechner E, et al. Utility of N-terminal pro-B–type natriuretic peptide to differentiate cardiac diseases from noncardiac diseases in young pediatric patients. Clin Chem 2006;52:1415-9. 27. Baptista MJ, Rocha G, Clemente F, Azevedo LF, Tibboel D, LeiteMoreira AF, et al. N-terminal-pro-B type natriuretic peptide as a useful tool to evaluate pulmonary hypertension and cardiac function in CDH infants. Neonatology 2008;94:22-30.
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et beriberi, a disease caused by thiamine deficiency, is a common diagnosis in parts of Southeast Asia.1,2 Thiamine deficiency is widespread among nursing mothers and their breast-fed infants in Prey Veng Province, Cambodia. Mothers in this region efficiently absorb oral thiamine and secrete it in breast milk, but they consume only approximately one-half of the recommended daily intake of thiamine, implicating maternal dietary inadequacy as the cause of infant thiamine deficiency.3-5 Further studies in this area of Cambodia found that up to one-half of deaths during the first year of life may be attributable to beriberi, but that both infants with a clinical diagnosis of beriberi and apparently healthy matched control infants have low thiamine diphosphate (TDP) concentrations.4,6 This implies that thiamine deficiency, as defined by reference ranges for US children with thiamine deficiency, is not necessarily sufficient to cause wet beriberi. The clinical diagnosis of wet beriberi is made when signs of congestive heart failure are present (tachypnea, tachycardia, wheezing, hepatomegaly), often with dysphonia, and the child improves after receiving thiamine.7 Autopsy data from infants with wet beriberi show right ventricular (RV) dilation and hypertrophy, with relative sparing of the left ventricle.8,9 The few available reports on echocardiography in infants with wet beriberi describe tricuspid regurgitation, right heart From the Mayo Medical School, College of Medicine, dilation, and pulmonary hypertension that resolved after thiamine therapy.10,11 Rochester, MN; Eastern Mennonite Missions, Prey Veng, Cambodia; Department of Pediatric and No previous studies have correlated echocardiographic assessment with blood Adolescent Medicine, Mayo Clinic, Rochester, MN; National Maternal and Child Health Center, University of thiamine or plasma N-terminal pro-B type natriuretic peptide (NT-proBNP) Health Science, Phnom Penh, Cambodia; Department of Pathology, University of Utah Health Sciences Center, concentrations in children with beriberi. Salt Lake City, UT; Department of Family Medicine, The specific aims of the present study were: (1) to use portable echocardiogInternational University, Phnom Penh, Cambodia; and Division of Gastroenterology and Hepatology, raphy to compare cardiac function in infants with clinical signs of wet beriberi Department of Medicine, Department of Biomedical Statistics and Informatics, and Division of Pediatric and apparently healthy control infants; (2) to evaluate cardiac changes in infants Cardiology, Department of Pediatric and Adolescent with clinically diagnosed beriberi over the first 48 hours of treatment; and (3) to Medicine, Mayo Clinic, Rochester, MN Supported by ARUP Laboratories, Salt Lake City, UT correlate echocardiographic findings and NT-proBNP levels with case-control (subsidized blood assays); Sonosite Corporation (loaned status and blood thiamine concentrations. ultrasound equipment); and Center for Translational 1
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ETK LV LVEF NT-proBNP RV TDP
Erythrocyte transketolase Left ventricular Left ventricular ejection fraction N-terminal pro-B type natriuretic peptide Right ventricular Thiamine diphosphate
Science Activities, Department of Pediatric and Adolescent Medicine and Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN (additional study expenses). These entities did not play a role in the study design, data collection, data analysis, writing of the manuscript, or decision to submit the paper for publication. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.01.049
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Methods Infants aged 2-47 weeks (n = 62) were enrolled in this prospective, observational study at the Svay Chrum clinic in the Mesang District of Prey Veng Province, Cambodia, between July 10, 2012, and August 3, 2012. All infants presenting to the clinic were screened for clinical findings of beriberi, and 20 met the study criteria. In addition, 42 control infants deemed healthy by their mothers were recruited from surrounding villages. Informed consent was obtained from all mothers. A survey was administered to mothers of all enrolled infants to elicit information on environmental and dietary exposures, as described previously.4 All infants underwent echocardiography and phlebotomy at enrollment. Infants with clinical beriberi received thiamine and underwent repeat echocardiography at 24 and 48 hours after presentation, as well as repeat phlebotomy at 48 hours, before the third daily thiamine administration. Ethics approval was obtained from the Mayo Clinic’s Institutional Review Board and from the Cambodian National Ethics Committee for Health Research. Infants were defined as having clinical beriberi who met all of the following criteria: hepatomegaly (liver edge $2 cm below the costal margin), respiratory rate $40/min, heart rate $140/min, and temperature <37.5 C. Infants with a heart rate >170/min or respiratory rate >70/min (necessitating immediate intervention), and those who had received thiamine treatment at any time since birth, were excluded from the study. This clinical definition was used in a previous study of infant beriberi in Cambodia and is a more specific derivation of the major criteria cited in the literature.1,2,4,7,8,11 Healthy control infants with tachypnea (>50 breaths/min), tachycardia (>150 beats/min), or a temperature >37.5 C were excluded. Enrolled healthy control infants were matched to infants with beriberi by sex and age (2 weeks for infants aged <2 months and 1 month for older infants). More control infants than sick infants were enrolled, because controls were enrolled synchronously and matched to cases at the conclusion of the study. All cases had at least 1 match by the foregoing criteria, and a second match was added when possible. Echocardiography was performed using a portable SonoSite M-Turbo ultrasound machine (SonoSite, Bothell, Washington). Standard parasternal long-axis, parasternal short-axis, apical 4-chamber, and subcostal images were obtained and stored digitally for later analysis. A total of 3 mL of blood was collected at each phlebotomy. Hematocrit was measured immediately. Because of logistical factors, samples from sick infants were frozen to 20 C within 20 minutes, whereas samples from healthy control infants were placed on ice within 2 minutes and frozen to 20 C within 4 hours. All specimens were transferred on dry ice to a 70 C freezer at the National Institute of Public Health in Phnom Penh, Cambodia within 2 weeks of collection. Frozen specimens were batch-shipped to ARUP Laboratories, Salt Lake City, Utah, in a Cryoport Dry Vapor Shipper (www.cryoport.com) at 70 C and were
thawed immediately before the thiamine assay, performed within 3 months of collection. Given this study’s observational nature, treatment of sick infants was determined by the local health practitioners. Immediately after the initial echocardiographic examination, all patients with clinical beriberi received 100 mg of thiamine intramuscularly, divided into 3 doses delivered over 90 minutes. This treatment was repeated at 24 and 48 hours after presentation, in accordance with local protocol. Plasma thiamine, thiamine monophosphate, and whole blood TDP assays were performed by high-performance liquid chromatography as described previously.12 The adult reference interval (derived from self-reported healthy US adults) is 8-30 nmol/L for total plasma thiamine (plasma thiamine + thiamine monophosphate) and 70-180 nmol/L for whole blood TDP. Pediatric thiamine reference ranges have not been formally established, but published TDP concentrations for healthy US infants fall within or above the adult reference range.4,13 NT-proBNP measurements were performed on a Roche Cobas e411 unit (Roche, Basel, Switzerland) as described previously.14 NT-proBNP reference ranges remain ill-defined in the normal pediatric population, but an upper limit of normal has been reported as 299-348.6 pg/mL (35.3-41.1 pmol/L) for infants aged 4 months to 1 year.15,16 Sahin et al17 and Nevo et al18 have proposed cutoff values for cardiac dysfunction screening of 514 pg/mL (60.7 pmol/L) and 415 pg/mL (49 pmol/L), respectively. A subset analysis of healthy neonates aged 1-5 days found a mean NT-proBNP of 1937 pg/mL (228.6 pmol/L), implying an age-related drop after the first few days of life.19 Digital echocardiography clips were stored electronically and subsequently analyzed by 2 independent reviewers (R.L. and A.C.) blinded to patient status. The following measures were assessed: left ventricular (LV) end-diastolic diameter, LV end-systolic diameter, degree of tricuspid regurgitation (trivial, mild, moderate, or severe), visual assessment of RV size (normal, borderline, mild, moderate, or severely increased), and the presence/absence of pericardial effusion. Visual assessment of RV systolic function (normal, mild, moderate, or severe reduction) was performed using qualitative data from all acoustic windows, as specified by the American Society of Echocardiography.20 LV ejection fraction (LVEF) was calculated according to standard methods (normal range), and LV dimensions were indexed to body surface area. Data were recorded as mean SD, median (range), or number (%) per group, as appropriate. To account for matching by age and sex, statistical comparisons between study groups were made with conditional logistic regression. Baseline variables were presented as median and range for each study group and were compared between study groups with conditional logistic regression. The impact of thiamine on cardiac function and vital signs in sick infants was assessed by measurements obtained at baseline and after 2 days, using the Wilcoxon signed-rank test or McNemar test as appropriate. Both LVEF and NT-proBNP were compared with 1457
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total plasma thiamine and TDP separately for cases and controls. These analyses are presented graphically with scatterplots and regression lines; the corresponding regression equations include study group and an interaction term to stratify the effect of thiamine by study group.
Results Twenty infants (12 males, 8 females) presenting to the Svay Chrum Health Clinic at a median age of 8 weeks (range, 3-31 weeks) met our clinical criteria for beriberi. Fortytwo healthy controls (22 males, 20 females), median age 14.5 weeks (range, 2-47 weeks), were enrolled from the surrounding community. Antibiotics were administered concurrently with thiamine in 6 of the 20 sick infants enrolled, at the discretion of local health care providers. All 62 subjects had normal LV size and normal calculated LVEF. There was no significant difference in LVEF, RV function, or presence of tricuspid regurgitation between beriberi cases and controls (Table I). RV size was normal in 17 of the 20 sick infants and in 41 of the 42 healthy controls. Two cases and 1 healthy control had mild RV enlargement at presentation, and 1 case had severe RV enlargement and severely diminished RV function. No subject had pericardial effusion. There was a trend toward higher NT-proBNP concentrations in sick infants compared with matched controls Table I. Baseline cardiac function, NT-proBNP, and thiamine: sick infants versus healthy matched controls Variable
Sick infants (n = 20)
Matched healthy control infants (n = 27)* P value
LVEF, %, median (range) 64.5 (58-72) 65 (58-72) Plasma NT-proBNP, pg/mL, 340 (79-45 246) 175 (56-1262) median (range) Total plasma thiamine, 2.6 (0-34.7) 4.4 (0-17.0) nmol/L, median (range) Whole blood TDP, nmol/L, 47.6 (21.3-114.9) 55.1 (32.7-176.3) median (range) RV size, n (%) Normal 17 (85.0) 27 (100.0) Mild 2 (10.0) 0 Moderate 0 0 Severe 1 (5.0) 0 Visual assessment of RV function, n (%) Normal 19 (95.0) 27 (100.0) Mildly reduced 0 0 Moderately reduced 0 0 Severely reduced 1 (5.0) 0 Tricuspid regurgitation, n (%) None/trivial 17 (85.0) 24 (88.9) Mild 2 (10.0) 3 (11.1) Moderate 1 (5.0) 0
.863 .099† .011z .346 .234
NCx
NCx
.676{
NC, not calculated. *Thirteen cases were matched to 1 control and 7 cases were matched to 2 controls, for a total of 27 case-control pairs. †Regression with outlier (sick infant with NT-proBNP 45 246 pg/mL) was excluded from the regression calculation because it was highly influential. zRegression with outlier included. xP values could not be calculated owing to lack of variability in the subjects. {P value for comparison of mild/moderate versus none/trivial.
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Vol. 164, No. 6 (P = .099), with a statistically significant difference when the outlier was included in the analysis (P = .011) (Table I). The median NT-proBNP concentration in sick infants of 340 pg/mL (40.1 pmol/L) was above the upper limit of normal as defined by Rauh et al16 (299 pg/mL [35.3 pmol/L]). There were no statistically significant differences in total plasma thiamine or whole blood TDP between cases and controls (Table I). However, mean TDP concentrations (cases, 54.9 nmol/L; all controls, 61.9 nmol/L) were substantially lower in the Cambodian infants compared with reported values of 132-177 nmol/L in healthy US infants.4,13 Baseline T and TDP concentrations were not correlated with child age or reported maternal environmental exposures. There was a significant positive correlation between LVEF and both total plasma thiamine (P < .001) and TDP (P = .004) concentrations in cases, but not in controls (P = .221 for T; P = .738 for TDP) (Figure 1). There was no significant correlation between NT-proBNP level and either total plasma thiamine or TDP level among cases or controls (Figure 1). Changes in cardiac function after thiamine administration were assessed in 19 of the 20 sick infants (1 sick infant did not undergo follow-up echocardiography). No statistically significant change in LVEF or NT-proBNP was noted after 48 hours (total thiamine dose, 300 mg), but statistically significant decreases in heart rate, respiratory rate, and liver size were recorded (Table II). After 48 hours, median total plasma thiamine concentrations increased from 2.1 nmol/L to 114.4 nmol/L (P < .001), and median TDP concentrations increased from 45.3 nmol/L to 223.7 nmol/L (P < .001). Of the 3 sick infants with RV enlargement, 2 improved to normal, including 1 infant with baseline severe enlargement and 1 infant with baseline mild enlargement. These 2 infants were considered to have echocardiographic findings consistent with beriberi. Their baseline TDP concentrations of 24 and 21 nmol/L, respectively, were the lowest recorded in this study. Their baseline NT-proBNP concentrations of 45 246 pg/mL (5339 pmol/L) and 882 pg/mL (104.1 pmol/L) improved to 4853 pg/mL (572.7 pmol/L) and 172 pg/mL (20.3 pmol/L), respectively, by 48 hours after treatment. Echocardiography in the infant with severe baseline RV enlargement at presentation showed a compressed, D-shaped left ventricle and tricuspid regurgitation at a velocity of 3.9 m/s (Figure 2, A). At 48 hours, the right ventricle had returned to normal size but remained hypertrophied; RV dysfunction and tricuspid regurgitation had resolved (Figure 2, B). The third infant presenting with mild RV enlargement exhibited no significant changes in echocardiography findings, vital signs, or blood chemistry measurements over 48 hours. None of these 3 infants received antibiotic therapy.
Discussion Endemic in parts of Asia, wet beriberi is characterized primarily by RV dilation, leading to signs and symptoms of heart failure.1,2,8,11 Although the exact mechanism of heart Porter et al
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Figure 1. A, Baseline plasma thiamine and B, whole blood TDP, LVEF, and plasma NT-proBNP levels in 62 Cambodian infants. Red circles and lines: x-axis versus LVEF (%), Blue triangles and lines: x-axis versus NT-proBNP (pg/mL). Open symbols and dashed regression lines represent sick infant cases; filled symbols and solid regression lines, matched healthy control infants. An outlier (NT-proBNP = 45 246 pg/mL) was excluded from the regression calculation because it was highly influential. Th, plasma thiamine; TMP, thiamine monophosphate.
failure in beriberi remains unclear, hemodynamic studies in adults have shown systemic vasodilation, leading to a highoutput state.21 Along with this peripheral vascular dysfunction, intrinsic myocardial dysfunction is likely present, possibly stemming from a combination of abnormal coronary perfusion and altered mitochondrial energy production owing to thiamine’s essential role as a cofactor in the Krebs cycle, though these theories have not yet been clearly proven.22 Thiamine deficiency is common in rural Cambodia, and in this setting afebrile, tachypneic infants are often treated empirically with thiamine.4,6 However, previous studies have shown little difference in the blood thiamine concentrations of Asian infants with clinical beriberi and matched control infants. In those studies, median TDP concentrations of apparently healthy infants ranged from 39 to 56 nmol/L, well below the median TDP concentrations of 132-177 nmol/L reported in healthy US infants.3,4,13 These data suggest that many tachypneic Cambodian infants do not have beriberi, even though they are thiamine-deficient; however, these studies were limited by the absence of independent assessments of cardiac
function. One previous study assessed serum markers of cardiac dysfunction as well as thiamine status in sick Laotian infants, and found higher troponin T (median, 0.07 ng/mL [0.07 mg/L]) and NT-proBNP concentrations (median, 35 000 pg/ mL [4130 pmol/L]) in infants with a clinical diagnosis of beriberi. However, that study assessed thiamine status by means of erythrocyte transketolase (ETK) activity, a functional measure of thiamine deficiency.23 The optimal interpretation of ETK results is uncertain, and conditions other than thiamine deficiency affect ETK activity.24 Our data imply that only very low blood TDP concentrations are associated with overt heart failure in sick Cambodian infants, and that the currently accepted signs and symptoms of beriberi may be nonspecific. Thiamine deficiency does not lead to significant, recognizable echocardiographic changes until the deficiency is severe. Our echocardiographic findings confirm a previous case report of RV dilation and tricuspid regurgitation in wet beriberi, but in contrast to previous reports, we did not find significant LVEF abnormalities in any of our sick infants, whose LVEF was similar to that of healthy control subjects.10,11
Table II. Changes in cardiac function, blood thiamine concentrations, and vital signs after thiamine administration in 19 sick infants Variable LVEF, %, median (range) RV size, n (%) Normal Mild enlargement Severe enlargement Respirations per minute, median (range) Heart rate per minute, median (range) Liver below costal margin, cm, median (range) Plasma NT-proBNP, pg/mL, median (range) Total plasma thiamine, nmol/L, median (range) Whole blood TDP, nmol/L, median (range)
Day 0 (n = 19)
Day 2 (n = 19)
65 (58-72)
65 (58-70)
16 (84.2) 2 (10.5) 1 (5.3) 48 (40-60) 152 (140-170) 3.0 (2.0-4.0) 292 (79-45 246) 2.1 (0-34.7) 45.3 (21.3-114.9)
18 (94.7) 1 (5.3) 0 40 (26-60) 140 (114-176) 2.5 (1.6-3.2) 245 (36-4853) 114.4 (65.1-236.6) 223.7 (110.2-462.6)
Paired difference (day 2-day 0) 0 (9 to 6)
P value .507* .500†
4 (26 to 16) 8 (56 to 22) 0.3 (1.1 to 0.3) 16 (40 393 to 166) 109.7 (46.2-211.4) 188.2 (35.7-391)
.015* .038* <.001* .588* <.001* <.001*
*Wilcoxon signed-rank test. †McNemar test.
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Figure 2. Echocardiography images of an infant with severe RV enlargement at presentation and a matched healthy control infant. All images are at a depth of 7.2 cm. RA, right atrium; LA, left atrium; TV, tricuspid valve; TR, tricuspid regurgitation (refers to blue color Doppler flow); IS, interventricular septum.
Other investigators have reported higher NT-proBNP concentrations in infants and children with cardiac disease (including right-sided heart disease) compared with those with illnesses of other etiologies.15,17,18,25-27 Only a small minority of the sick infants in our study had echocardiographic findings, but there was a difference in median NT-proBNP concentrations between the sick infants and healthy controls, although the statistical significance of this difference depends on inclusion of the outlier (Table I). This difference suggests the possible presence of subtle heart function abnormalities in the majority of the sick infants. However, there was no correlation between plasma NT-proBNP concentration and plasma thiamine or blood TDP concentration either with or without the outlier included in the analysis. Healthy control infants with similar thiamine concentrations had normal plasma NT-proBNP concentrations. Thus, our findings do not link NT-proBNP elevation to thiamine deficiency in this population. This study was limited by the small number of infants enrolled, the even smaller number with echocardiographic abnormalities, and the uncertainty regarding reference ranges for NT-proBNP in infants. We can conclude that thiamine deficiency likely must be severe (blood TDP concentration <25 nmol/L) before cardiac dysfunction is apparent on echocardiography. Further research is needed to confirm the thiamine concentration at which echocardiographic changes become apparent. Because clinical features of beriberi are nonspecific for diagnosis of thiamine deficiency or overt cardiac failure, empiric thiamine treatment continues to be 1460
warranted in sick infants living in areas with a high prevalence of thiamine deficiency. n The authors gratefully acknowledge the assistance of Rothanna Mork, RN, and Somonn Seab, RN, in study implementation and data collection, Rebecca Lindquist, RCCS, for analysis of echocardiographic studies, Jill Killian for her assistance with data analysis, and Jonathan Lowe for his help with the blood assays. Mengkheang Khin assisted with the translations and revisions of the manuscript. Submitted for publication Sep 24, 2013; last revision received Dec 13, 2013; accepted Jan 24, 2014. Reprint requests: Samuel G. Porter, BS, Mayo Medical School, 200 1st St SW, Rochester, MN 55905. E-mail: [email protected]
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June 2014 7. Thanangkul O, Whitaker J. Childhood thiamin deficiency in northern Thailand. Am J Clin Nutr 1966;18:275-7. 8. Wsickiams R. Toward the conquest of beriberi. Cambridge (MA): Harvard University Press; 1961. p. 82-5. 9. Andrews V. Infantile beriberi. Philipp J Sci 1912;7:67. 10. Khowsathit P, Pongpanich B, Layangool T. Cardiac beri-beri: report of a case with an echocardiographic study. Jpn Heart J 1990;31:265-9. 11. Rao SN, Chandak GR. Cardiac beriberi: often a missed diagnosis. J Trop Pediatr 2010;56:284-5. 12. Lu J, Frank EL. Rapid HPLC measurement of thiamine and its phosphate esters in whole blood. Clin Chem 2008;54:901-6. 13. Wyatt DT, Nelson D, Hsickman RE. Age-dependent changes in thiamin concentrations in whole blood and cerebrospinal fluid in infants and children. Am J Clin Nutr 1991;53:530-6. 14. Saunders JT, Nambi V, de Lemos JA, Chambless LE, Virani SS, Boerwinkle E, et al. Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study. Circulation 2011;123: 1367-76. 15. Nir A, Bar-Oz B, Perles Z, Brooks R, Korach A, Rein AJ. N-terminal proB–type natriuretic peptide: reference plasma levels from birth to adolescence: elevated levels at birth and in infants and children with heart diseases. Acta Paediatr 2004;93:603-7. 16. Rauh M, Koch A. Plasma N-terminal pro-B–type natriuretic peptide concentrations in a control population of infants and children. Clin Chem 2003;49:1563-4. 17. Sahin M, Portakal O, Karagoz T, Hascelik G, Ozkutlu S. Diagnostic performance of BNP and NT-ProBNP measurements in children with heart failure based on congenital heart defects and cardiomyopathies. Clin Biochem 2010;43:1278-81. 18. Nevo I, Erlichman M, Algur N, Nir A. N-terminal pro B–type natriuretic peptide levels in infants and children with acute non-cardiac diseases. Isr Med Assoc J 2011;13:420-4.
19. Nir A, Nasser N. Clinical value of NT-ProBNP and BNP in pediatric cardiology. J Card Fail 2005;11:S76-80. 20. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr 2010;23:685-713. 21. Akbarian M, Yankopoulos NA, Abelmann WH. Hemodynamic studies in beriberi heart disease. Am J Med 1966;41:197-212. 22. Attas M, Hanley HG, Stultz D, Jones MR, McAllister RG. Fulminant beriberi heart disease with lactic acidosis: presentation of a case with evaluation of left ventricular function and review of pathophysiologic mechanisms. Circulation 1978;58:566-72. 23. Soukaloun D, Lee SJ, Chamberlain K, Taylor AM, Mayxay M, Sisouk K, et al. Erythrocyte transketolase activity, markers of cardiac dysfunction and the diagnosis of infantile beriberi. PLoS Negl Trop Dis 2011;5:e971. 24. Talwar D, Davidson H, Cooney J, O’Resicky DSJ. Vitamin B(1) status assessed by direct measurement of thiamin pyrophosphate in erythrocytes or whole blood by HPLC: comparison with erythrocyte transketolase activation assay. Clin Chem 2000;46:704-10. 25. Geiger R, Hammerer-Lercher A, Url C, Schweigmann U, Puschendorf B, Sommer R, et al. NT-proBNP concentrations indicate cardiac disease in pediatric patients. Int J Cardiol 2007;123:63-5. 26. Hammerer-Lercher A, Geiger R, Mair J, Url C, Tulzer G, Lechner E, et al. Utility of N-terminal pro-B–type natriuretic peptide to differentiate cardiac diseases from noncardiac diseases in young pediatric patients. Clin Chem 2006;52:1415-9. 27. Baptista MJ, Rocha G, Clemente F, Azevedo LF, Tibboel D, LeiteMoreira AF, et al. N-terminal-pro-B type natriuretic peptide as a useful tool to evaluate pulmonary hypertension and cardiac function in CDH infants. Neonatology 2008;94:22-30.
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