Cardiac Function in Pediatric Septic Shock Survivors

Home , Artificial ventilation, Septic shock

ARTICLE Cardiac Function in Pediatric Septic Shock Survivors

Hendrika Knoester, MD; Jeanine J. Sol, MD; Pascal Ramsodit, MD; Irene M. Kuipers, MD, PhD; Sally-Ann B. Clur, MBBCh, MSc, FCP(SA)Paed; Albert P. Bos, MD, PhD

Objective: To evaluate the long-term effects of septic shock Results: No children had abnormalities when histories on cardiac function in children treated with inotropic and/or were taken or during physical examination that were at- vasoconstrictive agents for 24 hours or longer. tributable to cardiac dysfunction. Six children (6%) had cardiac abnormalities: polymorphic premature ventricu- Design: Cohort study. lar contractions during exercise and 24-hour electrocardiography registration (2 patients), decreased left ven- Setting: Tertiary pediatric intensive care unit and out- tricular function (2 patients), decreased left ventricular patient follow-up clinic. function and polymorphic premature ventricular contractions (1 patient), and decreased right ventricular func- Participants: One hundred eight of 144 eligible chil- tion (1 patient). dren who were admitted to our tertiary pediatric intensive care unit with septic shock from 1995 through 2005 Conclusions: In this small and diverse group of pedi- and were alive in 2006 were invited to participate and atric septic shock survivors, we found an excellent re- visit our outpatient follow-up clinic. Fifty-two healthy covery of cardiac performance in most patients. In a lim- controls were included. ited number of patients, we found rhythm disturbances Main Exposure: Septic shock survival. and decreased ventricular function. We believe that, against the background of aging, long-term cardiac fol- Outcome Measures: History, physical examination, low-up of these patients is important. electrocardiogram during rest and exercise, 24-hour electrocardiography registration, and left and right ventricular function. Arch Pediatr Adolesc Med. 2008;162(12):1164-1168

EPSIS IS ONE OF THE LEADING ticularly in children, long-term fol- causes of death in children. low-up studies may be important against Mortality ranges from 4% to the background of the development and 20%.1 Septic shock is charac- maturation of organs. Consider, for ex- terized by myocardial dys- ample, respiratory distress syndrome of the function,S loss of vascular tone, and cap- prematurely born infant (idiopathic res- illary leak leading to diminished organ piratory distress syndrome) and acute lung perfusion and the development of mul- injury in older children. Both have long- tiple organ system failure. Myocardial dys- term pulmonary consequences. The pri- function—caused by hypoperfusion, myo- mary insult occurs when the lung is ex- cardial cell death, and/or cardiodepressant posed to a damaging process (idiopathic circulating substances, such as tumor ne- respiratory distress syndrome or acute lung crosis factor ␣, IL-1 (interleukin 1), and injury); the secondary insult is caused by nitric oxide—is a key factor in the devel- mechanical ventilation.12,13 In children opment of circulatory failure during septic shock.2-4 Treatment includes ad- treated with inotropic and/or vasoconstrictive agents because of septic shock, the Author Affiliations: Pediatric equate fluid resuscitation and the admin- Intensive Care Unit istration of inotropic and/or vasoconstric- primary insult on the myocardium may be (Drs Knoester, Sol, Ramsodit, tive agents.5,6 the septic shock and the secondary insult and Bos) and Pediatric Mortality due to septic shock has de- may be treatment with these agents. This Cardiology Department creased owing to advances in pediatric in- may result in permanent damage to the de- (Drs Kuipers and Clur), Emma tensive care practices, such as improved veloping heart. The aim of this study was Children’s Hospital, Academic to evaluate the late (Ͼ6 months after pe- Medical Centre, Amsterdam, use of inotropic and vasoconstrictive the Netherlands. Dr Ramsodit is agents and early goal-directed fluid diatric intensive care unit [PICU] dis- 6-8 now with the Twenteborg therapy. Follow-up studies of children charge) effects of septic shock on cardiac Hospital, Almelo, the with septic shock have mainly focused on function in children and to analyze risk fac- Netherlands. mortality and short-term morbidity.9-11 Par- tors for cardiac abnormalities.

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/03/2021 METHODS trocardiogram recordings were performed only when rhythm disturbances were suspected. Echocardiography to evaluate systolic function of the right ventricle was not performed. The study was performed in the PICU of the Emma Children’s Hospital/Academic Medical Center Amsterdam. This is a ter- STATISTICAL ANALYSIS tiary multidisciplinary PICU with 14 beds serving the greater Amsterdam area. Data analysis was performed using SPSS (SPSS Inc, Chicago, Illinois). Mann-Whitney and ␹2 tests were done to compare par- PARTICIPANTS ticipants with nonparticipants and the control group with the patient group with regard to patient characteristics. The worst Patients were included if they had been admitted to the PICU shortening fraction during admission was compared with short- for septic shock between 1995 and 2005, had received inotro- ening fraction at follow-up using paired t tests. Shortening frac- pic and/or vasoconstrictive agents for 24 hours or longer (dopa- tion less than 30% and less than 28% during PICU admission mine, dobutamine, epinephrine, and/or norepinephrine), were and at follow-up were compared by using the Fisher exact test. alive in 2006, and had been followed up for longer than 6 months A significance level of PϽ.05 was used in all tests. after PICU discharge. Exclusion criteria were preexisting car- To analyze risk factors for cardiac abnormalities, patients diac disorders and serious psychomotor retardation. The hos- with cardiac abnormalities (rhythm disturbances, decreased left pital’s institutional review board approved the study protocol, ventricular function, and/or decreased right ventricular func- and written consent was obtained for all included patients and/or tion) were clustered because of the small number of patients. their parents. Mann-Whitney and ␹2 tests were used to compare characteristics of patients with and without cardiac abnormalities, such STUDY DESIGN as sex, age at PICU admission, age at follow-up, follow-up time, risk of mortality (Pediatric Index of Mortality 2), length of ven- Cardiac function was evaluated in our outpatient follow-up clinic tilation, and length of PICU stay. Furthermore, nonparamet- by patient history, physical examination, and electrocardio- ric correlations were performed to test the association be- gram (ECG) recorded during rest. Electrocardiogram record- tween cardiac abnormalities and the use of different inotropic ing during exercise was performed when the child was older and/or vasoconstrictive agents, and the dosage and duration of than 7 years at follow-up. Twenty-four-hour ECG recording treatment with these agents. A significance level of PϽ.001 was and echocardiography were performed as well. used in these tests to compensate for multiple testing. A structured checklist was used for history taking and the physical examination. Special attention was paid to syncope, RESULTS chest pain, skipped beats and heart palpitations, peripheral pul- sations, liver size, edema, and heart murmurs. Exercise testing was performed in children aged 7 years and older, as sum- One hundred forty-four patients who were admitted to marized in the Bruce protocol (younger children cannot perform our PICU for septic shock from 1995 through 2005 and this test owing to their size and lack of adequate concentration).14 survived fulfilled the inclusion criteria. Eleven patients Echocardiography was performed to evaluate systolic func- refused to participate and 25 patients could not be lo- tion of the left and right ventricles. Systolic function of the left cated. One hundred eight of 144 eligible patients (75%) ventricle was determined by measuring left ventricular end- were evaluated. No statistically significant differences were diastolic diameter (LVEDD) and shortening fraction. Shorten- found between participants and nonparticipants, ex- ing fraction is the percentage of change in the left ventricular cept for sex (Table 1). The age of PICU patients ranged cavity dimension during systole ([(LVEDD−left ventricular end- Ͼ systolic dimension)/LVEDD]ϫ100). In many studies, left ven- from newborns (with a birth weight 2 kg) to 18 years. tricular function is measured by the ejection fraction. In nor- Median follow-up time was 6.3 years (range, 0.8-12.7 mally shaped left ventricles, shortening fraction and ejection years). fraction are comparable. We chose to report shortening frac- The exercise test was performed in 87 of 108 patients tion. In pediatric literature, normal values for systolic func- (81%) aged 7 years or older. Twenty-four-hour ECG re- tion of the left ventricle differ from shortening fraction by more cording was successfully performed in 86 of 108 pa- 15-18 than 28% or more than 30%. Systolic function of the right tients (80%). Evaluations of systolic function of the left ventricle was determined by measuring tricuspid annular plane and right ventricles were successfully performed in 105 systolic excursion (TAPSE). There are no known reference data of 108 patients (97%) and 86 of 108 patients (80%), re- in the pediatric literature for TAPSE. As in adult literature, a TAPSE longer than 15.0 mm is considered normal.19 We also spectively. studied systolic cardiac function in a control group of 52 healthy Medical history and physical examination revealed no children with a benign murmur. Echocardiography was per- abnormalities in all but 1 patient (1%). This patient com- formed to exclude cardiac abnormalities. Diastolic function of plained of dyspnea while at rest and had a limited exer- the left ventricle was evaluated as well and will be published cise capacity due to respiratory obstruction caused by an, separately. until then, unknown tracheal stenosis, which was prob- During septic shock, sedation was administered when the ably due to intubation. All patients had normal ECG re- patient needed artificial ventilation, according to our sedation sults at rest and a good exercise capacity. Episodes of pre- protocol (morphine and midazolam). Patient characteristics at mature ventricular contractions (PVCs) were seen in PICU admission were obtained from medical records and the 7 of 87 patients (8%) during and after exercise (3 pa- patient data management system. In our PICU, it was not standard procedure to perform echocardiography to evaluate sys- tients [3.5%] had monomorphic PVCs during exercise, tolic function of the left ventricle or to perform an ECG dur- 3 patients (3.5%) had monomorphic PVCs during rest ing PICU admission. Echocardiography was performed when after exercise, and 1 patient (1%) had a series of poly- the pediatric-intensivist on duty wanted additional informa- morphic PVCs during exercise). In 3 of the aforemen- tion on cardiac function or if one was clinically indicated. Elec- tioned patients (3.5%), episodes of PVCs were seen on

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/03/2021 Table 1. Characteristics of Study Participants Table 3. Longitudinal Systolic Function During PICU and Nonparticipants Admission and at Follow-up in 65 of 108 Patients

Median (Range) Time of Assessment P Participants Nonparticipants P Systolic Fraction PICU Admission Follow-Up Value Characteristic (n=108) (n=36) Value Shortening fraction 27.0 (14.3-48.9) 36.2 (25.0-47.2) Ͻ.001a Age at PICU admission, y 3.5 (0.0-17.9) 5.7 (0.0-16.5) .38 median (range), % Length of PICU stay, d 6.0 (1.0-64.4) 5.0 (1.0-19.0) .29 Shortening fraction 36 (80) 6 (9) .21b Age at follow-up, y 9.9 (2.4-27.1) Ͻ30%, No. (%) Follow-up time, y 6.3 (0.812.7) Shortening fraction 34 (52) 2 (3) .49b Length of artificial 4.0 (0.0-40.0) 2.5 (0.0-18.0) .15 Ͻ28%, No. (%) ventilation, d Risk of mortality, PIM 2, % 7.0 (0.3-42.9) 6.5 (1.0-21.3) .98 Abbreviation: PICU, pediatric intensive care unit. Highest lactic acid, µmol/L 3.5 (0.7-23.0) 3.7 (1.1-14.4) .67 aPaired t test. Highest creatinine, mg/dL 0.67 (0.15-4.81) 0.66 (0.23-4.97) .92 bFisher exact test. Worst shortening fraction 27.0 (14.3-48.9) 28.7 (22.0-45.6) .18 a during PICU admission, % ing fraction of less than 28% had reduced left ventricu- Female sex, No. (%) 49 (57)b 12 (35) .02 Artificial ventilation, 67 (78) 23 (68) .12 lar function (shortening fraction of 25%) with paradoxi- No. (%) cal movement of the intraventricular septum and a series Organism, No. (%) of PVCs during exercise. This patient had a shortening Neisseria meningitidis 77 (71) 20 (56) .06 fraction of 25% at PICU discharge. He is an active ath- Other 31 (29) 16 (44) lete and has no complaints (Table 2). All the other children had normal wall motion of the left ventricle. Abbreviations: PICU, pediatric intensive care unit; PIM, Pediatric Index of Mortality. The median TAPSE at follow-up in 86 patients was SI conversion factor: To convert creatinine to micromoles per liter, multiply 20.7 mm (range, 13.5-32.3 mm); 1 of 86 children (1%) by 88.4. had a TAPSE shorter than 15 mm. No other abnormali- a Of 67 participants and 19 nonparticipants. ties at echocardiography were found (Table 2). bP Ͻ .05, participants vs nonparticipants. In 65 of 108 patients (60%), we compared shortening fraction measured during PICU admission and at follow-up (Table 3). During admission, the worst me- Table 2. Cardiac Abnormalities in Pediatric Septic Shock Survivors at Follow-Up dian shortening fraction was 27.0% (range, 14.3%- 48.9%); at follow-up, the median shortening fraction was Characteristic Patients, No. (%) 36.2% (range, 25.0%-47.2%). A statistical difference was found between worst median shortening fraction dur- History (n=108) 1 (1) Physical examination (n=108) 0 ing admission and median shortening fraction at follow- ECG during rest (n=108) 0 up. During admission, 36 of these 65 children (55%) had Exercise (n=87) a worst shortening fraction of less than 30%; 34 (52%) Exercise capacity 0 of them had a worst shortening fraction of less than 28%. PVCs on ECG 7 (8) At follow-up, 6 of these 65 children (9%) had a short- Polymorphic PVCs 1 (1) ening fraction of less than 30% and 2 children (3%) had 24-h ECG (n=86) a shortening fraction of less than 28% (Table 3). The chil- PVCs 3 (3) Polymorphic PVCs 2 (2) dren with a shortening fraction of less than 30% and those Sinus arrest 1 (1) with a shortening fraction of less than 28% during ad- Echocardiography mission were compared with children with a shortening Left ventricular function (n=105) fraction of less than 30% and those with a shortening frac- Shortening fraction, median (range), % 35.9 (25.0-47.2) tion of less than 28%, respectively, at follow-up by Fisher Ͻ Shortening fraction 30% 13 (12) exact test. No association was found (Table 3). Shortening fraction Ͻ28% 3 (3) Right ventricular function (n=86) The control group of 52 healthy children consisted of TAPSE, median (range), mm 20.7 (13.5-32.3) 22 girls and 30 boys with a median age of 5.9 years (range, TAPSE Ͻ15 mm 1 (1) 0.8-17.3 years). The median shortening fraction was 36.2% (range, 28.1%-44.9%), and the median TAPSE was 19.9 Abbreviations: ECG, electrocardiogram; PVCs, premature ventricular mm (range, 16.1-31.0 mm). The median age of the con- contractions; TAPSE, tricuspid annular plane systolic excursion. trol group was significantly less than that of the patient group (Table 4). the 24-hour ECG recording (polymorphic PVCs in 2 and Cardiac abnormalities were detected in 6 patients monomorphic PVCs in 1). One patient (1%) had a sinus (shortening fraction Ͻ28% in 2, shortening fraction Ͻ28% arrest of 2.6 seconds (Table 2). and polymorphic PVCs in 1, TAPSE Ͻ15 mm in 1, and The median shortening fraction at follow-up in 105 polymorphic PVCs in 2). No statistically significant dif- patients was 35.9% (range, 25.0%-47.2%); 13 of 105 chil- ferences were found between children with and without dren (12%) had a shortening fraction of less than 30%, cardiac abnormalities with respect to sex, age at PICU and 3 of 105 children (3%) had a shortening fraction of admission, age at follow-up, follow-up time, risk of mor- less than 28%. One of the children (1%) with a shorten- tality (Pediatric Index of Mortality 2), length of ventila-

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/03/2021 Table 4. Shortening Fraction and TAPSE in Patients Table 5. Characteristics of Inotropic and Vasoconstrictive and 52 Healthy Children Treatment of 108 Patients and Correlation Between Cardiac Abnormalities and Inotropic and Vasoconstrictive Treatment Median (Range) in 6 Patients

Controls Patients Correlation Characteristic (n=52) (n=108) Median With Cardiac P Female sex, No. (%) 22 (42) 49 (57) Characteristic (Range) Abnormalities Value a Age, y 5.9 (0.8-17.3) 9.9 (2.4-27.1) Patients undergoing Shortening fraction, % 36.2 (28.1-44.9) 35.9 (25.0-47.2) treatment, No. (%) TAPSE, mm 19.9 (16.1-31.0) 20.7 (13.5-32.3) Dopamine 103 (95) 0.053 .58 Dobutamine 78 (72) 0.120 .21 Abbreviation: TAPSE, tricuspid annular plane systolic excursion. Epinephrine 24 (22) 0.162 .09 a P Ͻ .05, control group vs patient group. Norepinephrine 71 (66) 0.005 .96 Duration of treatment, d tion, and length of PICU stay. No correlations were found Dopamine 3 (1-41) 0.132 .19 Dobutamine 3 (1-41) 0.312 .005 between cardiac abnormalities and inotropic and/or va- Epinephrine 2 (1-39) 0.215 .31 soconstrictive agents used or duration of treatment with Norepinephrine 1 (1-41) 0.261 .03 or dosage of these agents (Table 5). Maximum dose, µg/kg/min Dopamine 20 (5-30) 0.061 .54 Dobutamine 10 (2-30) 0.114 .31 COMMENT Epinephrine 0.30 (0.02-5.00) 0.001 Ͼ.99 Norepinephrine 0.20 (0.03-10.00) 0.126 .29 In this study of 108 pediatric septic shock survivors, 6 Total duration of 3 (1-41) 0.102 .29 children had cardiac abnormalities consisting of PVCs inotropic and/or vasoconstrictive during exercise with 24-hour ECG registration (2 pa- treatment, d tients), decreased left ventricular function (2 patients), decreased left ventricular function and PVCs (1 patient), and decreased right ventricular function (1 patient). Surprisingly, only 1 patient had abnormalities ac- strictive agents may cause cardiovascular damage.4,29-31 It cording to medical history and physical examination. is conceivable that children are even more at risk for tis- These complaints were caused by tracheal injury due to sue damage because of their still-developing organ sys- the endotracheal tube and not cardiac dysfunction. tems.32-34 In our study, left and right ventricular function The rhythm disturbances found in this study are diffi- was normal in almost all patients (only 3 patients had short- cult to interpret. Because ECG recording at PICU admis- ening fraction Ͻ28% and 1 patient with TAPSE Ͻ15 mm). sion was not standard procedure, we could not compare The implications for future cardiac function in children with our findings with ECG data in the acute phase. Studies of decreased function are unknown and need further research. healthy ambulatory children have documented various Becausecorrelationswithpossibleriskfactorswerenotfound, rhythm disturbances with a range of incidences. Mono- the data do not support our hypothesis. However, analy- morphic PVCs are benign; polymorphic PVCs may form a sis of risk factors is only possible to formulate hypotheses risk for ventricular tachycardia and sudden cardiac death.20-24 for future studies owing to the small number of children Only 3 children had polymorphic PVC. The incidence of with abnormalities. We believe that against the background rhythm disturbances in our study is probably not higher of aging, long-term cardiac follow-up of septic shock sur- than that found in the normal population. Literature on vivors and a healthy control group is important. incidences and clinical relevance of rhythm disturbances A number of limitations to this study should be taken in healthy children is scarce. Additional studies in pediat- into account. First, the response rate of our study was ric septic shock survivors and healthy control groups have 75%. Although other follow-up studies in the PICU have to be done. Our findings, however, are reassuring and sug- had similar response rates, this could have biased our re- gest excellent recovery after septic shock with inotropic sults. Second, the number of studied children is small; and/or vasoconstrictive support. owing to differences in age at PICU admission and fol- Septicemia is associated with acute myocardial failure. low-up and in follow-up times, strong conclusions are In adult studies, myocardial function during septic shock difficult. Follow-up times varied between 0.8 and 12.7 is evaluated predominantly with echocardiography. In these years; evaluation of late effects is not possible 0.8 years studies, reduced ejection fraction was found in 40% to 50% after discharge and thus our results may have been bi- of patients with septic shock. Right heart dilation and de- ased by including patients with the shortest follow-up creased right ventricular function have also been de- times. As damaging effects of septic shock may only be scribed in the acute phase. The decrease in left ventricular seen much later in life, our follow-up time may have been function was reversible with full recovery of cardiac func- too short. Third, we only had a healthy control group for tion in 7 to 10 days.25,26 Theoretically, it is conceivable that cardiac function. The median age of this control group myocardial damage due to the inflammatory response, cell was significantly younger than the median age of the study death, and apoptosis with remodeling does not repair com- patients. The prevalences of rhythm disturbances and de- pletely and leads to impaired myocardial function.27,28 Fur- creased right ventricular function in healthy children are thermore, shock combined with inotropic and/or vasocon- not well documented in the literature. The median TAPSE

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/03/2021 in our healthy controls was 19.9 mm (range, 16-31 mm). tions and septic state on mortality of critically ill children. Am J Respir Crit Care The cutoff for a normal TAPSE of 15 mm in children was Med. 2005;171(4):348-353. 8. Maat M, Buysse CM, Emonts M, et al. Improved survival of children with sepsis possibly too low. Fourth, because this is a retrospective and purpura: effects of age, gender, and era. Crit Care. 2007;11(5):R112. cohort study, it was not possible to analyze fluid at the 9. Goldacre MJ, Roberts SE, Yeates D. Case fatality rates for meningococcal dis- same time echocardiography was performed. It was also ease in an English population, 1963-98: database study. BMJ. 2003;327(7415): not possible to evaluate the effect of other cardiodepres- 596-597. sant medication possibly given in the acute phase. Fifth, 10. Judge D, Nadel S, Vergnaud S, Garralda ME. Psychiatric adjustment following meningococcal disease treated on a PICU. Intensive Care Med. 2002;28(5): the risk factor analysis is statistically questionable be- 648-650. cause of the small number of children with abnormali- 11. Plötz FB, van Vught H, Uiterwaal CS, Riedijk M, van der Ent CK. Exercise- ties. A prospective study with an adequate control group induced oxygen desaturation as a late complication of meningococcal septic shock is necessary to analyze risk factors for cardiac damage. syndrome. JAMA. 2001;285(3):293-294. 12. Schibler A. Physiological consequences of early-life insult. Paediatr Respir Rev. 2006;7(2):103-109. CONCLUSIONS 13. Baraldi E, Filippone M. Chronic lung disease after premature birth. NEnglJMed. 2007;357(19):1946-1955. 14. Morris CK, Myers J, Froelicher VF, Kawaguchi T, Ueshima K, Hideg A. Nomo- In this small and diverse group of pediatric septic shock gram based on metabolic equivalents and age for assessing aerobic exercise ca- survivors, we found excellent recovery of cardiac per- pacity in men. J Am Coll Cardiol. 1993;22(1):175-182. formance in most patients. In a limited number of chil- 15. Colan SD, Parness IA, Spevak PJ, Sanders SP. Developmental modulation of myo- dren, we found rhythm disturbances and decreased left cardial mechanics: age- and growth-related alterations in afterload and contractility. J Am Coll Cardiol. 1992;19(3):619-629. ventricular function. We believe that long-term cardiac 16. Hagmolen of ten Have W, Wiegman A, van den Hoek GJ, Vreede WB, Derkx HH. follow-up in these patients is important. Life-threatening heart failure in meningococcal septic shock in children: noninvasive measurement of cardiac parameters is of important prognostic value. Accepted for Publication: May 8, 2008. Eur J Pediatr. 2000;159(4):277-282. Correspondence: Hendrika Knoester, MD, Pediatric 17. Rowland DG, Gutgesell HP. Noninvasive assessment of myocardial contractility, preload, and afterload in healthy newborn infants. Am J Cardiol. 1995;75 Intensive Care Unit, Emma Children’s Hospital, Aca- (12):818-821. demic Medical Centre, Meibergdreef 9, 1105 AZ Am- 18. Park MK. Pediatric Cardiology for Practitioners. 5th ed. Philadelphia, PA: Mosby sterdam, the Netherlands ([email protected]). Elsevier; 2008. Author Contributions: Study concept and design: Knoes- 19. Kaul S, Tei C, Hopkins JM, Shah PM. Assessment of right ventricular function ter, Sol, Ramsodit, Kuipers, and Bos. Acquisition of data: using two-dimensional echocardiography. Am Heart J. 1984;107(3):526-531. 20. Bjelakovic B, Vukomanovic G, Vukomanovic V, et al. Heart rate variability in chil- Knoester, Sol, Ramsodit, and Kuipers. Analysis and in- dren with idiopathic ventricular tachycardia. Clin Auton Res. 2007;17(3):153- terpretation of data: Knoester, Sol, Ramsodit, Kuipers, Clur, 159. and Bos. Drafting of the manuscript: Knoester, Sol, Ram- 21. Chiu SN, Wang JK, Wu MH, et al. Cardiac conduction disturbance detected in a sodit, and Kuipers. Critical revision of the manuscript for pediatric population. J Pediatr. 2008;152(1):85-89. important intellectual content: Knoester, Sol, Ramsodit, 22. Iwamoto M, Niimura I, Shibata T, et al. Long-term course and clinical characteristics of ventricular tachycardia detected in children by school-based heart dis- Kuipers, Clur, and Bos. Statistical analysis: Knoester, Sol, ease screening. Circ J. 2005;69(3):273-276. and Ramsodit. Administrative, technical, and material sup- 23. Massin MM, Bourguignont A, Gerard P. Study of cardiac rate and rhythm patterns port: Knoester, Sol, Ramsodit, and Kuipers. Study super- in ambulatory and hospitalized children. Cardiology. 2005;103(4):174-179. vision: Knoester, Kuipers, Clur, and Bos. 24. 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