Relationship of pneumothorax to occurrence of intraventricular hemorrhage in the premature newborn

1982;69;144Pediatrics Alan Hill, Jeffrey M. Perlman and Joseph J. Volpe Premature Newborn Relationship of Pneumothorax to Occurrence of Intraventricular Hemorrhage in the http://pediatrics.aappublications.org/content/69/2/144 the World Wide Web at: The online version of this article, along with updated information and services, is located on ISSN: 0031-4005. Online ISSN: 1098-4275. PrintIllinois, 60007. Copyright © 1982 by the American Academy of Pediatrics. All rights reserved. by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, at Viet Nam:AAP Sponsored on February 10, 2014pediatrics.aappublications.orgDownloaded from at Viet Nam:AAP Sponsored on February 10, 2014pediatrics.aappublications.orgDownloaded from Relationship of Pneumothorax to Occurrence 144 PEDIATRICS Vol. 69 No. 2 February 1982 of Intraventricular Hemorrhage in the Premature Newborn Alan Hill, MD, PhD, Jeffrey M. Penman, MB, and Joseph J. Volpe, MD From the Departments of Pediatrics, Neurology, and Biological Chemistry, Washington University School of Medicine, St Louis ABSTRACT. The relationship of pneumothorax to the occurrence of intraventricular hemorrhage (IVH) has been studied in the premature newborn. The major ob- jective of the study was to determine whether the systemic hemodynamic changes that occur with pneumothorax are reflected in the cerebral circulation and whether these changes play a role in pathogenesis of IVH. Blood flow velocity was measured in the anterior cerebral after- ies by a transcutaneous Doppler technique in nine infants who developed pneumothorax in the first 3 days of life. At the time of pneumothorax there was a marked increase in flow velocity, especially during diastole, and, with resolution of pneumothorax, flow velocity returned to normal levels over the ensuing hours. The changes in flow velocity correlated closely with systemic hemodynamic changes that occurred with pneumothorax, ie, an increase in mean systemic blood pressure, especially diastolic pressure. IVH, documented by serial ultrasound scans, was observed shortly after pneumothorax in the nine infants. The data thus demonstrate a marked increase in flow velocity in the cerebral circulation at the time of pneumothorax. This increase is of importance in the genesis of IVH as is suggested further by the occurrence of IVH soon after the cerebral hemodynamic changes. Pediatrics 69:144-149, 1982; pneumothorax, cerebral hemodynamic changes, intraventricular hemorrhage. Pneumothorax is a frequent complication of mechanical ventilation in the premature infant with hyaline membrane disease.’ Recent studies2’3 have reported an association between the occurrence of pneumothorax and intraventricular hemorrhage (IVH) in such infants. However, a direct relationship between systemic hemodynamic changes, Received for publication June 8, 1981; accepted Aug 28, 1981. Reprint requests to (J.J.V.) St Louis Children’s Hospital, Wash- ington University School of Medicine, P0 Box 14871, St Louis, MO 63178. PEDIATRICS (ISSN 0031 4005). Copyright © 1982 by the American Academy of Pediatrics. which occur as a result of the pneumothorax, and subsequent alterations in the cerebral circulation, which may lead to IVH, has not been demonstrated. Because of the likelihood of disturbed cerebral au- toregulation in the premature infant,4 such systemic hemodynamic changes could be reflected directly in the cerebral circulation with consequent rupture of the vessels of the germinal matrix and, thus, IVH.5’6 The noninvasive measurement of cerebral blood flow velocity by a transcutaneous Doppler technique has been demonstrated in the newborn.7’8 In the present study, this technique was used to define the changes in flow velocity in the anterior cerebral arteries (ACAs) of newborn infants with pneumothorax. Following pneumothorax there were marked increases in flow velocity in the ACAS, followed by IVH. METHODS Patient Population The study group comprised 80 newborn infants admitted to the neonatal intensive care unit of St Louis Children’s Hospital between September 1980 and July 1981. Birth weights ranged from 650 to 1,500 gm (mean 900 gm). Mean gestational age was 30 weeks. Diagnosis of Intraventricular Hemorrhage Intraventricular hemorrhage was diagnosed by real-time ultrasound scan with an ATL (Advanced Technology Laboratories) sector scanner with 5- MHz rotary scan head placed over the anterior fontanel. Coronal images were defined by a plane through the Sylvian fissures and the head of each caudate nucleus. Parasagittal images were defined at Viet Nam:AAP Sponsored on February 10, 2014pediatrics.aappublications.orgDownloaded from P1 : S-D ARTICLES 145 by a plane through each lateral ventricle. Scans were performed on the first day of life and then daily for patients requiring mechanical ventilation. Additionally, ultrasound scans were performed on other occasions as indicated, eg, sudden deterioration in clinical condition or presence of RBCs in CSF; specifically, following pneumothorax, the ultrasound scan was repeated as soon as possible. Measurement of Pulsatility Index Blood flow velocity in the ACAS was measured with a Doppler flowmeter (Medasonics Versatone D-9) and two-channel recorder. With the infant quiet and in supine position, a 5-MHz transducer (Medasonics P-94) was placed over the anterior fontanel and directed toward each ACA independ- ently. Arterial pulsations were recorded and the mean systolic and diastolic amplitudes of flow were measured relative to a 1-kHz internal standard. A pulsatility index (P1) was calculated as adapted by Bada et al7 from Pourcelot’s index of resistance.9 Excellent correlation has been shown between this index and the extent of resistance to flow in the carotid arteries, as demonstrated by cerebral an- giography in both normal adult patients and in those with carotid occlusive disease.’#{176} The deriva- tion of the index is shown in Fig 1. It can be seen that P1 will vary inversely with blood flow velocity, particularly diastolic flow velocity. Thus, a high P1 is observed with low flow velocity, and a low P1 is found with high flow velocity. The P1 measurements in each ACA of individual patients differed by <0.02. A sequence of at least five peaks with highest amplitude were used for the calculation of P1. P1 measurements were made daily from the first day of life and more frequently if there was change in the infant’s clinical state. When pneumothorax occurred, P1 was measured as soon as possible and repeated frequently (not less than three times daily) until the pneumothorax resolved. Our normal value for P1 in the first month of life is 0.66 ± 0.06, derived from 50 patients ranging in 0 Fig 1 . Tracing of pulsations in anterior cerebral arteries (ACA) showing internal calibration of 1 kHz, mean systolic (5), and mean diastolic (D) amplitudes of flow and formula for calculation of pulsatility index (P1). gestational age from 30 to 40 weeks, without obvious evidence of cardiac, respiratory, or intracranial disease. Diagnosis and Management of Pneumothorax The diagnosis of pneumothorax was made on the basis of clinical findings, ie, deterioration in clinical condition, pallor, increased respiratory distress, decreased breath sounds on the affected side, and deterioration in blood gases, and was confirmed by radiologic findings ofextra-alveolar air with or without shift of mecliastinum. Treatment was by chest tube connected to underwater drainage. Subse- quent chest radiographs were obtained to assess resolution of the pneumothorax, and to check chest tube placement. Measurement of BlOOd Pressure Seven patients had an umbilical artery catheter in place; thus, both systolic and diastolic blood pressures were recorded. The catheter was connected by a Sorensen Intraflo System to a transducer (Bell and Howell) and a continuous record of blood pressure was provided by an Abbott’s arterial pressure monitor. In the remaining two patients, systolic blood pressure was recorded by a transcutaneous Doppler technique. RESULTS Relationship of IVH to Pneumothorax Nine infants with tension pneumothorax, which occurred between birth and 3 days of age, were observed. The age of occurrence of pneumothorax was <12 hours in four infants and between 12 and 36 hours in five infants. In each case, IVH, documented by ultrasound scan, was observed soon after pneumothorax. The temporal relationships of IVH to the occurrence of pneumothorax are presented in Table 1. In six infants (patients 1 through 6), serial ultrasound scans demonstrated absence of IVH prior to the pneumothorax. The interval of time between normal ultrasound scan and occurrence of pneumothorax was two hours in two patients, and 12 hours in four patients. In these six infants, IVH was diagnosed 0.5 hour after pneumothorax in one patient, two hours in one patient, six hours in one patient, 10 hours in two patients, and 24 hours in one patient. In three infants (patients 7 through 9), ultrasound examination was not performed prior to occurrence of pneumothorax. In patient 7, pneumothorax was observed at the age of 1 hour, and a small IVH was detected on the first ultrasound scan at the age of 11 hours. The size of the IVH (deter- at Viet Nam:AAP Sponsored on February 10, 2014pediatrics.aappublications.orgDownloaded from 0 z .J 4 U) -J Q. C. P) :063 146 PNEUMOTHORAX RELATED TO INTRAVENTRICULAR HEMORRHAGE TABLE 1 . Temporal and Intraventricular He Relationships of Pneumothorax morrhage (IVH) Patient Age at Diagnosis of Pneumotho- rax (hr) Interval from Normal Ultrasound Scan to Diag- nosis of Pneu- mothorax (hr) Interval from Diagnosis of Pneumothorax to Diagnosis of IVH (hr) 1 6 2 0.5 2 16 2 24 3 24 12 6 4 24 12 10 5 24 12 2 6 32 12 10 7* 1 36 -t 2t 11 0.5 8 10 -t 6 9 6 -t 0.5 * See text for details t Pneumothorax occurred prior to ultrasound scan. t Ultrasound scan showed small IVH (ie, scan was not strictly normal) prior to diagnosis of pneumothorax. Fol- lowing pneumothorax, however, ultrasound scan showed massive extension of IVH. mined by serial ultrasound scans) remained con- stant until recurrence of extraalveolar air at age 36 hours resulted in an immediate and marked extension of IVH. In patient 8, pneumothorax was observed at the age of 10 hours, and IVH was seen on the first ultrasound scan at the age of 16 hours. In patient 9, whose condition was stable clinically until the pneumothorax occurred at the age of 6 hours, IVH was diagnosed within 0.5 hour. Changes in Pulsatility Index with Pneumothorax The changes in P1 that accompanied pneumothorax are listed in Table 2. Prior to pneumothorax, the P1 values in patients 1 through 7 ranged from 0.54 to 0.69 (mean ± SE 0.63 ± 0.04). With the occurrence of pneumothorax, the range of P1 values decreased to 0.35 to 0.52 (mean ± SE 0.41 ± 0.06). In patients 8 and 9, P1 and ultrasound studies were not obtained prior to development of pneumothorax. However, at the time of pneumothorax, the P1 values were low in each case (0.42 and 0.36). Follow- ing drainage of the pneumothorax, the P1 values increased to normal in the eight infants on whom measurements were made (range 0.64 to 0.74, mean ± SE 0.70 ± 0.03). This normalization of blood flow velocity occurred during a period of 30 hours (Fig 2). The decrease in P1 at the time of pneumothorax and the return to normal values following resolution are statistically significant (P < .001). (During the course of this study we observed one infant who exhibited similar changes in P1 with pneumothorax, but who did not develop IVH.) In Fig 3 are shown the changes in the cranial Doppler tracings, before, at the time of, and after resolution of pneumothorax, in a typical case. The decrease in P1 is principally due to a marked increase in the diastolic component of flow velocity in the ACM, and to a lesser extent, to an increase in systolic flow velocity (Fig 3). These changes appear to reflect the changes in diastolic and systolic blood pressure (see next section), which may be transmitted to the cerebral vessels in a pressure- passive manner because of impaired autoregula- tion.4 TABLE 2. Relationship of Pulsatiity Index (P1) to Pneumothorax Pa- tient Pulsat iity Index (Mean ± SE) Prior to At Time of Following Pneumothorax Pneumothorax Resolution of Pneumothorax 1 0.63 ± 0.01 0.35 ± 0.01 2 0.63 ± 0.02 0.52 ± 0.03 0.72 ± 0.03 3 0.68 ± 0.02 0.50 ± 0.03 0.70 ± 0.04 4 0.69 ± 0.03 0.47 ± 0.02 0.68 ± 0.04 5 0.54 ± 0.02 0.36 ± 0.02 0.54 ± 0.02 6 0.63 ± 0.02 0.38 ± 0.03 0.63 ± 0.02 7* 0.65 ± 0.04 0.40 ± 0.02 0.66 ± 0.03 8 -t 0.42 ± 0.02 0.72 ± 0.03 9 -t 0.36 ± 0.03 0.74 ± 0.03 * Data shown refer to second pneumothorax (see Table 1); no measurements were made prior to or at time of first pneumothorax, which occurred at another hospital. t Pneumothorax occurred prior to P1 measurements. TIME (HOURS) Fig 2. Time course of changes in pulsatiity index (P1) with occurrence and resolution of pneumothorax. Note marked decrease in P1 at time of pneumothorax and subsequent return to normal values within 30 hours. A B. P(:032 P10.66 Fig 3. Typical Doppler tracing in an infant before (A), at the time of (B), and following resolution (C) of pneumothorax. Note increase in diastolic flow velocity and thus decrease in pulsatility index at time of pneumothorax. at Viet Nam:AAP Sponsored on February 10, 2014pediatrics.aappublications.orgDownloaded from ARTICLES 147 TABLE 3. Relationship of Blood Pressure (BP) to Pulsatility Index (P1) Before and at Time of Diagnosis of Pneumothorax Patient Before Pneumothorax At Time o f Pneumothorax Systolic! Pulse Mean BP P1 (Mean ± SE) Systolic! Pulse Mean BP P1 (Mean ± SE) Diastolic Pressure Diastolic Pressure 1 30/13 17 21 0.63 ± 0.01 28/21 7 25 0.35 ± 0.01 2 44/28 16 30 0.63 ± 0.02 42/30 12 35 0.52 ± 0.03 3 42/20 22 28 0.68 ± 0.02 39/27 12 34 0.50 ± 0.03 4 46 . . . . . . 0.69 ± 0.03 50 . . . . . . 0.47 ± 0.02 5 35/14 21 28 0.54 ± 0.02 51/37 14 40 0.36 ± 0.02 6 56 . . . . . . 0.63 ± 0.02 60 . . . . . . 0.38 ± 0.03 7* 44/22 22 29 0.65 ± 0.04 48/33 15 42 0.40 ± 0.02 8 37/19 18 26 . . . 39/26 13 34 0.42 ± 0.02 9 41/24 17 30 . . . 40/28 12 33 0.36 ± 0.03 * Data shown refer to second pneumothorax (see footnote to Table 2). Changes in Blood Pressure with Pneumothorax The changes in blood pressure at the time of pneumothorax are shown in Table 3. In each of the seven patients whose diastolic blood pressure was measured, an increase was documented. In all of these infants there was a consequent narrowing of pulse pressure. The mean blood pressure increased in all cases. These changes in diastolic pressure (P < .01), pulse pressure (P < .05), and mean blood pressure (P < .01) are statistically significant. Changes in pH and Pco2 Values in Infants with Pneumothorax The pH and Pco2 values were determined in each infant with pneumothorax. A marked decrease in pH occurred in each infant at the time of pneumothorax and an increase occurred following resolution. Mean values ± SD prior to, at the time of, and following resolution of pneumothorax were, respectively, 7.33 ± 0.06, 7.16 ± 0.07, and 7.35 ± 0.03. There was an increase in Pco2 in each infant at the time of pneumothorax and a decrease following resolution. Values prior to, at the time of, and following resolution of pneumothorax were, respectively, 42 ± 5, 54 ± 4, and 45 ± 4. The individual changes in pH (P < .0001) and Pco2 (P < .01) for each patient were statistically significant. CASE REPORT The following case history illustrates the major relationships between pneumothorax, IVH, and blood flow velocity in the ACAs. The patient was born at 27 weeks’ gestation to a 20- year-old gravida 2, para 0 following a pregnancy that was uncomplicated until the time of premature labor. Birth weight was 1,000 gm and Apgar scores were 4 and 7 at one and five minutes, respectively. The patient was in- tubated immediately following delivery. Chest radiograph was compatible with severe hyaline membrane disease and the infant was placed on a Bournes BP 200 Infant Pressure Respirator. At age 4 hours, an ultrasound scan of the head was normal (Fig 4, top) and the P1 was 0.63. At age 6 hours, there was a sudden clinical deterioration, characterized by pallor and marked deterioration in blood gases. Transillumination of the chest indicated pneumothorax, which was confirmed by chest radiograph. The P1 was 0.38. A chest tube was inserted and connected to underwater drainage. Thirty minutes following insertion of the chest tube, ultrasound scan of the head showed massive IVH (Fig 4, bottom). Subsequent chest radiographs showed resolution of the pneumothorax, but two Fig 4. Ultrasound scans (coronal section) of patient 1 prior to (top) and 30 minutes following (bottom) pneumothorax. Top, No defmite hemorrhage in subependymal germinal matrix can be detected. Bottom, Note marked intraventricular hemorrhage, greater on right than on left. at Viet Nam:AAP Sponsored on February 10, 2014pediatrics.aappublications.orgDownloaded from IDECREASEDVENOUS RETURN] DECREASED CARDIAC OUTPUT NARROW PULSE PRESSURE INCREASE PRES ) VENOUS URE FLOW AT INCREASED PRESSURE IN GERMINAL MATRIX CAPILLARIES IINTRAVENTRICULAR HEMORRHAGEJ 148 PNEUMOTHORAX RELATED TO INTRAVENTRICULAR HEMORRHAGE hours later there was a recurrence of pneumothorax and the infant died. DISCUSSION The present data report marked changes in blood flow velocity in the ACAS with the occurrence and resolution of pneumothorax in premature newborns who were undergoing mechanical ventilation. A direct relationship between pneumothorax and IVH has also been described. The changes in flow velocity suggest a mechanism by which pneumothorax may lead to IVH in the premature newborn. A close association between pneumothorax and the occurrence or exacerbation of IVH has been reported previously.2’3 Thus, Lipscomb et al3 have reported that of 14 ventilated premature infants who developed pneumothorax, 12 (86%) developed IVH. In an extensive study of IVH, reported by Dykes et al,2 the presence of extraalveolar air was shown to be a significant risk factor for the development of IVH. These studies raised the question of whether pneumothorax is related to IVH in a causative manner or whether pneumothorax and IVH are separate consequences of some common event(s). The data presented in this report suggest that the relationship between pneumothorax and IVH is an etiologic one and that the pathogenetic mechanism includes an abrupt increase in cerebral blood flow at the time of pneumothorax. A proposed scheme of the sequence of systemic and cerebrovascular hemodynamic events by which pneumothorax may lead to IVH is shown in Fig 5. It has been shown in animal studies that pneumothorax causes an increase in intrathoracic pressure which, in turn, causes a decrease in venous return to the heart.’ The decrease in venous return may be accentuated by the increase in pulmonary vascular resistance that follows lung collapse.’ The important result is a decrease in cardiac output. Thus, Simmons et al,” in a study of acute circulatory effects of pneumothorax in dogs, have demonstrated a decrease in cardiac output followed by a compensatory increase in peripheral vascular resistance and an increase in mean systemic blood pressure. In related experiments in human adult patients, increased intrathoracic pressure (eg, as occurs with the Valsalva maneuver) has been shown to cause a decrease in both cardiac output and in pulse pressure.’2 The narrow pulse pressure, by means of its effect on carotid sinus baroreceptors and aortic arch receptors, causes reflex vasocon- striction of the systemic circulation.’2 Animal studies have also confirmed that a narrow pulse pressure produces an increase in systemic blood pressure secondary to an increase in peripheral vasoconstric- tion.’3 Our observations agree with these findings; NCREASED PERIPHERAL RESIS ‘ANCE INCREASED SYSTEMIC BLOOD PRESSURE (PRINCIPALLY DIASTOLIC) ftpH,tpCO INCREASED FLOW VELOCITY IN ACA (DECREASED P1) Fig 5. Proposed scheme of sequence of systemic and cerebrovascular hemodynamic events by which pneumothorax may lead to intraventricular hemorrhage (see text for details). ACA, anterior cerebral arteries; P1, pulsatility index. thus, a consistent increase in diastolic and mean systemic blood pressure, together with a narrow pulse pressure, was documented with pneumothorax. The decrease in P1 in the ACAS at the time of the pneumothorax reflects a marked increase in principally diastolic flow velocity. These changes in cerebral blood flow velocity reflect the systemic hemodynamic effects of pneumothorax. Thus, in the presence of impaired cerebral vascular autoreg- ulation in the premature infant with pneumothorax,4 the increase in mean systemic blood pressure, particularly diastolic blood pressure, may be transmitted directly to the cerebral vessels in a pressure- passive fashion and a disproportionate amount of the systemic arterial circulation may be directed toward the cerebral vessels during diastole. The increase in Pco2 (and acidemia) that may accom- pany pneumothorax could act further to increase blood flow to the brain by dilating cerebral vessels.’4 Finally, in addition to the effects on the arterial side of the circulation, impeded venous return to at Viet Nam:AAP Sponsored on February 10, 2014pediatrics.aappublications.orgDownloaded from ARTICLES 149 the heart may result in generalized venous conges- tion and, more importantly, an increase in cerebral venous pressure (Fig 5)#{149}15 The latter might be ex- pected to cause a decrease in arterial flow velocity rather than the increase that we have reported. The fact that an increase does occur suggests that the cerebral capillary bed is subjected to simultaneous pressure-flow stresses from the arterial and the venous sides of the circulation. Those capillaries most vulnerable to such stresses, eg, those of the germinal matrix, would be likely to rupture and result in IVH. This final result, ie, P/H, was documented shortly after pneumothorax and the asso- ciated alterations in cerebral blood flow velocity. Note Added in Proof. Since the submission of this manuscript, we have observed six additional premature infants in whom IVH was documented within ten minutes to six hours after the occurrence of pneumothorax in the first two days of life. In each case, the changes in blood flow velocity described in this report were documented. REFERENCES 1. Monin P, Vert P: Pneumothorax. Clin Perinatol 5:335, 1978 2. Dykes FD, Lazzarra A, Ahmann P, et al: Intraventricular hemorrhage: A prospective evaluation of etiopathogenesis. Pediatrics 66:42, 1980 3. Lipscomb AP, Thornburn RJ, Reynolds EOR, et a!: Pneu- mothorax and cerebral hemorrhage in preterm infants. Lan- cet 1:414, 1981 4. Lou HC, Lassen NA, Friis-Hensen B: Impaired autoregula- tion of cerebral blood flow in the distressed newborn. J Pediatr94:118, 1979 5. Pape KE, Wigglesworth JS: Hemorrhage, Ischemia and the Perinalal Brain. London, Spastics International Medical Publications, 1979 6. Volpe JJ: Neurology of the Newborn. Philadelphia, WB Saunders Co, 1981 7. Bada HS, Hajjar W, Chua C, et a!: Noninvasive diagnosis of neonatal asphyxia and intraventricular hemorrhage by Dop- pler ultrasound. J Pediatr 95:775, 1979 8. Hill A, Volpe JJ: Decrease in pulsatile flow in the anterior cerebral arteries in infantile hydrocephalus. Pediatrics 69:4, 1982 9. Pourcelot L: Diagnostic ultrasound for cerebral vascular disease, in Donald I, Levi S (eds): Present and Future in Diagnostic Ultrasound. Rotterdam, Kooker Scientific Pub- lications, 1976, p 141 10. Grossman BL, Wood EH: Doppler ultrasonic evaluation of extracranial cerebrovascular disease, in Tarases JM, Fisch- gold H, Dilenge D (eds): Recent Advances in the Study of Cerebral Circulation. Springfield, IL, Charles C Thomas, 1970, p 175 11. Simmons DH, Hemingway A, Ricchiuti N: Acute circulatory effects ofpneumothorax in dogs. JAppiPhysiol 12:255, 1958 12. Sharpey-Schafer EP: Effect of respiratory acts on the circulation, in Dow P (exec ed): Handbook of Physiology. Section 2: Circulation, vol 3; WF Hamilton (section ed). Washington DC, American Physiological Society, 1965, pp 1875-1886 13. Ead HW, Green JH, Neil E: A comparison of the effects of pulsatile and nonpulsatile blood flow through the carotid sinus on the reflexogenic activity of the sinus baroreceptors in the cat. JPhysiol 118:509, 1952 14. Lessen NA: Control of cerebral circulation in health and disease. Circ Res 34:749, 1974 15. deLemos RA, Tomosovic JJ: Effects of positive pressure ventilation on cerebral blood flow in the newborn infant. Clin Perinatol 5:395, 1978 at Viet Nam:AAP Sponsored on February 10, 2014pediatrics.aappublications.orgDownloaded from 1982;69;144Pediatrics Alan Hill, Jeffrey M. Perlman and Joseph J. Volpe Premature Newborn Relationship of Pneumothorax to Occurrence of Intraventricular Hemorrhage in the Services Updated Information & http://pediatrics.aappublications.org/content/69/2/144 including high resolution figures, can be found at: Citations http://pediatrics.aappublications.org/content/69/2/144#related-urls This article has been cited by 6 HighWire-hosted articles: Permissions & Licensing http://pediatrics.aappublications.org/site/misc/Permissions.xhtml or in its entirety can be found online at: Information about reproducing this article in parts (figures, tables) Reprints http://pediatrics.aappublications.org/site/misc/reprints.xhtml Information about ordering reprints can be found online: Online ISSN: 1098-4275. Copyright © 1982 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it at Viet Nam:AAP Sponsored on February 10, 2014pediatrics.aappublications.orgDownloaded from

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