Children at High Altitude: Pulmonary and Renal Abnormalities

Transcription

1 Children at High Altitude: Pulmnary and Renal Abnrmalities By Richard L. Naeye, M.D. At elevatins abve 10,000 feet alvelar hypxia leads t pulmnary arterial hypertensin, arterial hypxemia, and secndary plycythemia in mst persns. 1 ' 2 The adjustments f adults t this hypxic envirnment have been extensively studied but there is relatively little infrmatin pertaining t nenates and yung children. The nly published catheterizatin study n yung children at high altitude is that f Penalza et al. wh reprted that in seven infants the average pulmnary arterial pressure was greater than that fund in lder children r adults. 1 The studies t be described belw reveal anatmical abnrmalities f the pulmnary vasculature and renal glmeruli in children reared at high altitudes, thus prviding an anatmical basis fr the pulmnary hypertensin bserved by Penalza. SUBJECTS Fifteen children wh died in Leadville, Clrad, during the perid 1954 t 1960 were selected fr study. The altitude f Leadville is 10,150 feet and the mean barmetric pressure 525 mm Hg. All children in the study died as a cnsequence f accidents r as a result f shrt illnesses including infectius prcesses. Three were stillbrn. Cases with renal r cardiac malfrmatins were specifically excluded. Ages ranged frm stillbrn t 11 years. The 80 cntrl infants with whm the Leadville children were cmpared varied in age frm stillbrn t 12 years. AH had resided near sea level. Nne were cyantic r had malfrmatins f the heart, lungs, r kidneys. Methds Previusly described methds were used t Frm the Department f Pathlgy, The University f Vermnt Cllege f Medicine, Burlingtn, Vermnt. Supprted in part by Grant HE frm the Natinal Heart Institute, U. S. Public Health Service. Received fr publicatin June 30, measure arterial changes in the pulmnary circulatin. 8 In each case, multiple blcks f lung and kidney were sectined at six micrns and stained with Verheff and van Giesn stains. Duplicate slides were stained with hematxylin and esin stains. With tiie aid f a camera lucida and a planimeter, the relative crss-sectinal areas f lumen, intima, and media f small muscular arteries were determined. Crss-sectinal areas were als determined fr individual nuclei in bth intima and media. All arteries fund in crss sectin which had a ttal diameter f 30 micrns r less were measured. All arteries were muscular in type and adjacent t respiratry brnchiles, alvelar ducts r alveli. Sme might classify these vessels as arteriles but we chse nt t d s because in the lung the term has been defined in s many different ways. The mean size f renal glmeruli was determined in a similar manner. 4 Blcks f renal tissue were taken t include the entire crtex. Glmeruli were utlined after prjectin nt paper with a camera lucida. In the selectin prcess, micrscpic fields were chsen in a pattern passing frm kidney surface t medulla since glmerular size ften varies in the different crtical znes. The glmeruli measured were selected n a randm basis in the individual micrscpic fields. Using a planimeter, the relative areas f 20 t 40 glmeruli were determined and the mean area calculated fr each case. The values determined were relative rather than abslute since measured glmeruli were in varying planes f sectin. A mean value fr glmerular, parenchymal cell density was als determined in each case. Parenchymal cell density was determined in individual glmeruli by dividing the number f parenchymal cells by ttal glmerular area. Sectins frm cases under study and frm cntrls were mixed and examined in a randm manner t avid bias. Results Fr pulmnary arteries f 30 micrns r less in diameter, intimal areas were almst identical fr high altitude and cntrl cases. In this age grup, the intima cnsists chiefly f endthelial cells. N intimal prliferative lesins were bserved. These bservatins Circulatin Rtiurch, Vl. XVI, Jtnutry 196} 33

2 NAEYE 34 FIGURE 1 Small pulmnary muscular artery frm a 40-day-ld nnhypxic, cntrl infant. The arterial media is seen between the tw pinters. (Verheff and van Giesn stains.) aided further analysis. The relative area f intima was selected as a cnvenient reference base line t which the arterial medial mass culd be cmpared. As in previus studies,3'4 a numerical expressin: area arterial media intimal area + internal elastic membrane was adpted as a relative measure f arterial muscle mass. In each case this value was determined fr 15 t 25 arteries. In infants frm high altitude, the medial muscle cat was nrmal at birth. In mst f thse wh survived three weeks r mre this muscle mass did nt underg a nrmal decrease (figs. 1 and 2). It usually remained at levels intermediate between birth and nrmal values (fig. 3). The variatin in muscle mass frm case t case is striking, sme children having a near nrmal mass f arterial muscle and thers a greatly increased mass, clse t that fund at birth. Bth smth muscle hyperplasia and hypertrphy cntribute t the increased bulk f pulmnary arterial muscle at high altitude. number f medial nuclei number f intimal nuclei was adpted as a relative measure f the number The rati: f smth muscle cells in individual arteries. In nrmal children there was a prgressive decrease in this rati after birth, suggesting a relative decline in the number f muscle cells (fig. 4). In cntrast, this rati remained at the birth level in sme children at high altitude, shwing a variable decline in thers (fig. 4). A relative muscular hypertrphy at high altitude is suggested by cmparing muscle mass with number f medial cells in the Leadville and cntrl cases. In cntrl cases after birth, muscle mass decreased mre rapidly than the relative number f smth muscle cells. In Leadville children ften neither change tk place (figs. 3 and 4). Thus, at high altitude, sme children after birth retain the relatively large pulmnary arterial muscle cells which nrmally are present nly befre r at birth. This relative hypertrphy at high altitude appears t be due t retentin f cytplasmic mass f individual muscle fibers since the mean size f individual muscle nuclei is similar in Leadville and in cntrl cases (fig. 5). N abnrmalities were fund in the pulmnary veins r capillaries f the Leadville children. N smth muscle was visible in the small pulmnary veins f either the Leadville r cntrl cases. Data are presented in figure 6 indicating FIGURE 2 Small pulmnary muscular artery frm 40-day-ld infant frm high altitude. The arterial media, lcated between the pinters, is thicker than that in cntrl case (fig. 1). (Verheff and van Giesn stains.) Circulatin Research, Vl. XVI, January 1965

3 CHILDREN AT HIGH ALTITUDE 35 that children at high altitude have nrmal sized glmeruli at birth. Subsequently glmeruli became abnrmally enlarged in all but tw f the Leadville children. The density f parenchymal cells in glmeruli f Leadville children was the same as that fund in cntrl patients. Since n abnrmal cells r tissue were fund in these enlarged glmeruli n histlgic examinatin, it is cncluded that the enlargement was due t a prlifera MONTHS AFTII URTH FIGURE 3 A rati reflecting arterial muscle mass fr small pulmnary arteries is pltted against age fr hypxic and nnhypxic children. After furth week f life, values are greater fr hypxic (Leadville) children. c 9-lMMIt c 2D l A t cc c - * c « S~ "TO" Mnth! After Birth FIGURE 4 A rati reflecting number f medial muscle cells fr small pulmnary arteries is pltted against age fr hypxic and nnhypxic children. After fur mnths f life, values are greater fr hypxic (Leadville) children, indicating a larger number f medial cells. This measurement was undertaken in nly 32 f the 80 cntrl cases. Circulatin Reiurcb, Vl. XVI, Jintury 196}

4 36 NAEYE tin f nrmal glmerular elements. This prliferatin may have resulted frm an elngatin f glmerular lps r an increase in their number; we d nt knw which prcess was respnsible. Discussin In the current study, stillbrn and newbrn infants frm high altitude had a nrmal medial mass f smth muscle in small pulmnary arteries. This suggests that antenatal pulmnary arterial pressures were within nrmal limits. Such factrs as hypervlemia and increased pulmnary bld flw which lead t antenatal hypertensin are prbably absent in infants brn at high altitude. 4 " 0 Subsequently, the large pulmnary arterial muscle mass present at birth decreased nrmally Mnths After Birth 12 /////16 24/////10 FIGURE 5 The mean size f individual muscle nuclei in small pulmnary arteries is similar in 15 hypxic (Leadville) and 32 cntrl cases. Mean values are expressed in arbitrary planimeter units. O MONTH! «"l» IIHTH FIGURE 6 After birth, glmeruu becme abnrmally enlarged in mst children residing at high altitude (Leadville). Renal tissue was available fr study in nly 13 f the 15 Leadville cases. Mean areas are expressed in arbitrary planimeter units. CircttUiia Research, Vl. XVI, Umm*ry 196}

5 CHILDREN AT HIGH ALTITUDE 37 in sme f the Leadville children but nt in thers. This may well be crrelated with the finding that sme children at high altitude have pulmnary arterial pressures as lw as thse fund at sea level while thers have pressures as high as thse nrmally present at birth In cattle at high altitude, pulmnary arterial pressure can be directly crrelated with pulmnary arterial muscle mass in individual animals. 9 Cntractin f the increased arterial muscular mass may be crrelated with the increased pulmnary arterial pressure respnse t exercise nted in children at high altitude. 1 ' 2 Children wh shw such a hyperreactin t exercise are usually the same children wh hyperreact t increased hypxia. 2 In general the pulmnary arterial changes in Leadville children resemble thse recrded in children develping alvelar hypxia at lw altitudes due t alvelar hypventilatin. 10 The present study extends ur knwledge f the pulmnary arterial muscular respnse t hypxia at the cellular level. It is nw clear that the reductin in muscle mass bserved in nrmal infants in the first tw weeks after birth is due largely t the lss f cytplasm frm individual smth muscle cells. This might be cmpared t the rapid lss f sarcplasm frm skeletal muscle fibers with disuse. 11 It appears that the nenatal lss f pulmnary arterial smth muscle cytplasm, nrmal at lw altitude, des nt ccur in many children at high altitude. This phenmenn at high altitude may reflect a cntinuatin f the prenatal vasmtr stimulus if the thesis is crrect that hypxemia r alvelar hypxia helps t maintain the high pulmnary vascular resistance nrmally fund in fetal life. 10 ' 12 The present study als shws that pstnatal hypxia can prevent the relative decrease in number f arterial medial cells which nrmally ccurs within a few mnths f birth. It seems likely that the increased pulmnary arterial muscle mass present at high altitude is the cause as well as the cnsequence f the hypertensin. The increased pulmnary arterial pressures recrded in residents at Circmlf.im Resurcb, Vl. XVI, Itnusrj 196} high altitude decrease nly slightly fllwing the injectin f acetylchline r the inhalatin f a gas mixture which raises the alvelar po 2 t values nrmal at sea level. 18 ' 14 When lng-term human r bvine residents at high altitude are returned t sea level it takes weeks r mnths fr the pulmnary arterial hypertensin t disappear. 14 ' 15 In fact, pulmnary hypertensin persists after hypervlemia and plycythemia have disappeared. 14 An increased medial muscle mass in individual pulmnary arteries is nt the nly vascular abnrmality fund in children at high altitude. Arias-Stella and Saldana fund an increased number f precapillary vessels adjacent t alvelar ducts with a muscular media. 10 They did nt find an increased muscle mass abut individual arteries as reprted in the present study. This may be related t the prbable inability f Arias-Stella's methd t demnstrate medial hypertrphy when arteries are dilated. Since pulmnary arteries are dilated in adults at high altitude, it is prbable that they are dilated in children as well. 3 The dilatatin has been related t an increased bld vlume which apparently exists at all ages. 3 ' 7 The renal glmerular changes fund in Leadville children resemble thse fund in children with cyantic types f cngenital cardiac malfrmatins. 17 In bth grups, glmeruli enlarge after the first mnth f life. This enlargement is due t a prliferatin f nrmal glmemlar elements. Several factrs present in children at high altitude may be respnsible fr the enlargement. These factrs include increased bld vlume, increased bld viscsity, arterial hypxemia, and reduced renal parenchyma! xygen tensin. Increased bld vlume and viscsity are assciated with abnrmal glmerular enlargement in a variety f disrders befre and after birth. These include recipient twins with the mnchrinic, crss-placental, transfusin syndrme, adults with chrnic cr pulmnale and the afrementined infants with cyantic types f cardiac malfrmatins. 4 ' 17 ' 18 Infants with cardiac malfrmatins and adults with chrnic cr pulmnale

6 38 NAEYE ften have arterial hypxemia as well. A rle fr renal parenchymal hypxia is suggested by the bservatin that individuals with sickle cell anemia have glmerular enlargement in the inner crtex where reductins in parenchymal xygen tensin are presumably mst severe. 10 Current infrmatin des nt make it pssible t decide which f these factrs may be significant at high altitude. The glmerular changes suggest the pssibility f an increased glmerular filtratin surface. Hwever, it may be difficult t ascertain what the influence f the glmerular changes is n renal functin because f cncmitant changes in bld vlume, renal parenchymal xygen tensin, and bld viscsity. It wuld be interesting t knw if residents at high altitude eventually develp the sclertic glmerular lesins fund in sme lder patients with cyantic cngenital cardiac malfrmatins. 20 Summary Changes in pulmnary arteries and renal glmeruli were assessed in children brn and resident at high altitude (Leadville, Clrad). The hypxia appears t arrest nrmal nenatal decrease f pulmnary arterial smth muscle in sme f these children. N abnrmalities were fund in pulmnary veins r capillaries. A quantitative study als demnstrated enlargement f renal glmeruli in the hypxic children after the first mnth f life, apparently due t a prliferatin f nrmal glmerular elements. References 1. PENALOZA, D., SEME, F., BANCHEBO, N., AND GAMBOA, R.: Pulmnary hypertensin in healthy man brn and living at high altitude. Med. Thracalis 19: 257, VOCEL, J. H. K., WEAVER, W. F., ROSE, R. L., BLOUNT, S. G., JR., AND GROVER, R. F.: Pulmnary hypertensin n exertin in nrmal man living at 10,150 feet (Leadville, Clrad). Med. Thracalis 19: 269, NAEYE, R. L.: Hypxemia and pulmnary hypertensin. Arch. Pathl. 71: 447, NAEYE, R. L.: Human intrauterine parabitic syndrme and its cmplicatins. New Engl. J. Med. 268: 804, LICHTY, J. A., TING, R. Y., BRUNS, P. D., AND DYER, E.: Studies f babies brn at high altitude. Am. Med. Assc. J. Diseases Children 93: 666, NAEYE, R. L.: Perinatal vascular changes assciated with underdevelpment f the left heart. Am. J. Pathl. 41: 287, SIME, F., BANCHERO, N., PENALOZA, D., GAMBOA, R., CRUZ, J., AND MARTICORENA, E.: Pulmnary hypertensin in children brn and living at high altitudes. Am. J. Cardil. 11: 143, VOCEL, J. H. K., PRYOR, R., AND BLOUNT, S. G.: The cardivascular system in children frm high altitude. J. Pediat. 64: 315, ALEXANDER, A. F.: The bvine lung: Nrmal vascular histlgy and vascular lesins in high muntain disease. Med. Thracalis 19: 336, NAEYE, R. L., AND LETTS, H. W.: The effects f prlnged nenatal hypxemia n the pulmnary vascular bed and heart. Pediatrics 30: 92, TOWER, S. S.: Trphic cntrl f nn-nervus tissues by the nervus system: A study f muscle and bne innervated frm an islated and quiescent regin f spinal crd. J. Cmp. Neurl. 67: 241, NAEYE, R. L.: Arterial changes during the perinatal perid. Arch. Pathl. 71: 121, ROTTA, A., CANEPA, A., HURTADO, A., VELASQUEZ, T., AND CHAVEZ, R.: Pulmnary circulatin at sea level and at high altitudes. J. Appl. Physil. 9: 328, PENALOZA, D., SIME, F., BANCHERO, N., GAMBOA, R., CRUZ, J., AND MARTICORENA, E.: Pulmnary hypertensin in healthy men brn and living at high altitudes. Am. J. Cardil. 11: 150, KUIDA, H., HECHT, H. H., LANCE, R. L., BROWN, A. M., TSACARJS, T. J., AND THORNE, J. L.: Brisket disease. III. Spntaneus remissin f pulmnary hypertensin and recvery frm heart failure. J. Clin. Invest 42: 589, ARIAS-STELLA, ]., AND SALDANA, M.: The muscular pulmnary arteries in peple native t high altitude. Med. Thracalis 19: 484, NAEYE, R. L.: Glmerular changes with cngenital heart disease. Bil. Nenatrum. In press. 18. ELLIS, P. A.: Renal enlargement in chrnic cr pulmnale. J. Clin. Pathl. 14: 552, BERNSTEIN, J., AND WHTTTEN, C. F.: A histlgic appraisal f the kidney in sickle cell anemia. Arch. Pathl. 70: 407, SPEAR, G. S.: Glmerular alteratins in cyantic cngenital heart disease. Bull. Jhns Hpkins Hsp. 106: 347, Circulatin Rtitsrcb, Vl. XVI, Jinuiry 196}