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nary vasodilation in pulmonary hypertension. Lancet 1991; 338:173-4.

8. Kinsella JP, Toews WH, Henry D, Abman SH. Selective and sustained pulmonary vasodilation with inhalation nitric oxide therapy in a child with idiopathic pulmonary hypertension. J Pediatr 1993;112:803-6.

9. Kinsella JP, Abman SH. Recent developments in the patho- physiology and treatment of persistent pulmonary hyperten- sion. J Pediatr 1995;126:853-64.

10. Dantzker DR, D'Alonzo GE, Gianotti L, Fuentes F, Nickeson D, Emerson M. Vasodilators in primary pulmonary hyperten- sion: variability of long term response. Chest 1989;95:1185-9.

11. Rubin L J, Mendoza J, Hood M, McGroon M, Barst R, William WB, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol): results of randomized trial. Ann Intern Med 1990; 112:485-91.

12. Rubin LJ, Groves BM, Reeves JT, Frosolono M, Handel F, Cato AE. Prostacyclin-induced acute pulmonary vasodilatation in primary pulmonary hypertension. Circulation 1982;66:334-8.

13. Higenbottam TW, Wells F, Wheeldon D, Wallwork J. Long- term treatment of primary pulmonary hypertension with con- tinuous intravenous epoprostenol (prostacyclin). Lancet 1984; 1 : 1046-7.

14. Higenbottam TW, Spiegelhalter D, Scott JP, Fuster V, Dinh-

Xvan AT, Caine N, et al. Prostacyclin (epoprostenol) and heart-lung transplantation as treatments for severe pulmonary hypertension. Br Heart J 1993;70:366-70.

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20. Mizushima Y. Lipid microspheres as novel drug carriers. Drugs Exp Clin Res 1985;11:595-600.

inflammatory processes may predispose children to high-altitude pulmonary edema

Anthony G. Durmowicz, MD, Edward Noordeweir, MD, Richard Nicholas, MD, and John T. Reeves, MD From the Departments of Pediatrics and Family Medicine, University of Colorado Health Sciences Center, Denver, and Snake River Medical Clinic, Dillon, Colorado

We investigated retrospectively whether the preexistence of inflammation-pro- ducing illnesses such as viral respiratory tract infections contributed to the devel- opment of high-altitude pulmonary edema in children. We found that the large majority of native low-altitude children, but not adults, who had this form of edema after traveling to high altitude also had evidence of a preexisting illness. We speculate that the release of inflammatory mediators associated with these illnesses may be tolerated at sea level but may predispose children to increased capillary permeability when superimposed on hypoxia and, possibly, cold and exercise. (J Pediatr 1997;130:838-40)

High-altitude pulmonary edema is a form of noncardiogenic

pulmonary edema observed in unacclimatized individuals

who rapidly ascend to altitudes greater than 2500 meters or

Supported by a Clinician-Scientist Award from the American Heart Association, a grant from the Society of Critical Care Medicine, and a Giles Filley Award from the American Physiological Society.

Submitted for publication April 17, 1996; accepted Sept. 25, 1996. Reprint requests: Anthony G. Durmowicz, MD, Pediatric Critical Care, Box B-131, University of Colorado Health Sciences Center, 4200 E. Ninth Ave., Denver, CO 80262.

Copyright �9 1997 by Mosby-Year Book, Inc. 0022-3476/97/$5.00 + 0 9/22/78500

in high-altitude natives who return home after a stay at low

altitude.l The incidence of HAPE is significantly greater in

teenage and younger children than adults; however, the rea-

son(s) for the increased incidence in children is unknown. 2

The presence of an ongoing pulmonary inflammatory pro-

HAPE URI

High-altitude pulmonary edema Upper respiratory tract infection

cess at the time of ascent to high altitude has previously been

hypothesized as a possible risk factor for the development of

HAPE, although no data exist either to support or to refute

this speculation, l Clinically, it appeared to one of us (E.N.)

The Journal ~[ Pediatrica Durmowicz et al. 8 3 9 Volume 130, Number 5

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Fig. l. Incidence of preexisting illnesses in children and adults with HAPE.

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URI Bronchitis Otitis Sinusitis Streptococcal Media Pharyngitis

Fig. 2. Type and distribution of preexisting illnesses in children with HAPE at presentation.

that many of the children visiting high altitude who had HAPE at presentation had evidence of a preexisting inflam- mation-producing illness, such as a viral upper respiratory tract infection, otitis media, or group A streptococcal phar- yngitis, that had begun before their ascent to high altitude.

M E T H O D S

To assess the frequency with which preexisting inflam- marion-producing illnesses were associated with the devel-

opment of HAPE in children, we exarnir~ed retrospectiveIy the medico! records of all children aged 1 to )6 years who

had HAPE at presenlation lo 1he Snake River Medical Cen- ter, in Dillon, Colo. (2800 m), during a 4-year pefio& HAPE

was diagnosed by the attending clinic physician and included the presence of hypoxemia as delermined by oxygen saturation,

the presence of crackles or frothy sputum on examination, a chest x-ray film consistent with puhnonary edema, and im- provement 12 to 24 hours after the institution of oxygen ther- apy. Charts were analyzed for age, sex, temperature, and oxy- gen saturation on initial presentation. The presence of preexist- ing illness was made from the medical history, prior or current

use of antibiotics, and/or physical examination findings. Sus- pected streptococcal pharyngitis was con_firmed by rapid test-

ing of a throat swab specimen. A total of 28 episodes of HAPE were assessed in 27 children. No patient was using acetz.zc~1a-

mide as prophylaxis for HAPE. In addition, the medical records of 127 patients with HAPE, ranging in age from 17 to 78 years,

were examined to assess ['or the presence of an intlanunatory

condition in adults before theh" ascent 1o high altitude and sub- sequent development of HAPE.

8 4 0 Durmowicz et al. The Journal of Pediatrics May 1997

R E S U L T S

In children with HAPE, there was an approximately equal

male/female ratio (52% to 48%). In four episodes of HAPE in children, it could not be determined whether symptoms of a preexisting illness were present before the child came to high altitude. Of the remaining 24 episodes of HAPE exam- ined, 19 (79%) were associated with the presence of a pre-

existing inflammatory process (Fig. 1). Presumed URIs were found to be the most common preexisting illness in children

(53%), followed by bronchitis (21%) and otitis media (16%) (Fig. 2). There were no significant differences in age

(8.3 • 0.9 vs 8.4 +_ 1.4 years), temperature (100.1 ~ +- 0.4 ~

vs 99.6 ~ -+ 0.7 ~ F) or initial oxygen saturation (78% + 2% vs 74% +-- 6%) between those children with preexisting ill-

ness (n = 19) and those without (n = 5) (normal oxygen sat- uration in children at this altitude is 91.7% +- 2.1% 3. Of the 127 adults who had HAPE at presentation, there was a large male preponderance (82% male vs 18% female). Seventeen adults with HAPE (13%) were found to have had an asso-

ciated preexisting inflammatory process, all of which were thought to be viral URIs (Fig. 1).

D I S C U S S I O N

The existence of a concurrent pulmonary infection has been speculated to be a possible risk factor for the develop- ment of HAPE. 1 This is the first study to examine directly

the question of whether there is an association between a preexisting inflammation-producing illness and the devel- opment of HAPE. We have shown a strong association between the presence of a preexisting illness and the devel- opment of HAPE in children visiting high altitude and

also, but to a lesser extent, in adults. Although the pathogen- esis of HAPE is unknown, both increased pulmonary vascu- lar hydrostatic pressure caused by hypoxic pulmonary vasoconstriction and fibrin-rich proteinaceous pulmonary edema fluid resulting from increased capillary permeability are present in persons with HAPE. 4, 5 Viruses and bacteria are known to release a variety of mediators and cytokines, some of which have been shown to alter vascular perme- ability, or possibly cause an exaggerated hypoxic vasocon-

strictor response, thereby increasing pulmonary vascular hydrostatic pressure and the development of pulmonary edema.6, 7 Another possibility is that a viral or bacterial

infection (or products released from the inflammatory response from such an infection) may increase the perme-

ability of the pulmonary epithelial cell barrier. If there is, as most data suggest, increased endothelial cell perme-

ability in response to hypoxia, 8 then a simultaneous increase in epithelial cell permeability may now result in clinical

pulmonary edema. The development of spontaneous HAPE in high-altitude residents who acquire relatively mild

respiratory tract illnesses seems to support this specula- tion. 9

Questions arise as to why children showed a much stron- ger association between the presence of a preexisting illness and the development of HAPE than did adults and why chil- dren with HAPE had an equivalent gender ratio, whereas in adults there was a large male preponderance. With regard to the former question, one speculation is that because the vas-

cular endothelial cell tight junctions of immature animals are not as well developed as those present in mature adult blood

vessels, they have an increased potential for capillary leak.l~

Another explanation is that because children have many

more viral and simple bacterial infections than adults, the probability of a preexisting illness in children in whom

HAPE develops is substantially increased. As for the latter, unpublished observations lead us to speculate that women are somehow "protected" from HAPE after puberty.

In summary, the great majority of children in whom HAPE developed during a high-altitude visit were found to have had a preexisting illness such as a URI, otitis media, or

streptococcal pharyngitis. We suggest that though these ill- nesses, with their subsequent release of inflammatory medi- ators, may cause only mild discomfort at sea level, when su-

perimposed on exposure to high altitude and perhaps exer-

cise, a previous subclinical increase in capillary permeability may now predispose the child visiting high altitude to HAPE.

R E F E R E N C E S

1. Hackett PH, Roach RC. High altitude pulmonary edema. J Wild Med 1990;1:3-26.

2. Hultgren HN. High altitude pulmonary edema. Adv Cardiol 1970;5:24-31.

3. Nicholas N, Yaron M, Reeves JR. Oxygen saturation in chil- dren living at moderate altitude. J Am Board Fam Pract 1993;6:452-6.

4. Lockhardt A, Saiag B. Altitude and human pulmonary circu- lation. Clin Sci 1981;60:599-605.

5. Schoene RB, Hackett PH, Henderson WR, Sage EH, Chow M, Roach RC, et al. High altitude pulmonary edema: characteris- tics of lung lavage fluid. JAMA 1986;256:63-9.

6. Grega GJ, Adamski SW, Dobbins DE. Physiological and phar- macological evidence for the regulation of permeability. Fed- eration Proc 1986;45:96-100.

7. Stevens T, Janssen PL, Tucker A. Acute and long-term TNF-c~ administration increases pulmonary vascular reactivity in iso- lated rat lungs. J Appl Physiol 1992;73:708-12.

8. Stelzner TJ, O'Brien RF, Sato K, Weil JV. Hypoxia-induc- ed increases in pulmonary transvascular protein escape in rats: modulation by glucocorticoids. J Clin Invest 1988;82:1840-7.

9. Fasules JW, Wiggins JW, Wolfe RR. Increased lung vasoreac- tivity in children from Leadville, Colorado, after recovery from high altitude pulmonary edema. Circulation 1985;72:957- 62.

10. Bertossi M, Mancini L, Favia A, Nico B, Ribatti D, Virgintino D, et al. Permeability-related structures in developing and ma- ture microvessels of the chicken optic tectum. Biological Structures & Morphogenesis 1992;4:144-52.