pulmonary structural in neonatalpulmonary structural changes in neonatal hyaline membrane disease...

Thorax (1969), 24, 689.

Pulmonary structural changes in neonatal hyalinemembrane disease treated with high pressure

artificial respirationM. J. BECKER AND J. G. KOPPE

From the Laboratory for Pathological Anatomy and the Department of Neonatal Paediatrics,University of Amsterdam, Wilhelmina Gasthuis, Amsterdam, Holland

Fourteen babies with hyaline membrane disease were treated with artificial respiration usingintermittent positive pressure. At present six children are in good health; four still showalterations on the chest radiograph. Eight babies died; in these, high pressures (50 cm. H20 onthe average) were used with high concentrations of oxygen (up to 100%). Severe pulmonarychanges were found. The lungs were heavy and non-aerated. There was emphysema only in thechild treated for six weeks. Bronchi and bronchioli showed a marked epithelial hyperplasia as wellas squamous-cell metaplasia, whereas at other sites epithelial necrosis was apparent. The muscularlayer was hypertrophic and mucous glands appeared hyperplastic. Hyaline membranes containingbilirubin pigment were found in six of the eight cases. The alveolar epithelium was extremelyatypical. The interstitium showed a proliferation of fibroblasts which resulted in a pronouncedinterstitial fibrosis in the child treated for six weeks. It is suggested that this treatment may aggra-vate the pathological changes caused by the hyaline membrane disease itself. Therefore, artificialpositive pressure respiration should be used only when other measures fail to help the infantduring the period when spontaneous recovery is possible.

In spite of many clinical investigations and ofmuch experimental work the aetiology and patho-genesis of the hyaline membrane disease (H.M.D.)of the newborn infant is still unknown.The mortality in premature infants remains high,

especially in infants born after a gestation of lessthan 34 weeks, in spite of treatment with oxygenand intravenous infusions of glucose and alkalinefluids.

In recent years, in many centres artificial re-spiration with intermittent positive pressure hasbeen employed successfully in some children. Inother infants, however, there was no improvementof the funotioning of the lungs after some days ofartificial respiration; on the contrary, it wasnecessary to use very high concentrations ofoxygen and to increase the pressures during theartificial respiration. Both created new problemsbecause of the fact that high oxygen concentra-tions as well as high pressures of 40 cm. HaO ormore may be deleterious to the lung tissue. There-fore the treatment may lead to a vicious circleand these infants ultimately die or survive withincomplete recovery from the disease.

From July 1965 until September 1968, 14 pre-maturely born infants (Table) with clinical respira-tory distress syndrome were treated with artificialrespiration, using the so-called KeuskampAmsterdam infant ventilator, which is based on amodified Ayre's T-piece (Keuskamp, 1963).The clinical diagnosis of H.M.D. was made on

the following criteria: dyspnoea with sternal andintercostal retractions, expiratory grunting, a reti-culogranular appearance with an air-bronchogramon the radiograph of the chest, excluding all othercases of respiratory distress like meconium aspira-tion, congenital diaphragmatic hernia, etc. Allbabies were initially treated with glucose 10%and tris hydroxymethyl aminomethane (THAM)intravenously in order to correct the metabolicand respiratory acidosis, which was frequentlyestimated with the Astrup-method. The indicationsfor artificial respiration were apnoeic spells, in-crease of the Pco2 ajbove 80 mm. Hg, or severehypoxia when given 100% oxygen. (During theperiod of these observations catheterization of theumbilical artery was not yet done in this hospital ;the criterion of capillary oxygen saturation was

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M. J. Becker and J. G. Koppe

TABLE

Clinical Data

Case Sex Gestat. BirthAge Weight

(Weeks) (g.)

I M 35 2,220

2 M 30 1,680

3 M 33 2,180

4 F 34 2,010

5 F 27 1,320

6 M 30 1,710

7 M 31 1,720

8 M 31 1,980

9 F 32 1,960

10 M 32 1,840

11 F 28 1,030

12

13

14

M

M

M

30

32

33

Duration Maximumof Pressure

Artificial UsedRespiration (cm.

(Days) l-O)

3.1 3542 45

4 35

6 40

1 30

7

61

2

4

50

50

50

30

30

35

50

35

50

1,800 11,

2,200 33

2,310 4

Follow-up

Died after4 days

Died after6 weeks

Good health24 months



Died after8 days

Died after231 days

Died after7 days


Good health9 months

Died after12 days

Died after31 days

Good health6 months

Died after5 days

therefore used instead of arterial oxygen ten-sion.)

Six of these 14 children recovered and are atpresent in good health, although in four of themthe chest radiograph is not yet completely normal.Some clinical and necropsy data of the eightchildren who died will be reviewed, whereas thesevere structural alterations in the lungs will bediscussed separately in greater detail.

CASE REPORTS

CASE 1 A boy weighing 2,220 g. and aged 35 weeks,born by caesarean section, was severely asphyxiated.Since spontaneous respiration failed, he was imme-diately intubated and artificial respiration was per-formed. Although a few gasps followed, extubationwas not possible because of inability to ventilate thelungs. Artificial respiration was continued, using pres-sures up to 35 cm. H20, but the child died on thefourth day of life. At necropsy, apart from theatelectatic lungs, small subependymal haemorrhageswere found. This case is unusual in that the extremeform of respiratory distress syndrome immediatelyfollowed the period of asphyxia without an inter-vening period of recovery as a result of the resuscita-tion procedures.

CASE 2 A boy weighing 1,680 g. and aged 30 weekswas admitted 5 hours after birth with severe signs ofH.M.D. When the clinical condition deteriorateddespite conventional therapy, artificial respiration byendotracheal intubation was started at 28 hours.

During the first week radiographs showed progressiveopacification of both lung fields; weaning from therespirator proved to be impossible. Pressures necessaryfor ventilation had to be increased and at last pres-sures of 60 cm. H20 were used. After the first week,radiographs of the lungs showed rounded areas ofradiotranslucency scattered throughout the lungs, and,finally, there was an irregular pattern of translucentareas alternating with areas of density. After six weeksthe child died with signs of interstitial and sub-cutaneous emphysema and pneumothorax. The vocalcords were completely atrophied due to the continuousintubation.

CASE 6 This boy, weighing 1,710 g., who was thzfirst of twins born after 30 weeks' gestation, developedsigns of H.M.D. during the first half-hour. Artificialrespiration was started 31 hours after birth becauseof apnoeic spells. This was continued for seven days,using 80°' oxygen and increasing pressures up to 50cm. H20 because the function of the lungs did notimprove. The general condition remained very poorand during the 8th day of life, signs of kernicterusappeared. The bilirubin content of the blood at thattime was 13-7 mg./100 ml., but had been maximally16-9 mg./ 00 ml. on the 6th day of life. As the babywas clearly succumbing and died a few hours later,no exchange transfusion was performed. (Subse-quently, we have performed an exchange transfusionin babies with disturbances in acid-base balance whenthe bilirubin content is reaching 15 mg./ 100 ml.)At necropsy a kemicterus and an intraventricularhaemorrhage were found.

CASE 7 A boy weighing 1,720 g., born after 31weeks' gestation, developed the respiratory distresssyndrome soon after birth and artificial respirationhad to be started within 6 hours of birth. Pressuresof 40 cm. H20 and 80% oxygen were given, but theoxygenation of the blood decreased, probably as aresult of a progressive right-to-left shunt of the blood.The baby died after three and a half days. At nec-ropsy, a thrombosis of the portal vein and a focalnecrosis of the liver were found.

CASE 8 This baby, weighing 1,980 g., was born after31 weeks. From about four weeks there had existedsevere hydramnios of unknown cause. The infant wasoedematous and developed the typical signs of H.M.D.during the first half-hour. Artificial respiration wasstarted after 24 hours, but the radiograph of thechest showed no improvement during the followingdays: there remained a complete opacity. The childdied after seven days. At necropsy, periventricularleucomalacia and a subependymal haemorrhage werefound. The vocal cords were atrophied.

CASE 11 Immediately after birth this girl developedH.M.D. Twenty hours after birth repeated episodesof apnoea made it necessary to apply the respirator.Despite the administration of 100% oxygen, blood

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FIG. 1. Squamous-cell metaplasia of bronchial epithelium (H. and E. x 425).

FIG. 2. Atypia of alveolar epithelium (H. and E. x 680).

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L FIG. 3. Proliferation offibroblasts in the interstitium (Heidenhain's aniline-blue stain x 425).

FIG. 4. Pronounced interstitial fibrosis (van Gieson's stain x 425).



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Pulmonary structural changes in neonatal hyaline membrane disease

oxygenation was inadequate with a maximum satura-tion of 66%. The baby died, hypoxaemic, 36 hoursafter birth. At necropsy, a subependymal haemorrhagewas found.

CASE 12 This boy developed signs of H.M.D. duringthe first half-hour. The clinical condition deterioratedgradually despite conventional measures. Artificialrespiration was started 58 hours after birth. Pressuresof 50 cm. H20 and a concentration of 80% oxygenwere used. The baby died 32 hours later. At necropsyan intraventricular haemorrhage and a thrombosis ofthe sagittal sinus were found. The voal cords showedhaemorrhage and atrophy and there was degenerationof the left lobe of the liver.

CASE 14 After one hour this baby developedgradually progressive H.M.D. Generalized cyanosispersisted despite the administration of 100% oxygen.Arterial oxygen saturation of blood reached 80%,and the Pco2 fluctuated between 60 and 80 mm. Hg.Spontaneous respiration stopped 24 hours after birthand artificial respiration was started. It proved to benecessary to use a pressure of 50 cm. H20 and anoxygen concentration of 80%. Despite this treatment,the Pco2 did not go below 60 mm. Hg, whereas thePo2 reached a maximum level of 50 mm. Hg. Afterfive days the child died, and at necropsy, thrombosisof the sinus transversus and tracheitis were found.

PATHOLOGICAL FINDINGS

In all cases impressive pathological changes werefound in the lungs. The lungs were heavy, theweights varying between 60 and 120 g. Moreover,they appeared to be compact and non-aeratedexcept in one child treated for six weeks (case 2).In this particular case emphysema and distinctpools of mucous material were detected.The microscopical changes could be divided

into three groups: those in the bronchial system,in the alveolar apparatus, and in the interstitium.The bronchi and bronchioli showed marked

epithelial alterations. In several sites the epithelialcells appeared to be necrotic, whereas elsewherethe epithelial layer was detached. Apart from this,hyperplasia and squamous-cell metaplasia werenoted (Fig. 1). Mitoses were numerous. Moreover,the muscular layer of the bronchi showed hyper-trophy combined with hyperplastic mucous glands.The alveolar epithelium was extremely atypical

with signs of degeneration, including pyknosis ofnuclei and eosinophilia of the cytoplasm, as wellas signs of regeneration, such as mitoses (Fig. 2).Hyaline membranes were found in many alveolarducts. Sometimes a mixture of hyaline masseswith degenerated alveolar cells completely filledthe lumen. In nearly all cases the hyaline mem-branes contained bilirubin pigment.

3D

The alveolar spaces and ducts were widelyseparated by a loose connectivetissue in which adistinct proliferation of fibroblasts was apparent(Fig. 3). This loose texture was seen in all casesexcept in the child treated for six weeks (case 2).In this case a pronounced interstitial fibrosis wasfound (Fig. 4). The pulmonary arteries showedmedial hypertrophy, whereas the lymphatics weredilated.

DISCUSSION

Fourteen newborn infants with H.M.D. weretreated with artificial respiration using intermittentpositive pressure (I.P.P.). Eight babies died withsevere pulmonary changes. There appeared to bea marked difference in severity of the pathologicalchanges between the seven babies treated for oneto six and a half days and the one child treatedfor six weeks. In that particular case a distinctinterstitial fibrosis existed, whereas in the otherseven children only a proliferation of fibroblastswas apparent with little formation of fibres. Thismay be an indication that there is a progressiontowards an irreversible stage. However, in thissmall series an intermediate group was not present.Northway, Rosan, and Porter (1967) studied 32

children with H.M.D. treated with I.P.P. artificialrespiration and high oxygen concentrations. Nine-teen babies died with severe pulmonary changescomparable to our findings, which they termed'broncho-pulmonary dysplasia'. These authorsdistinguished four stages. First, there was a stageof the hyaline membrane disease sui generis, fol-lowed by the second stage between four and 10days, where, at necropsy, necrosis and regenerationof alveolar epithelium were found with persistenthyaline membranes. In the third stage (between10 and 20 days) a gradual transition into a chronicphase occurred which could lead to stage four,after one month, in which a distinct fibrosis wasapparent. Thzy were able to study two cases fromthe third stage, which is lacking in our series, andfound a distinct proliferation of fibroblasts in theinterstitium with spare formation of fibres. Thisstrongly suggests that this process shows progres-sion that ultimately may result in irreversible lungdamage. In the series of Northway et al. (1967),none of the children treated for more than 10days survived. Moreover, in their group of 13survivors there were four babies, treated for fiveto 10 days, who showed pulmonary insufficiency.The question arises as to whether these changes

can be interpreted as the natural course of H.M.D.or whether these alterations are induced by thetreatment. It has been pointed out by Boss and

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Craig (1962) and by Robertson (1964), in studiesof H.M.D. not treated with high pressure ventila-tion, that from the age of 3 to 4 days a reparativeprocess in the alveolar walls may be found. How-ever, in our seven babies treated for one to sixand a half days the pulmonary structural altera-tions were distinctly more severe as compared tothe changes descrilbed by these authors for thesame period. This may indicate that I.P.P. artificialrespiration may interfere with the natural courseof H.M.D. in such a way that the reparative pro-cess is accentuated. The possible influence of thistreatment may further be indicated by the workof Nash, Blennerhassett, and Pontoppiddan (1967),Regele (1967), and Barter, Finlay-Jones, andWalters (1968), who studied the lungs of adultpatients treated with artificial respiration and highoxygen concentrations for various conditions. Intheir patients, hyaline membrane-like structureswith interstitial fibrosis and metaplasia of alveolarepithelium appeared. It may be noted that five ofthe six babies in our series who survived weretreated with relatively low pressures of 35 cm.H2O, whereas the oxygen concentrations in threeof these reached values of 50% and in only twocases 80 %. One baby was treated for six dayswith pressures of 40 cm. H20 and oxygen concen-trations of 80%. However, four of these childrenstill present pulmonary alterations on the chestradiographs. Although it is tempting to speculateon the fact that the low pressures used exerted afavourable effect, it seems more likely that thenatural course of the disease in these childrenwould have been better than in the others.The question remains as to the factors involved

when studying the work of Stern, Ramos,Outerbridge, and Beaudry (1968) and Shepard,Johnston, Klatte, Burko, and Stahlman (1968),who treated babies with H.M.D. with a negative-pressure artificial respirator. Both reports give in-conclusive data with regard to the effects of thetreatment on the natural course of the disease.

Likewise, the influence of the positive pressure andthe oxygen concentration is not yet clear. Our dataalso give no distinct indication whether the pres-sures, the oxygen concentrations or both areresponsible for aggravating the lung pathology.A remarkable finding in our cases, which to our

knowledge has not been described before, is theaccumulation of bilirubin pigment in the hyalinemembranes. The maximum blood level for bili-rubin in our series was 196 mg./100 ml. Theaccumulation of bilirubin in hyaline membraneswas found in all cases, except in one baby treatedfor only one and a half days, with a low level ofbilirubin, and the baby treated for six weeks inwhom no hyaline membranes could be found atall. We therefore assume that the intermediateperiod resulted in such severe damage to thecapillary-alveolar structures that excretion of thealbumin fraction with bilirubin was facilitated.As mentioned above, since we treated the oneinfant with kernicterus, exchange transfusion isnow performed at lower bilirubin levels.

REFERENCESBarter, R. A., Finlay-Jones, L. R., and Walters, M. N. I. (1968).Pulmonary hyaline membrane: sites of formation in adult lungsafter assisted respiration and inhalation of oxygen. J. Path. Bact.,95, 481.Boss, J. H., and Craig, J. M. (1962). Reparative phenomena in lungsof neonates with hyaline membranes. Pediatrics, 29, 890.Keuskamp, D. H. G. (1963). Automatic ventilation in paediatricanaesthesia using a modified Ayre's T-piece with negative pressureduring expiratory phase. Anaesthesia, 18, 46.Nash, G., Blennerhassett, J. B., and Pontoppidan, H. (1967). Pul-

monary lesions associated with oxygen therapy and artificialventilation. New Engl. J. Med., 276, 368.

Northway, W. H., Rosan, R. C., and Porter, D. Y. (1967). Pulmonarydisease following respirator therapy of hyaline-membranedisease. Ibid., 276, 357.Regele, H. (1967). Veranderungen der menschlichen Lungen unter

maschineller Beatmung. Beitr. path. Anat., 136, 165.Robertson, B. (1964). Pulmonary hyaline membranes of the newborn.

Acta path. microbiol. scand., 62, 581.Shepard, F. M., Johnston, R. B., Klatte, E. C., Burko, H., and

Stahlman, M. (1968). Residual pulmonary findings in clinicalhyaline-membrane disease. New Engl. J. Med., 279, 1063.

Stern, L., Ramos, A. D., Outerbridge, E. W., and Beaudry, P. H(1968). Management of respiratory failure in the newborn infantwith a negative pressure respirator. Pediat. Res., 2, 400.

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