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Postasphyxial lung disease in newborn infants with severe pennatal acidosis
FETUS, PLACENTA, AND NEWBORN Postasphyxial lung disease in newborn infants with severe perinatal acidosis Donald W. Thibeault, M.D., Frederick K. Hall, D.O., Michael B. Sheehan, M.D., and Robert T. Hall, M.D. Kansas City, Missouri The pulmonary course and respiratory management of 65 asphyxiated infants with at least one arterial pH :s7.00 within the first 2 hours of life was determined. Asphyxia in the preterm and term infants in the absence of respiratory distress syndrome or meconium aspiration syndrome was associated with a transient respiratory insufficiency requiring assisted ventilation which markedly improved in the first 24 hours of life. In contrast, infants with asphyxia complicated by respiratory distress syndrome or meconium aspiration syndrome developed profound lung disease including pulmonary hemorrhage and persistence of the fetal circulation. The course of their illness was significantly worse than control infants without asphyxia. Ineffective neonatal resuscitation allowing for the development of meconium aspiration syndrome and persistent respiratory acidosis contributed to the severity of illness in more than 50% of the infants. Central nervous system pathologic conditions were present in asphyxiated infants with and without severe pulmonary disease. We conclude that severe asphyxia in the absence of underlying lung disease results in a predictable postasphyx ial transient respiratory insufficiency, with marked improvement in the first 24 hours of life. (AM J OBSTET GVNECOL 1984;150:393-9.)
The pulmonary course and the respiratory management of severely asph yxiated infants is not well defined. Perinatal asphyxia, severe acidosis,' and hypoxia" 3 are known to cause increased pulmonary vascular resistance with right to left sh u nting through fetal channels and depression of surfactant metabolism."? However, it has been difficult in human infants to separate th e effects of perinatal asp hyxia and severe acidosis on pulmonary function from those alterations associated with common newborn conditions such as the respiratory distress syndrome, meconium aspiration syndrome." 9 and pulmonary hypoplasia." The purpose of this report is to define the nature and severity of lung disease caused by perinatal asph yxia in preterm and term newborn infants .
Material and methods Sixty-five infants consecutively admitted to a newborn tertiary intensive care unit with at least one arteFrom the Section of Ne ona tology, Th e Children's Mer cy Hospital, Un iversity of M issouri, Kansas City, School of M edicine. R eceivedfor publication J uly 27,1983 ; revised Ap ril 6, 1984 ; accepted May 23, 1984 . R eprint requests: Donald W . Thibeault, M.D., The Children's M ercy Hospital, 24th and Gillham, Kansa s City, MO 64108.
rial pH $7.00 within the first 2 hours of life were studied . These infants were born in primary and secondary hospitals and transferred within the first 4 hours oflife to the tertiary hospital by a transport team that included a neonatologist and a nurse. The ability to resu scitate the infants at the referring hospitals var ied from having a neonatologist present at the deli ver y to th at of ha ving a delivery room nurse without an y special training in resuscitation. Infants with sepsis , con gen ital he art disease, and other congenital anomalies were excluded. Prenatal , intrapartum, and newborn re cords were obtained from the referring hospitals. Details of deli very room re suscitation and subsequent ventilatory support were obtained directly from the records of nurses or physicians who were present at the delivery. The precise time of arterial blood gas measurements was established in all cases. Arterial blood gas values, ventilator settings, and inspired ox ygen concentrations were obtained from the patient's neonatal intensive care unit flow record . Infants requiring ven tilator care were treated with Baby Bird or Bournes BP-200 re spirators. Respiratory distress syndrome was diagnosed if all of the following criteria were met: (I) deep chest wall re-
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Table I. Comparative data of infants with pH ~7.00
Table II. Predisposing conditions for the
in the first 2 hours of life Preterm
No. of infants 26 Gestational age (wk) 31.0 ± Birth weight (kg) 1.56 ± Apgar score, I min 2.8 ± 4.6 ± Apgar score, 5 min Time pH measured (hr) l.l ± pH 6.92 ± Pco, 79 ± Po, 81 ± Flo, 89 ± Base excess -19.8 ±
0.6* 0.14 0.4 0.4 0.2 0.01 6 14 3 l.l
Term
39 41.1 3.46 2.2 3.4 1.0 6.86 67 92 86 -24.4
± 0.3 ± 0.10 ± 0.3
± 0.4
± 0.1 ± ± ± ± ±
October 15. 1984 J Obstet GynecoI
0.02 6 15 4 0.6
*Mean ± SEM. tractions, (2) an audible expiratory grunt, (3) an increased ambient oxygen concentration for 48 hours to keep the arterial oxygen tension greater than 50 mm Hg, and (4) radiologic evidence of reduced lung volume with a diffuse reticular granular pattern and prominent air bronchograms. Meconium aspiration syndrome was diagnosed if all the following criteria were met: (1) a history of meconium in the amniotic fluid, (2) meconium in the mouth at delivery, (3) increased respiratory rate with an increased anteroposterior diameter of the chest, and (4) Roentgenographic evidence of pulmonary infiltrates and air trapping. An additional 30 preterm infants with respiratory distress syndrome and 20 term infants with meconium aspiration syndrome consecutively admitted but without severe acidosis (pH >7.20) serveJ as study control subjects. All the control preterm infants required assisted ventilation but only eight of the control term infants with meconium aspiration syndrome required ventilator treatment. Results
There were 26 preterm infants who had a pH :s7.00 in the first 2 hours of life (Table I). Their gestational ages ranged from 26 to 36 weeks with a mean of 31.0 ± 0.6 weeks. Birth weight range was 0.76 to 2.86 kg with a mean of 1.56 ± 0.14 kg. Twelve of the 26 preterm infants had respiratory distress syndrome in addition to asphyxia. Mean gestational ages and birth weights were not significantly different between infants with and without respiratory distress syndrome. The control preterm infants with respiratory distress syndrome but without severe asphyxia had a mean gestational age of 32.2 ± 0.4 weeks and birth weight of 1.59 ± 0.08 kg, which measurements were not significantly different from those of severely asphyxiated preterm infants. Thirty-nine term infants had a pH :s7.00 within the first 2 hours of life. Their gestational ages ranged from
development of severe acidosis of pH ~7.00 in infants in the first 2 hours of life
No. of infants Respiratory distress syndrome Meconium aspiration Third-trimester bleeding Anemia at birth (hemoglobin ,,;10 gm %) Prolapsed umbilical cord or tight nuchal cord Difficult high-forceps delivery Monitoring of fetal heart rate Late deceleration Severe variable deceleration Precipitous delivery Maternal hypotension Abruptio placentae Maternal lupus Ineffective resuscitation
Preterm
Term
26 12 0 4 2
39 0 25 0 0 5
I
12 4
4 2 I
3 0 17
4 32 21 8 I
2 4 I
16
38 to 44 weeks with a mean of 41.1 ± 0.3 weeks. Twenty-five of these term infants had meconium aspiration syndrome as well as asphyxia and 14 had asphyxia without meconium aspiration syndrome. The mean gestational age of the infants with meconium aspiration syndrome was significantly greater than that of term infants with asphyxia alone, 41.6 ± 1.4 weeks versus 40.2 ± 1.6 weeks (p < 0.01). Only seven of the 25 infants with meconium aspiration syndrome had tracheal aspiration prior to administration of positive pressure resuscitation. The skill demonstrated and quality of this procedure were quite heterogenous. The control term infants with meconium aspiration syndrome without severe asphyxia had a mean gestational age of 41.1 ± 0.4 weeks and birth weight of 3.45 ± 0.11 kg, which measurements were not significantly different from those of the severely asphyxiated term infants. Predisposing conditions to the severe acidosis in both preterm and term infants are shown in Table II. Both the 1- and 5-minute Apgar scores were markedly depressed (Table I). Twenty-one of the 26 preterm infants and 34 of the 39 term infants had 5-minute Apgar scores :s6.0. Seventeen preterm infants and 16 term infants appeared to have ineffective delivery room and early newborn resuscitation based upon the observation that following the initial resuscitation efforts the pH remained :s7.00 with an elevated Pco, 2':55 mm Hg. In addition, 18 of the 25 severely asphyxiated infants with meconium aspiration did not have tracheal suctioning at birth. These results indicate that both in utero asphyxia and ineffective newborn resuscitation contributed to the severe postnatal acidosis. The arterial pH :s7.00 was initially detected in the 26
Postasphyxial lung disease in newborn infants 395
Volume 150 Number 4
o NO RDS (SEVERE ACIDOSIS)
• RDS (SEVERE ACIDOSIS) • RDS (MILD OR NO ACIDOSIS)
1 2
4
8
24
48
96
120
Fig. 1. Serial relationship of peak ventilator pressure (mean ± SEM) in asph yxiated pre term infant s with and without respiratory distress syndrom e (RD S) and in nonseverely asphyxiated preterm infants with respiratory distress syndrome . Severely asphyxiated infants with respiratory distre ss syndrome required significantly higher peak ventilator pressure s between 4 and 96 hours (p < 0.025) than those infants who were asphyxiated but without respi rator y distress syndr ome. Infants with respiratory distress syndrome but without severe asphyxia required significantly lower pressures in comparison to severely asphyxiated infants with respiratory distress syndrome between I and 24 hours (p < 0.025). Numbers indicate infants alive at any age.
preterm infants at a mean age of 1.1 ± 0.2 hours oflife and in the 29 term infants at 1.0 ± 0.1 hours (T able 1). It was not possible to accurately determine the length of time the pH was below 7.00 ; however, most infants had respiratory distress fo r a prolonged period prior to the first pH measurement. Comparison of the mean arterial pH, Pco. ; POz, ba se deficit, a nd Flo, between the preterm and term infants revealed th at they were not sig n ifica n tly d ifferent at the time the initi al pH was :57 .00 (T able I). Infants in both groups had a combined respiratory a nd metabolic acidosis . The relativel y normal mean arterial POz va lu es are misle ading in that most infants were re ce iving some type of assisted ve ntilatio n and all were breathing an enriched a m bie n t ox ygen co ncen tratio n at the time of measurem ent. Seventeen of the 26 severely asph yxiated preterm infants developed seizures at a mean age of 33.3 ± 9 hours. The mean age at o nse t was 37 .1 ± 10 hours in those with respiratory di stress syndrome and 29.3 ± 9 hours in those without respiratory di stress syndrome. Twenty-six of 39 asph yxiated term infants developed seizures at a mean age of 12.9 ± 4.8 hours with a range of 30 minutes to 96 hours. Seventeen of 25 infants with meconium aspiration syndrome and as p hyxia had seizures whi ch began at a mean age of 18.2 ± 5.8 hours.
Nine of 14 infants who were asph yxiated witho ut meconium as p ira tion synd rome had seizures which began at a me an age of 2.8 ± 1.1 hours. Pulmonary course of preterm infants All the preterm infants that had a pH :57.00 required ventilator assistance for at leas t 24 hours following resuscitation. Me an duration of ven tilato r assistance was 85.5 ± 29 hours among su rv iving in fants. Ventilator su ppo rt in th e preterm infants is summarized in Figs. 1 to 3. The se verity and co urs e of pulmonary in suffi ciency in asph yxiated preterm in fants without re spiratory d istress syndrome is of particular interest. The highest mean ventilator inspirat ory pressure and mean airway pressure in this group were 20.2 ± 0.4 ern HzO and 9.5 ± 0.3 cm HzO, respectively, which occurred at 1 hour of ag e . Thereafter peak ventilator pressure requirements and me an air way pressure progressivel y decreased over the fir st 24 hours of life to mean le vels of 8.5 ± 2.1 cm H zO a nd 3.3 ± 1.0 cm H zO, respectively. Me an in spired oxygen requirements followed the same pattern as the pressures, declining from a high of 0.80 ± 0.06 at 1 hour to 0.44 ± 0.08 at 24 hours of ag e . Seven of 14 preterm infants without respiratory dis-
396
Thibeault et al. Am
October 15, 1984 J Obstet Gynecol
o NO RDS (SEVERE ACIDOSIS)
• RDS ( SEVERE ACIDOSIS) • RDS (MILD OR NO ACIDOSIS)
0N
J:
E
. .
~
Gl :::I
10
01 01
Gl
Q.
>
III
~
Ci
5
l: III Gl
~
1
4
8
'
..
48
24
96
120
AGE (Hrs)
Fig. 2. Serial re latio nshi p of me an airway pressu re (mea n e SEM) in asph yxiated pret erm in fants with and witho ut respi rato r y di stress synd ro me and in non severely asphyxiated preterm in fants with respiratory d istr ess synd ro me . Severely asphyxiated in fants with respiratory distress syndrome had significan tly high er me an airway pressures between 4 and 96 hours than tho se in fan ts asphyx iated but without resp irat o ry distress synd ro me. Infants with respiratory distress syndrome but with out seve re asphyxia required sign ifican tly lower mean pressures in co m parison to severely asp hyx iated infa nts with respi r atory d istr ess syndro me bet ween I and 8 hours (p < 0.0 25). Nu mbers indicat e in fan ts alive at any age .
tress syndro me d ied at a mean age of 99 ± 26.3 hours . The me an inspired ox ygen requirement at the time o f th eir de ath was 0.28 ± 0.0 3 with a me an peak ventilator pressure of 10.1 ± 1.7 em H 20 . These pressure and inspired oxygen concentrations in dicate that lung disease was not the cause of death in these infants. None of the 14 infants developed severe persistence of the fe tal circ u lation, i.e., none requi red high respirator pressure >30 em H 20, pulmon a ry vasod ilators, or pH >7.45 to maintain an adequate art erial ox ygen tension. The cause of death in th e seve n infa n ts was anoxic ence pha lo malacia (4 cases), renal failure (2), and m yocardial insufficiency with co ngestive heart failure (I ). Preterm infants with respiratory d istre ss syn d rome as well as asp hyxia had de terio rat ion o f lung function with in the fir st 24 hours of life rath er than an improvement. The mean peak insp irat ory pressure at 24 hours of ag e was 26.1 ± 1.3 em H 20 and the mean airway pressure 11.2 ± 1.3 em H 20 while breathing oxy gen with a mean Flo, of 0.72 ± 0.06. These FIo 2 and pressure measurements were signi fican tly higher th an those in the asph yxiat ed infants without respiratory distress syndrome (Figs . I to 3). Nin e of the 12 asphyxiated infants with respiratory di stres s syndrome died at a mean age of 67.7 ± 20 hours . These infants had severe pulmonary insuffi-
ciency at the time of de ath with a mean Fl o, of 0.61 ± 0.09, a mean peak inspirat ory pressure of 23.3 ± 2.8 em H 20, and a mean airw ay pr essure of 12.0 ± 2.4 em H 20 . Seven infants had auto psies and all had diffuse h yaline membranes; five had pulmonary hemorrhage, th ree had anoxic encephalomalacia, an d six had intracra n ial hemorrhages. The co n tro l preterm infants with respiratory distress syn d ro me but without severe asp hyxia h ad less pulmonary insufficiency than those with res pirato ry distress synd ro me and asph yxia (Figs. 1 to 3). Unlike the condi tion of the asphyxiated infants with re spiratory di stress syn d ro me, the pulmon ary insu fficiency was relatively mild in the first 8 hours of life and peaked at 24 to 48 hours. Only one o f the 30 infants died . Pulmonary course of term infants
Pulmonary findin gs of th e 39 te rm infants with pH :::0;7.00 are show n in Figs. 4 an d 5. All but two infants with severe perinatal asphyxia req uire d assisted ventilatio n follow ing resuscitation. The mean duration of assisted ventilation of those 37 infants was 66.0 ± 12.0 hours with a range of 2 to 3 12 hours. There were 14 infants without meconium aspiration in which asphyxia appeared to be the only cause of the pulmonary insufficiency. Mean pe ak ventilator pres-
Postasphyxial lung disease in newborn infants 397
Volum e 150 Number 4
o NO
RDS (SEVERE ACIDOSIS) • RDS (SEVERE ACIDOSIS) _RDS (MILD OR NO ACIDOSIS)
....1'1
0
u::: cG)
1.0
Cl
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..
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'C G)
.80
'c, III .E .60
-
................ ,T
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0 :;: .40
..
o
III II.
AGE (HRS)
.20
1
4
8
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24
48
~C5- - -0 96
120
Fig. 3. Serial rela tionship of ins pired oxygen requirements (mean ± SEM) in asphyxiated pre ter m infan ts with and witho ut respiratory di stress syndrome, and in no nsev e rely asphyxiated preterm infan ts with respiratory d istress syndrome. Severely asphyxiated infants with respiratory distress syn d rome had significantly higher oxygen requirements between 4 and 48 hours than did those infants asphyxiated but without respiratory distress syndrome (p < 0.025) . The oxygen requirements in severely asphyxiated infants with respiratory distress syndrome and those infants with respiratory dis tress syndrome but not severel y asphyxiated were not significantly different.
•
o
•
MAS (WITH SEVERE ACIDOSIS) NO MAS (WITH SEVERE ACIDOSIS) MAS (MILD OR NO ACIDOSIS)
..... 48
~
96
AGE (Hrs)
Fig. 4. Serial relationship of peak ven tilator pressure (mean ± SEM) in as phyxiated term infants with and without meconium asp iration syndrome (MAS) and in nonseverely asphyxiated infants with meconium aspiration syndrome. Severely asphyxiated infants with meconium aspiration syndrome require sign ificantly hig her peak ventilator pressures at 8 hours and from 72 to 120 hours than do those infants asphyxiated but without meconium aspiration syndrome (p < 0.05) . Infants with meconium aspiration syndrome but without severe asph yxia had significantly lower peak ventilator pressure from I to 120 hours (p < 0.025) when compared to those severely asphyxiated infants with meconium aspiration syndrome. Numbers indicate infants alive at an y age.
sure and mean airway pressure III these 14 infants reached a maximum during the first 8 hour s of life of 14.5 ± 4.6 em H 2 0 and 7.6 ± 2.5 em H 2 0 , respectively, and declined progressively un til 72 hours of age, a t which time only o ne infant was receiving assisted ventilatio n. The Fl o, followed the same declining tren d , approaching th at of room ai r at 96 hours of life. Seven of these 14 infants died within the firs t 96 hours of life. T h ree of these 7 infants at death were breathing ambien t air, requirin g no vent ilato ry assistance, and ap-
peared to have no lu ng disease. They d ied of anoxic encephalomalacia. T he remaining four infants had severe lung disease at death, requiring FIo 2 of 1.0 and peak ventilatory pressures ranging from 20 to 40 em H 20 . At autopsy these four infants had severe diffuse p ulmonary hemorrhage. Three of these infa nts had had fran k blee di ng th rough the intuba tion tube prior to death . T he 25 infants who had mecon ium asp iration in addi tion to asp hyxia had severe lu ng disease; findings in
398 Thibeault et al.
October 15, 1984 Am J Obstet Gynec ol
Comment •
MAS( WITH SEVERE ACIDOSIS) o NO MAS (WITH SEVERE ACIDOSIS) • MAS (MILD OR NO ACIDOSIS)
,
48
i
72
AGE (Hrs)
Fig. 5. Serial rel at ion ship of oxygen req uire me nts (mean ± SEM) in asphyxia ted term in fan ts with an d without me conium aspiratio n synd ro me and in non severely asphyxiated in fan ts with meco nium aspi ration syndrome . Severely asph yxiated infants with me con ium aspira tio n syndrome had significan tly h igh er oxygen requiremen ts at 8 hours and from 96 to 120 hours th an d id those infants who were seve rely asphyxiate d bu t witho ut me conium aspiratio n syndrome . Seve rely asphyxiated infants with meco nium aspira tion synd ro me had significantly higher oxygen requ irem en ts fro m I to 120 hours th an infan ts with me conium aspira tion syndrome who were no t seve re ly asphyxiated (p < 0.05) . Nu mbe rs ind icat e infan ts alive at any age .
15 cases were compatible with the d iagnosis of persistence o f the fetal circulation . The highest mean peak ins pira to ry pressure and me an air way pressure occur red at 8 hours of age and were 21.8 ± 3.0 em H 2 0 and 10.0 ± 2.0 em H 2 0 , respectivel y. Lung disease in th ese infants with meconium asp ira tion and asphyxia a p peared to stay relatively con stant over the first 48 hou rs of life and then slowly diminished. However, sig nifican t lung disease still persisted at 5 da ys of age. Seven of the 25 infants died at a me an age o f 59 ± 15 hours. Three died a brain d eath at a mean age of 90 hours with little or mi nimal lung d isease. However, four died with persistent fetal circu latio n at a mean age of 35 hours while requiring an Flo, of 1.0 and a peak inspirat ory pressure of 32 to 56 em H 2 0 . Curio usly, none of these seven infants had pulmonary hemorrh age at ne cropsy. All had histolo gic evid ence of meco n iu m aspiration pneumonia. The control term infants with mec onium aspiration synd ro me but with out severe perinat al asp hyxia had less pulmonary insufficiency th an the as phyxiated infa n ts with meconium aspiration synd ro me (Figs. 4 and 5). Unlike the condition of the as p hyx iated infants, the pulmonary disease in these control infants had largely been resolved by 48 hours o f age . There were no deaths in this group.
T he purpose of this stu d y was to d efine th e course o f pulmonary dysfunction in pret errn and term infants with severe asphyxia. The effects a p pear to be qualitatively an d quantitatively similar in both term and the sma llest preterm infants . Respirat ory fun ction was only modestl y impaired at all gestations in th e absence of pulmonary hemorrhage, meconium as piratio n synd rome, o r respirato ry distress synd ro me, although most infants required assisted vent ilation for at least 24 hours. Our results indicate th at ac ute asphyxia per se d oe s no t cause a life-threatening persistent fetal circulation ; however, these infants had right to left shunting and may well have had a tempo rary pulmonary hyperten sion ." Ventilator pressures and am bien t oxygen requirem ents remained moderat ely elev ated for approximatel y I to 8 hours and th en decreased progressively during the first da y of life . A similar transient left ventri cul ar d ysfunction followin g seve re perinatal asph yxia was described in 1961 by Burnard and james!' and mo re recently by Siassi et al." Postasphyxial lung d ysfunction has been reported to be rel ated to vario us factors; th e most important a p pears to be increased vascu lar resistance with ri gh t to le ft sh un tin g. I -a In vivo an d in vitro human and ani ma l stu di es ha ve also shown a de crease in surfactant p roduction .' :" Nevert heless , eve n with severe acid osis, both th e cha nges in vascular resistan ce and decreased su r fac ta n t production are temporary as shown by the co urse of o u r infants. The o nly as phy xiated infants th at developed seve re lung disease in the absence of respiratory distress syndrome or meconium aspiration syndrome were four term infants with diffuse pulmonary hemorrhage. The pulmonary hemorrhage may in part be related to ischemic m yocardial dysfunction or a bleeding diathesis as well as to pulmonary vascul ar d amage from profound acidos is. In fants with underlying lung d isease in ad d itio n to as phyx ia did develop life-th reat enin g lung disease. Asp hyx ia in the presen ce o f me conium as piratio n or resp ir atory d istress syndro me produced pulmonary insufficiency requiring high ventilato r pressures associated with severe right to left sh u nt ing . Asphyxia in th e preterm infants with re spirat ory distress syndrome accelerated the classical , slow worsening course of pulmonary insuffi ciency over the first hours ofl ife, i.e ., the severe ph ase of pulmonary insu fficiency in respiratory d istress synd rome with as p hyxia began immediately after birth (Fig. I). Our data are co m patible with th e general co nclusio ns of Kenny et al. 13 that acidosis do es not a p pear to be a majo r facto r in the development of re sp iratory distress syndrome ; howeve r, profound acid osis does cause respiratory insu fficiency and aggravate s the course of respiratory di stress syndrome.!" Asphyxiated infants with meconium aspiration syn-
Postasphyxial lung disease in newborn infants 399
Volume 150 Number 4
drome developed lung disease compatible with persistence of the fetal circulation. The syndrome of persistence of fetal circulation has been primarily related to chronic in utero hypoxia" and meconium aspiration syndrome." Our term asphyxiated infants without meconium aspiration syndrome appeared to have acute hypoxia perinatally rather than chronic hypoxia, and this may account for the absence of persistence of the fetal circulation in this group. The most striking effect of severe acidosis in our infants was the mortality and morbidity resulting from central nervous system damage. Seventy percent of the infants had seizures. Although the majority had low land 5-minute Apgar scores that indicated fetal distress and asphyxia prior to delivery, it also appears that delayed or ineffective postnatal resuscitation contributed to the acidosis in more than 50% of the infants. This observation suggests that a great deal of mortality and morbidity in these infants was preventable by more effective neonatal resuscitation and management. We can conclude that acute acidosis in preterm and term infants without respiratory distress syndrome or meconium aspiration syndrome and without the complication of pulmonary hemorrhage does not lead to irreversible persistence of the fetal circulation, and with proper ventilator therapy, marked improvement should occur within the first 24 hours of life. However, acidosis in the presence of underlying lung disease may produce life-threatening pulmonary insufficiency including persistent pulmonary hypertension, pulmonary hemorrhage, and a severe form of hyaline membrane disease. Aggressive neonatal resuscitation has a significant potential for reduction of pulmonary morbidity associated with perinatal asphyxia.
3.
4.
5.
6. 7. 8. 9.
10.
11. 12.
13. 14. 15.
REFERENCES 1. Rudolph AM, Yuan S. Response of the pulmonary vasculature of hypoxia and H+ ion concentration changes. J Clin Invest 1966;45:339. 2. James LS, Rowe RD. The pattern of response of pulmo-
16.
nary and systemic arterial pressures in newborns and older infants to short period of hypoxia. J Pediatr 1957;51:5. Gersony WM, Morishima HO, Daniel SS, Kohl S, Cohen H, Brown W, James LS. The hemodynamic effects of intrauterine hypoxia: an experimental model in newborn lambs. J Pediatr 1976;89:631. Gluck L, Kulovich MV, Eidelman AI, Cordero L, Khazin AF. Biochemical development of surface activity in mammalian lung. IV. Pulmonary lecithin synthesis in the human fetus and newborn and etiology of the respiratory distress syndrome. Pediatr Res 1972;6:81. Reynolds ER, Jacobson HW, Motoyama EK, Kikkawa Y, Craig JM, Orzalesi MM, Cook CD. The effect of immaturity and prenatal asphyxia on the lungs and pulmonary function of newborn lambs: The experimental production of respiratory distress. Pediatrics 1966;35:382. Brumley GW, Crenshaw C. Fetal lamb lungs phosphatidyicholine: response to asphyxia and recovery. J Pediatr 1980;97:631. Merritt T A, Farrell PM. Diminished pulmonary lecithin synthesis in acidosis: Experimental findings as related to the respiratory distress syndrome. Pediatrics 1976;57:32. Hutchison AA, Russell G. Effective pulmonary capillary blood flow in infants with birth asphyxia. Acta Paediatr Scand 1976;65:669. Pro'hom LS. The paediatric aspect of fetal asphyxia: the post-asphyxia syndrome. In: Basel S, Karger AG, eds. Proceedings of the Second European Congress on Perinatal Medicine, London, 1970. 1971:131. Thibeault DW, Beatty EC, Hall RT, Bowen S. Prolonged rupture of fetal membranes (PROM) and hypoplastic lungs without the oligohydramnios tetrad. Pediatr Res 1983; 17:392A. Burnard ED, James LS. Failure of the heart after undue asphyxia at birth. Pediatrics 1961 ;28:545. Siassi S, Devore G, Ackerman R, Yeh S, Cabal L. Transient left ventricular dysfunction secondary to severe perinatal asphyxia in newborn infants. Pediatr Res 1983; 17: 122A. Kenny JD, Adams JM, Corbet AJS, Rudolph AJ. The role of acidosis at birth in the development of hyaline membrane disease. Pediatrics 1976;58: 184. James LS. Perinatal events and respiratory distress syndrome. N Engl J Med 1975;292: 1291. Goldberg SJ, Levy RA, Siassi B, Betten J. The effects of maternal hypoxia and hyperoxia upon the neonatal pulmonary vasculature. Pediatrics 1971;48:528. Fox WW, Gewitz MH, Dinwiddie R, Drummond WH, Peckham GJ. Pulmonary hypertension in the perinatal aspiration syndromes. Pediatrics 1977;59:205.
The pulmonary course and the respiratory management of severely asph yxiated infants is not well defined. Perinatal asphyxia, severe acidosis,' and hypoxia" 3 are known to cause increased pulmonary vascular resistance with right to left sh u nting through fetal channels and depression of surfactant metabolism."? However, it has been difficult in human infants to separate th e effects of perinatal asp hyxia and severe acidosis on pulmonary function from those alterations associated with common newborn conditions such as the respiratory distress syndrome, meconium aspiration syndrome." 9 and pulmonary hypoplasia." The purpose of this report is to define the nature and severity of lung disease caused by perinatal asph yxia in preterm and term newborn infants .
Material and methods Sixty-five infants consecutively admitted to a newborn tertiary intensive care unit with at least one arteFrom the Section of Ne ona tology, Th e Children's Mer cy Hospital, Un iversity of M issouri, Kansas City, School of M edicine. R eceivedfor publication J uly 27,1983 ; revised Ap ril 6, 1984 ; accepted May 23, 1984 . R eprint requests: Donald W . Thibeault, M.D., The Children's M ercy Hospital, 24th and Gillham, Kansa s City, MO 64108.
rial pH $7.00 within the first 2 hours of life were studied . These infants were born in primary and secondary hospitals and transferred within the first 4 hours oflife to the tertiary hospital by a transport team that included a neonatologist and a nurse. The ability to resu scitate the infants at the referring hospitals var ied from having a neonatologist present at the deli ver y to th at of ha ving a delivery room nurse without an y special training in resuscitation. Infants with sepsis , con gen ital he art disease, and other congenital anomalies were excluded. Prenatal , intrapartum, and newborn re cords were obtained from the referring hospitals. Details of deli very room re suscitation and subsequent ventilatory support were obtained directly from the records of nurses or physicians who were present at the delivery. The precise time of arterial blood gas measurements was established in all cases. Arterial blood gas values, ventilator settings, and inspired ox ygen concentrations were obtained from the patient's neonatal intensive care unit flow record . Infants requiring ven tilator care were treated with Baby Bird or Bournes BP-200 re spirators. Respiratory distress syndrome was diagnosed if all of the following criteria were met: (I) deep chest wall re-
393
394
Thibeault et al. Am
Table I. Comparative data of infants with pH ~7.00
Table II. Predisposing conditions for the
in the first 2 hours of life Preterm
No. of infants 26 Gestational age (wk) 31.0 ± Birth weight (kg) 1.56 ± Apgar score, I min 2.8 ± 4.6 ± Apgar score, 5 min Time pH measured (hr) l.l ± pH 6.92 ± Pco, 79 ± Po, 81 ± Flo, 89 ± Base excess -19.8 ±
0.6* 0.14 0.4 0.4 0.2 0.01 6 14 3 l.l
Term
39 41.1 3.46 2.2 3.4 1.0 6.86 67 92 86 -24.4
± 0.3 ± 0.10 ± 0.3
± 0.4
± 0.1 ± ± ± ± ±
October 15. 1984 J Obstet GynecoI
0.02 6 15 4 0.6
*Mean ± SEM. tractions, (2) an audible expiratory grunt, (3) an increased ambient oxygen concentration for 48 hours to keep the arterial oxygen tension greater than 50 mm Hg, and (4) radiologic evidence of reduced lung volume with a diffuse reticular granular pattern and prominent air bronchograms. Meconium aspiration syndrome was diagnosed if all the following criteria were met: (1) a history of meconium in the amniotic fluid, (2) meconium in the mouth at delivery, (3) increased respiratory rate with an increased anteroposterior diameter of the chest, and (4) Roentgenographic evidence of pulmonary infiltrates and air trapping. An additional 30 preterm infants with respiratory distress syndrome and 20 term infants with meconium aspiration syndrome consecutively admitted but without severe acidosis (pH >7.20) serveJ as study control subjects. All the control preterm infants required assisted ventilation but only eight of the control term infants with meconium aspiration syndrome required ventilator treatment. Results
There were 26 preterm infants who had a pH :s7.00 in the first 2 hours of life (Table I). Their gestational ages ranged from 26 to 36 weeks with a mean of 31.0 ± 0.6 weeks. Birth weight range was 0.76 to 2.86 kg with a mean of 1.56 ± 0.14 kg. Twelve of the 26 preterm infants had respiratory distress syndrome in addition to asphyxia. Mean gestational ages and birth weights were not significantly different between infants with and without respiratory distress syndrome. The control preterm infants with respiratory distress syndrome but without severe asphyxia had a mean gestational age of 32.2 ± 0.4 weeks and birth weight of 1.59 ± 0.08 kg, which measurements were not significantly different from those of severely asphyxiated preterm infants. Thirty-nine term infants had a pH :s7.00 within the first 2 hours of life. Their gestational ages ranged from
development of severe acidosis of pH ~7.00 in infants in the first 2 hours of life
No. of infants Respiratory distress syndrome Meconium aspiration Third-trimester bleeding Anemia at birth (hemoglobin ,,;10 gm %) Prolapsed umbilical cord or tight nuchal cord Difficult high-forceps delivery Monitoring of fetal heart rate Late deceleration Severe variable deceleration Precipitous delivery Maternal hypotension Abruptio placentae Maternal lupus Ineffective resuscitation
Preterm
Term
26 12 0 4 2
39 0 25 0 0 5
I
12 4
4 2 I
3 0 17
4 32 21 8 I
2 4 I
16
38 to 44 weeks with a mean of 41.1 ± 0.3 weeks. Twenty-five of these term infants had meconium aspiration syndrome as well as asphyxia and 14 had asphyxia without meconium aspiration syndrome. The mean gestational age of the infants with meconium aspiration syndrome was significantly greater than that of term infants with asphyxia alone, 41.6 ± 1.4 weeks versus 40.2 ± 1.6 weeks (p < 0.01). Only seven of the 25 infants with meconium aspiration syndrome had tracheal aspiration prior to administration of positive pressure resuscitation. The skill demonstrated and quality of this procedure were quite heterogenous. The control term infants with meconium aspiration syndrome without severe asphyxia had a mean gestational age of 41.1 ± 0.4 weeks and birth weight of 3.45 ± 0.11 kg, which measurements were not significantly different from those of the severely asphyxiated term infants. Predisposing conditions to the severe acidosis in both preterm and term infants are shown in Table II. Both the 1- and 5-minute Apgar scores were markedly depressed (Table I). Twenty-one of the 26 preterm infants and 34 of the 39 term infants had 5-minute Apgar scores :s6.0. Seventeen preterm infants and 16 term infants appeared to have ineffective delivery room and early newborn resuscitation based upon the observation that following the initial resuscitation efforts the pH remained :s7.00 with an elevated Pco, 2':55 mm Hg. In addition, 18 of the 25 severely asphyxiated infants with meconium aspiration did not have tracheal suctioning at birth. These results indicate that both in utero asphyxia and ineffective newborn resuscitation contributed to the severe postnatal acidosis. The arterial pH :s7.00 was initially detected in the 26
Postasphyxial lung disease in newborn infants 395
Volume 150 Number 4
o NO RDS (SEVERE ACIDOSIS)
• RDS (SEVERE ACIDOSIS) • RDS (MILD OR NO ACIDOSIS)
1 2
4
8
24
48
96
120
Fig. 1. Serial relationship of peak ventilator pressure (mean ± SEM) in asph yxiated pre term infant s with and without respiratory distress syndrom e (RD S) and in nonseverely asphyxiated preterm infants with respiratory distress syndrome . Severely asphyxiated infants with respiratory distre ss syndrome required significantly higher peak ventilator pressure s between 4 and 96 hours (p < 0.025) than those infants who were asphyxiated but without respi rator y distress syndr ome. Infants with respiratory distress syndrome but without severe asphyxia required significantly lower pressures in comparison to severely asphyxiated infants with respiratory distress syndrome between I and 24 hours (p < 0.025). Numbers indicate infants alive at any age.
preterm infants at a mean age of 1.1 ± 0.2 hours oflife and in the 29 term infants at 1.0 ± 0.1 hours (T able 1). It was not possible to accurately determine the length of time the pH was below 7.00 ; however, most infants had respiratory distress fo r a prolonged period prior to the first pH measurement. Comparison of the mean arterial pH, Pco. ; POz, ba se deficit, a nd Flo, between the preterm and term infants revealed th at they were not sig n ifica n tly d ifferent at the time the initi al pH was :57 .00 (T able I). Infants in both groups had a combined respiratory a nd metabolic acidosis . The relativel y normal mean arterial POz va lu es are misle ading in that most infants were re ce iving some type of assisted ve ntilatio n and all were breathing an enriched a m bie n t ox ygen co ncen tratio n at the time of measurem ent. Seventeen of the 26 severely asph yxiated preterm infants developed seizures at a mean age of 33.3 ± 9 hours. The mean age at o nse t was 37 .1 ± 10 hours in those with respiratory di stress syndrome and 29.3 ± 9 hours in those without respiratory di stress syndrome. Twenty-six of 39 asph yxiated term infants developed seizures at a mean age of 12.9 ± 4.8 hours with a range of 30 minutes to 96 hours. Seventeen of 25 infants with meconium aspiration syndrome and as p hyxia had seizures whi ch began at a mean age of 18.2 ± 5.8 hours.
Nine of 14 infants who were asph yxiated witho ut meconium as p ira tion synd rome had seizures which began at a me an age of 2.8 ± 1.1 hours. Pulmonary course of preterm infants All the preterm infants that had a pH :57.00 required ventilator assistance for at leas t 24 hours following resuscitation. Me an duration of ven tilato r assistance was 85.5 ± 29 hours among su rv iving in fants. Ventilator su ppo rt in th e preterm infants is summarized in Figs. 1 to 3. The se verity and co urs e of pulmonary in suffi ciency in asph yxiated preterm in fants without re spiratory d istress syndrome is of particular interest. The highest mean ventilator inspirat ory pressure and mean airway pressure in this group were 20.2 ± 0.4 ern HzO and 9.5 ± 0.3 cm HzO, respectively, which occurred at 1 hour of ag e . Thereafter peak ventilator pressure requirements and me an air way pressure progressivel y decreased over the fir st 24 hours of life to mean le vels of 8.5 ± 2.1 cm H zO a nd 3.3 ± 1.0 cm H zO, respectively. Me an in spired oxygen requirements followed the same pattern as the pressures, declining from a high of 0.80 ± 0.06 at 1 hour to 0.44 ± 0.08 at 24 hours of ag e . Seven of 14 preterm infants without respiratory dis-
396
Thibeault et al. Am
October 15, 1984 J Obstet Gynecol
o NO RDS (SEVERE ACIDOSIS)
• RDS ( SEVERE ACIDOSIS) • RDS (MILD OR NO ACIDOSIS)
0N
J:
E
. .
~
Gl :::I
10
01 01
Gl
Q.
>
III
~
Ci
5
l: III Gl
~
1
4
8
'
..
48
24
96
120
AGE (Hrs)
Fig. 2. Serial re latio nshi p of me an airway pressu re (mea n e SEM) in asph yxiated pret erm in fants with and witho ut respi rato r y di stress synd ro me and in non severely asphyxiated preterm in fants with respiratory d istr ess synd ro me . Severely asphyxiated in fants with respiratory distress syndrome had significan tly high er me an airway pressures between 4 and 96 hours than tho se in fan ts asphyx iated but without resp irat o ry distress synd ro me. Infants with respiratory distress syndrome but with out seve re asphyxia required sign ifican tly lower mean pressures in co m parison to severely asp hyx iated infa nts with respi r atory d istr ess syndro me bet ween I and 8 hours (p < 0.0 25). Nu mbers indicat e in fan ts alive at any age .
tress syndro me d ied at a mean age of 99 ± 26.3 hours . The me an inspired ox ygen requirement at the time o f th eir de ath was 0.28 ± 0.0 3 with a me an peak ventilator pressure of 10.1 ± 1.7 em H 20 . These pressure and inspired oxygen concentrations in dicate that lung disease was not the cause of death in these infants. None of the 14 infants developed severe persistence of the fe tal circ u lation, i.e., none requi red high respirator pressure >30 em H 20, pulmon a ry vasod ilators, or pH >7.45 to maintain an adequate art erial ox ygen tension. The cause of death in th e seve n infa n ts was anoxic ence pha lo malacia (4 cases), renal failure (2), and m yocardial insufficiency with co ngestive heart failure (I ). Preterm infants with respiratory d istre ss syn d rome as well as asp hyxia had de terio rat ion o f lung function with in the fir st 24 hours of life rath er than an improvement. The mean peak insp irat ory pressure at 24 hours of ag e was 26.1 ± 1.3 em H 20 and the mean airway pressure 11.2 ± 1.3 em H 20 while breathing oxy gen with a mean Flo, of 0.72 ± 0.06. These FIo 2 and pressure measurements were signi fican tly higher th an those in the asph yxiat ed infants without respiratory distress syndrome (Figs . I to 3). Nin e of the 12 asphyxiated infants with respiratory di stres s syndrome died at a mean age of 67.7 ± 20 hours . These infants had severe pulmonary insuffi-
ciency at the time of de ath with a mean Fl o, of 0.61 ± 0.09, a mean peak inspirat ory pressure of 23.3 ± 2.8 em H 20, and a mean airw ay pr essure of 12.0 ± 2.4 em H 20 . Seven infants had auto psies and all had diffuse h yaline membranes; five had pulmonary hemorrhage, th ree had anoxic encephalomalacia, an d six had intracra n ial hemorrhages. The co n tro l preterm infants with respiratory distress syn d ro me but without severe asp hyxia h ad less pulmonary insufficiency than those with res pirato ry distress synd ro me and asph yxia (Figs. 1 to 3). Unlike the condi tion of the asphyxiated infants with re spiratory di stress syn d ro me, the pulmon ary insu fficiency was relatively mild in the first 8 hours of life and peaked at 24 to 48 hours. Only one o f the 30 infants died . Pulmonary course of term infants
Pulmonary findin gs of th e 39 te rm infants with pH :::0;7.00 are show n in Figs. 4 an d 5. All but two infants with severe perinatal asphyxia req uire d assisted ventilatio n follow ing resuscitation. The mean duration of assisted ventilation of those 37 infants was 66.0 ± 12.0 hours with a range of 2 to 3 12 hours. There were 14 infants without meconium aspiration in which asphyxia appeared to be the only cause of the pulmonary insufficiency. Mean pe ak ventilator pres-
Postasphyxial lung disease in newborn infants 397
Volum e 150 Number 4
o NO
RDS (SEVERE ACIDOSIS) • RDS (SEVERE ACIDOSIS) _RDS (MILD OR NO ACIDOSIS)
....1'1
0
u::: cG)
1.0
Cl
>>C
..
0
'C G)
.80
'c, III .E .60
-
................ ,T
0
0 ..
c
. . . - . . . 0.. .
0 :;: .40
..
o
III II.
AGE (HRS)
.20
1
4
8
..
24
48
~C5- - -0 96
120
Fig. 3. Serial rela tionship of ins pired oxygen requirements (mean ± SEM) in asphyxiated pre ter m infan ts with and witho ut respiratory di stress syndrome, and in no nsev e rely asphyxiated preterm infan ts with respiratory d istress syndrome. Severely asphyxiated infants with respiratory distress syn d rome had significantly higher oxygen requirements between 4 and 48 hours than did those infants asphyxiated but without respiratory distress syndrome (p < 0.025) . The oxygen requirements in severely asphyxiated infants with respiratory distress syndrome and those infants with respiratory dis tress syndrome but not severel y asphyxiated were not significantly different.
•
o
•
MAS (WITH SEVERE ACIDOSIS) NO MAS (WITH SEVERE ACIDOSIS) MAS (MILD OR NO ACIDOSIS)
..... 48
~
96
AGE (Hrs)
Fig. 4. Serial relationship of peak ven tilator pressure (mean ± SEM) in as phyxiated term infants with and without meconium asp iration syndrome (MAS) and in nonseverely asphyxiated infants with meconium aspiration syndrome. Severely asphyxiated infants with meconium aspiration syndrome require sign ificantly hig her peak ventilator pressures at 8 hours and from 72 to 120 hours than do those infants asphyxiated but without meconium aspiration syndrome (p < 0.05) . Infants with meconium aspiration syndrome but without severe asph yxia had significantly lower peak ventilator pressure from I to 120 hours (p < 0.025) when compared to those severely asphyxiated infants with meconium aspiration syndrome. Numbers indicate infants alive at an y age.
sure and mean airway pressure III these 14 infants reached a maximum during the first 8 hour s of life of 14.5 ± 4.6 em H 2 0 and 7.6 ± 2.5 em H 2 0 , respectively, and declined progressively un til 72 hours of age, a t which time only o ne infant was receiving assisted ventilatio n. The Fl o, followed the same declining tren d , approaching th at of room ai r at 96 hours of life. Seven of these 14 infants died within the firs t 96 hours of life. T h ree of these 7 infants at death were breathing ambien t air, requirin g no vent ilato ry assistance, and ap-
peared to have no lu ng disease. They d ied of anoxic encephalomalacia. T he remaining four infants had severe lung disease at death, requiring FIo 2 of 1.0 and peak ventilatory pressures ranging from 20 to 40 em H 20 . At autopsy these four infants had severe diffuse p ulmonary hemorrhage. Three of these infa nts had had fran k blee di ng th rough the intuba tion tube prior to death . T he 25 infants who had mecon ium asp iration in addi tion to asp hyxia had severe lu ng disease; findings in
398 Thibeault et al.
October 15, 1984 Am J Obstet Gynec ol
Comment •
MAS( WITH SEVERE ACIDOSIS) o NO MAS (WITH SEVERE ACIDOSIS) • MAS (MILD OR NO ACIDOSIS)
,
48
i
72
AGE (Hrs)
Fig. 5. Serial rel at ion ship of oxygen req uire me nts (mean ± SEM) in asphyxia ted term in fan ts with an d without me conium aspiratio n synd ro me and in non severely asphyxiated in fan ts with meco nium aspi ration syndrome . Severely asph yxiated infants with me con ium aspira tio n syndrome had significan tly h igh er oxygen requiremen ts at 8 hours and from 96 to 120 hours th an d id those infants who were seve rely asphyxiate d bu t witho ut me conium aspiratio n syndrome . Seve rely asphyxiated infants with meco nium aspira tion synd ro me had significantly higher oxygen requ irem en ts fro m I to 120 hours th an infan ts with me conium aspira tion syndrome who were no t seve re ly asphyxiated (p < 0.05) . Nu mbe rs ind icat e infan ts alive at any age .
15 cases were compatible with the d iagnosis of persistence o f the fetal circulation . The highest mean peak ins pira to ry pressure and me an air way pressure occur red at 8 hours of age and were 21.8 ± 3.0 em H 2 0 and 10.0 ± 2.0 em H 2 0 , respectivel y. Lung disease in th ese infants with meconium asp ira tion and asphyxia a p peared to stay relatively con stant over the first 48 hou rs of life and then slowly diminished. However, sig nifican t lung disease still persisted at 5 da ys of age. Seven of the 25 infants died at a me an age o f 59 ± 15 hours. Three died a brain d eath at a mean age of 90 hours with little or mi nimal lung d isease. However, four died with persistent fetal circu latio n at a mean age of 35 hours while requiring an Flo, of 1.0 and a peak inspirat ory pressure of 32 to 56 em H 2 0 . Curio usly, none of these seven infants had pulmonary hemorrh age at ne cropsy. All had histolo gic evid ence of meco n iu m aspiration pneumonia. The control term infants with mec onium aspiration synd ro me but with out severe perinat al asp hyxia had less pulmonary insufficiency th an the as phyxiated infa n ts with meconium aspiration synd ro me (Figs. 4 and 5). Unlike the condition of the as p hyx iated infants, the pulmonary disease in these control infants had largely been resolved by 48 hours o f age . There were no deaths in this group.
T he purpose of this stu d y was to d efine th e course o f pulmonary dysfunction in pret errn and term infants with severe asphyxia. The effects a p pear to be qualitatively an d quantitatively similar in both term and the sma llest preterm infants . Respirat ory fun ction was only modestl y impaired at all gestations in th e absence of pulmonary hemorrhage, meconium as piratio n synd rome, o r respirato ry distress synd ro me, although most infants required assisted vent ilation for at least 24 hours. Our results indicate th at ac ute asphyxia per se d oe s no t cause a life-threatening persistent fetal circulation ; however, these infants had right to left shunting and may well have had a tempo rary pulmonary hyperten sion ." Ventilator pressures and am bien t oxygen requirem ents remained moderat ely elev ated for approximatel y I to 8 hours and th en decreased progressively during the first da y of life . A similar transient left ventri cul ar d ysfunction followin g seve re perinatal asph yxia was described in 1961 by Burnard and james!' and mo re recently by Siassi et al." Postasphyxial lung d ysfunction has been reported to be rel ated to vario us factors; th e most important a p pears to be increased vascu lar resistance with ri gh t to le ft sh un tin g. I -a In vivo an d in vitro human and ani ma l stu di es ha ve also shown a de crease in surfactant p roduction .' :" Nevert heless , eve n with severe acid osis, both th e cha nges in vascular resistan ce and decreased su r fac ta n t production are temporary as shown by the co urse of o u r infants. The o nly as phy xiated infants th at developed seve re lung disease in the absence of respiratory distress syndrome or meconium aspiration syndrome were four term infants with diffuse pulmonary hemorrhage. The pulmonary hemorrhage may in part be related to ischemic m yocardial dysfunction or a bleeding diathesis as well as to pulmonary vascul ar d amage from profound acidos is. In fants with underlying lung d isease in ad d itio n to as phyx ia did develop life-th reat enin g lung disease. Asp hyx ia in the presen ce o f me conium as piratio n or resp ir atory d istress syndro me produced pulmonary insufficiency requiring high ventilato r pressures associated with severe right to left sh u nt ing . Asphyxia in th e preterm infants with re spirat ory distress syndrome accelerated the classical , slow worsening course of pulmonary insuffi ciency over the first hours ofl ife, i.e ., the severe ph ase of pulmonary insu fficiency in respiratory d istress synd rome with as p hyxia began immediately after birth (Fig. I). Our data are co m patible with th e general co nclusio ns of Kenny et al. 13 that acidosis do es not a p pear to be a majo r facto r in the development of re sp iratory distress syndrome ; howeve r, profound acid osis does cause respiratory insu fficiency and aggravate s the course of respiratory di stress syndrome.!" Asphyxiated infants with meconium aspiration syn-
Postasphyxial lung disease in newborn infants 399
Volume 150 Number 4
drome developed lung disease compatible with persistence of the fetal circulation. The syndrome of persistence of fetal circulation has been primarily related to chronic in utero hypoxia" and meconium aspiration syndrome." Our term asphyxiated infants without meconium aspiration syndrome appeared to have acute hypoxia perinatally rather than chronic hypoxia, and this may account for the absence of persistence of the fetal circulation in this group. The most striking effect of severe acidosis in our infants was the mortality and morbidity resulting from central nervous system damage. Seventy percent of the infants had seizures. Although the majority had low land 5-minute Apgar scores that indicated fetal distress and asphyxia prior to delivery, it also appears that delayed or ineffective postnatal resuscitation contributed to the acidosis in more than 50% of the infants. This observation suggests that a great deal of mortality and morbidity in these infants was preventable by more effective neonatal resuscitation and management. We can conclude that acute acidosis in preterm and term infants without respiratory distress syndrome or meconium aspiration syndrome and without the complication of pulmonary hemorrhage does not lead to irreversible persistence of the fetal circulation, and with proper ventilator therapy, marked improvement should occur within the first 24 hours of life. However, acidosis in the presence of underlying lung disease may produce life-threatening pulmonary insufficiency including persistent pulmonary hypertension, pulmonary hemorrhage, and a severe form of hyaline membrane disease. Aggressive neonatal resuscitation has a significant potential for reduction of pulmonary morbidity associated with perinatal asphyxia.
3.
4.
5.
6. 7. 8. 9.
10.
11. 12.
13. 14. 15.
REFERENCES 1. Rudolph AM, Yuan S. Response of the pulmonary vasculature of hypoxia and H+ ion concentration changes. J Clin Invest 1966;45:339. 2. James LS, Rowe RD. The pattern of response of pulmo-
16.
nary and systemic arterial pressures in newborns and older infants to short period of hypoxia. J Pediatr 1957;51:5. Gersony WM, Morishima HO, Daniel SS, Kohl S, Cohen H, Brown W, James LS. The hemodynamic effects of intrauterine hypoxia: an experimental model in newborn lambs. J Pediatr 1976;89:631. Gluck L, Kulovich MV, Eidelman AI, Cordero L, Khazin AF. Biochemical development of surface activity in mammalian lung. IV. Pulmonary lecithin synthesis in the human fetus and newborn and etiology of the respiratory distress syndrome. Pediatr Res 1972;6:81. Reynolds ER, Jacobson HW, Motoyama EK, Kikkawa Y, Craig JM, Orzalesi MM, Cook CD. The effect of immaturity and prenatal asphyxia on the lungs and pulmonary function of newborn lambs: The experimental production of respiratory distress. Pediatrics 1966;35:382. Brumley GW, Crenshaw C. Fetal lamb lungs phosphatidyicholine: response to asphyxia and recovery. J Pediatr 1980;97:631. Merritt T A, Farrell PM. Diminished pulmonary lecithin synthesis in acidosis: Experimental findings as related to the respiratory distress syndrome. Pediatrics 1976;57:32. Hutchison AA, Russell G. Effective pulmonary capillary blood flow in infants with birth asphyxia. Acta Paediatr Scand 1976;65:669. Pro'hom LS. The paediatric aspect of fetal asphyxia: the post-asphyxia syndrome. In: Basel S, Karger AG, eds. Proceedings of the Second European Congress on Perinatal Medicine, London, 1970. 1971:131. Thibeault DW, Beatty EC, Hall RT, Bowen S. Prolonged rupture of fetal membranes (PROM) and hypoplastic lungs without the oligohydramnios tetrad. Pediatr Res 1983; 17:392A. Burnard ED, James LS. Failure of the heart after undue asphyxia at birth. Pediatrics 1961 ;28:545. Siassi S, Devore G, Ackerman R, Yeh S, Cabal L. Transient left ventricular dysfunction secondary to severe perinatal asphyxia in newborn infants. Pediatr Res 1983; 17: 122A. Kenny JD, Adams JM, Corbet AJS, Rudolph AJ. The role of acidosis at birth in the development of hyaline membrane disease. Pediatrics 1976;58: 184. James LS. Perinatal events and respiratory distress syndrome. N Engl J Med 1975;292: 1291. Goldberg SJ, Levy RA, Siassi B, Betten J. The effects of maternal hypoxia and hyperoxia upon the neonatal pulmonary vasculature. Pediatrics 1971;48:528. Fox WW, Gewitz MH, Dinwiddie R, Drummond WH, Peckham GJ. Pulmonary hypertension in the perinatal aspiration syndromes. Pediatrics 1977;59:205.