Perinatal stress and the premature neonate

THE JOURNAL OF

PEDIATRICS SEPTEMBER

1963

V o l u m e 63

Number 3

Perinatal stress and the premature neonate Z Effect of fluid

and

calorie deprivation

The metabolic adjustments o[ the premature in[ant with or without accompanying perinatal stresses such as respiratory distress, asphyxia, toxemia in the mother, or a breech delivery were evaluated [or the first 6 days o[ li[e. During the first 72 hours no fluid or calories were given. Basic similarities in the patterns o[ change in all groups were remarkable. Hypernatremia and prolonged acidosis were [requent findings in in[ants initially. asphyxiated; increased weight loss and increased potassium excretion were seen in the lowest weight group in association with respiratory distress.

Alice G. Beard, M.D., Theodore C. Panos, M.D., James C. Burroughs, M.D.,* Benito V. Marasigan, M.D., ** and A. Giilen Oztalay, M.D. "x''x" LITTLE

ROCK,

ARK.

T I-i E homeostatic adjustments in the premature infant during the first moments and days of life are poorly understood. Although metabolic alterations have long been recognized during the perinatal period, it is apparent that the effects of added stresses such

as neonatal asphyxia, toxemia or diabetes in the mother, or a breech or cesarean section delivery need to be documented and compared with the findings in infants with no complications except for prematurity. With expanded knowledge of these homeostatic adjustments, the problem of the advisability of early versus late feeding of prematures may be resolved on the basis of biochemical and physiologic alterations. It is the purpose of this presentation to report observations on 46 premature infants studied serially from birth through 6 days

From the Department o[ Pediatrics, University o[ Arkansas Medical Center. Supported by National Institutes of Health Grant No. A3174, United States Public Health Service. *Research Fellow, July, 1960-1961. ~X'Research Fellow, 1961-1962.

361

3 62

September 1963

Beard et al.

who received no food or fluid within the first 72 hours. A second report will deal with observations on infants fed within the first 6 hours. HISTORICAL

BACKGROUND

As early as 1916 Yllp51 r e p o r t e d a l o w e r e d p H v a l u e in b o t h the v e n o u s b l o o d a n d s e r u m of p r e m a t u r e infants. H e a t t r i b u t e d this to a n increase in n o n v o l a t i l e acids, a n d conc l u d e d t h a t the n e w b o r n p r e m a t u r e i n f a n t h a d a t e n d e n c y t o w a r d acidosis. H o a g a n d K i s e r 2 f o u n d an a v e r a g e s e r u m p H v a l u e of

7.52 but a slightly lowered serum bicarbonate value for the first 13 days of life in 73 normal full-term breast-fed infants. Marples and Lippard ~ studied 40 normal newborn breastfed infants between 1 and 9 days of age and found their mean serum bicarbonate value to be 22.1 m M . per liter as compared to 27.6 mM. per liter in the adult controls. These data were interpreted as indicating a mild compensated acidosis most marked during the second and third days of life coincident with the period of greatest weight loss. Branning 4 reported studies on 15 healthy

Table I. Summary of previous investigations of effects of early or delayed feeding of the neonate Food withheld No.

Investigator

Type and time No, babies Comment of feeding fed early 9 50 ml. ITI20/Kg./day No hypernatremia No deaths from birth 8% weight loss in Found hypernatre72 hours mia, hemoconcen7 50 ml. 2.5-10% glu- No hypernatremia tration, 13% cose/Kg./day in 6% weight loss in weight loss water 72 hours No deaths

babies

Hours

1. Hansen and Smith 24

9

72

2. Yllp52~

No series. Favors early feeding

3. Gleiss 26

92

36

Comment

41% mortality 102

4. Bauman27

26

36

8% mortality First at 5 hours: CNS hemorrhage Second at 106 hours : sepsis

5. Reardon 18 48 33% mortality et al. 29 (Few given glucose 6 died of H M D be(IDM) and water on tween 11 and 50 first day) hours of age

24

37

First feeding : 12 I/2 hours Type: 1 ml. HM and 1 ml. 5% glucose in H20 2 ml. every 3 hours Breast milk

28% mortality

First feeding: 6 hours Type: 5% glucosein 21% mortality 0.45% saline, 3 of 5 who died 60 ml./Kg./24 had H M D hours First feeding: 2-12 hours Type: 5% glucosein 3% mortality 0'.45% saline, 1 died at 4 hours 30ml./lb./24 of age, H M D hours

First feeding: 3-6 hours 28 Type: 5% glucose in 14% mortality 0.45% saline, 16 had RD, 4 30 ml./lb./day died (all had HMD) HMD, Hyaline membrane disease. RD, Respiratory distress. HM, Breast milk. IDM, Infants of diabetic mothers.

6. Rudolph et aL so (IDM)

28

48

3% mortality 11 had RD 1 died H M D at 5 days

Volume 63 Number 3

premature infants, only 2 of whom were evaluated during the first week of life. He found the CO2 content to be low by adult standards: 14.5 to 20.5 mEq. per liter at 11 to 58 days of age in all but 2 infants. By calculating the difference between the total base and the sum of the chlorides, COx content, sulfate, phosphate, and protein fractions, he concluded that blood organic acid content was two to three times the amount considered normal for adults. Urinary organic acid content was also found to be two to five times the values for adults. Several babies were considered to be sick because they were hyperpneic; in these, the CO~ content was lower than in the "good" group. H e concluded that premature infants always seem to be on the borderline of acidosis while noting that some of the "good" prematures thrived despite a COx content as low as 13.4 to 14 mEq. per liter. Later, in collaboration with McBryde, 5 he advocated sodium lactate subcutaneously to relieve the acidosis. Also working with prematures, R~iih~i,6 like Branning, demonstrated a consistent elevation of serum organic acids which were highest at 24 hours of age. He also found the urinary excretion of organic acids to be elevated primarily as a result of increased pyruvic acid content and postulated that the newborn infant responds to anoxia with an increase in anaerobic metabolism. Until 1950, the available literature consisted chiefly of reports of single determinations of an electrolyte or of hydrogen ion , concentration in premature and term newborn infants of mixed ages, with few determinations in the first days of life. Reardon and associates ~ studied 60 premature infants, of whom 52 were considered well and 8 sick. All babies were started on a partially skim milk (Dryco) or an evaporated milk formula by the second day of life. Disregarding the factor of the age of the premature infants, which ranged from 1 to 65 days, they reported an average serum p H of 7.31 in well babies, 7.30 in sick babies, with an average CO~ content between 19.5 and 20.2 mEq. per liter in both groups. Serum chloride values were 111 to 112 mEq. per liter and

Perinatal stress in the premature in[ant

363

the total base was 5 to 6 mEq. per liter higher than that found in adult controls. These authors concluded that premature infants throughout the first 2 months of life tend to have an increase in blood hydrogen ion, in total base, in serum organic acids, and in chloride concentration, and a decreased carbon dioxide content, indicating .a compensated metabolic acidosis. More recent observations of the metabolic alterations during the immediate neonatal period indicate that there is a tendency toward hypocalcemia, hypoglycemia, hyperkaliemia, and respiratory and metabolic acidosis. Although the biological relationships remain obscure, hypocalcemia has frequently been reported in premature infants, s, g infants of diabetic mothers, 1~ 11 and those delivered by cesarean section2 Others have recognized symptomatic hypoglycemia accompanying respiratory distress in infants born of toxemic mothers, 12, is in premature infants with cyanosis and grunting, ~4, 15 and in term infants with cold injury. 16 Hyperkaliemia has been recognized in premature infants of low birth weight and in those with the respiratory d i s t r e s s syndromeY, is Blystad 1~ has reported on blood determinations in premature infants with varying stages of anoxia, respiratory distress, and apnea. H e emphasized the progressing respiratory and metabolic acidosis that occurred in infants who later died. Similar findings with relation to asphyxia from many causes have been demonstrated in this country by othersY ~ The effects of early or late feeding upon the metabolic alterations found in the immediate neonatal period are only partially known. This is a consideration of particular importance in view of the widespread practice of withholding feedings of any type from premature infants for as long as 72 to 96 hours. Table I summarizes previous reports relating to this problem. Hansen and Smith x4 found that the quantity of electrolytes excreted in the urine was unaffected by water intake and that the amount excreted by infants with a gestational age of less than 35 weeks was 2 to 3 times as large as that excreted by the more mature infants. Serum concentrations

3 64

September 1963

Beard et al.

of sodium, chloride, and blood urea nitrogen (BUN) rose in all infants who did not receive water. They felt that, although the infants were unable to maintain homeostasis, their clinical status remained satisfactory during the study and their serum concentrations returned nearly to normal after one day of water and glucose administration. Yllp525 reported clinical impressions derived from observations of premature infants in two institutions, each with 25 beds. In one, the infants were kept on a full fast for 2 to 4 days, whereas, in the other, fluids were begun during the first day of life. Although the mortality rates in both hospitals were practically identical, it was Yllp6's impression that "vomiting and edema could not be prevented by a full fast and that the babies were better able to combat 'gastric acidity,' renal immaturity and acidosis when fed fluids and calories early." In a controlled clinical study by Gliss, 26 92 premature infants who were given no calories or fluid for 36 hours had an over-all mortality of 41 per cent. In the 102 premature infants receiving very small feedings from 1 2 ~ hours of age the mortality was 28 per cent. However, the former group contained 17 infants with a birth weight of less than 1,250 grams and the latter only 11; in addition, the latter group contained a larger number of infants with a birth weight over 1,750 grams. Although some of the prematures who were fed early did have minimal respiratory distress, this did not in Gleiss' opinion militate against early feeding. Bauman 27 reported that respiratory distress was three to four times as frequent in the group fed early as in the group from which food was withheld. He drew no conclusions but noted that 3 of the babies from the group fed early had hyaline membrane disease at autopsy. Babies of diabetic mothers are optimally delivered at 35 to 36 weeks of gestation and have complications, despite their size, comparable to those of premature infantsY s Therefore, two studies of babies born to diabetic mothers are included in Table I. Reardon's 29 incompletely controlled series in-

cluded one death (at 4 hours of age from hyaline membrane disease) in 37 babies of diabetic mothers who were fed 5 per cent glucose in 0.45 per cent normal saline during the first 12 hours of life. She concluded that early feeding seemed to lower the mortality rate of babies of diabetic mothers. Rudolph, 3~ however, from studies of a similar number of infants of diabetic mothers under somewhat better control conditions, reported more respiratory distress, more hyaline membrane disease, and a higher mortality rate among infants given oral fluids at 3 to 6 hours of age. MATERIALS

AND

METHODS

About 60 per cent of the approximately 2,500 women delivered each year at the University of Arkansas Medical Center have had no prenatal care. The prematurity rate is consistently 12 to 14 per cent. Between April, 1960, and October, 1961, there were 46 premature infants (25 males, 21 females) on whom serial metabolic determinations were made during the first 6 days of life. In an effort to evaluate the effect of added stress on the metabolic responses of the neonate, infants with birth weights ranging from 1,000 to 2,476 grams were included in the study if the research fellow had been present at delivery. In this manner, the following complications could be studied: asphyxia as expressed by an initial Apgar 1 to 3 ratings, respiratory distress, toxemia in the mothers, or breech delivery. A control group was also delineated, consisting of babies whose delivery was by vertex presentation unassociated with complications other than occasional premature rupture of the membranes not accompanied by sepsis. In this control group the initial Apgar rating was 8 to 10 and there was no respiratory distress. Respiratory distress was considered to be present when intercostal retraction was noted with or without an accompanying expiratory grunt. Infants of toxemic mothers included those whose mothers had definite proteinuria, hypertension, and edema, as well as those with eclampsia. Apgar ratings ~1 were made

Volume 63 Number 3

between 1 and 2 minutes of age. Intratracheal intubation with oxygen administration was necessary to resuscitate most infants with Apgar ratings of 1 to 3. Some infants were members of more than one group (e.g., Case 4 in Table II). Observations were begun at the time of birth, the initial Apgar score, type of resuscitation needed, and the condition of the placenta being noted. Within the first 15 minutes of life 2.5 ml. of venous blood was drawn into a heparinized syringe. Determination of p H was done at body temperature on 0.5 ml. of this blood with the Beckman Model G pH meter. For CO2 content, 0.25 ml. of blood was centrifuged under oil and the content determined on a Natelson microgasometer? 2 True glucose was determined by an enzymatic reaction on the prepared zinc sulfate and barium hydroxide filtrate with Glucostat. "~3~ The remainder of the blood was centrifuged and the plasma separated and frozen for later duplicate determinations as follows: Sodium and potassium values were obtained by the method outlined for the Model 21 Coleman flame photometer; chloride values were determined by the method outlined for the Cotlove chloridometer3~; inorganic phosphorus levels were read on a Beckman D U spectrophotometer with the use of the Caraway modification of the method of Fiske and Subbarow. a5 Calcium determinations were done by the colorimetric method of Appleton? 6 Microbilirubin values were determined on a Spectronic 20 by the method of Meites? 7 Plasma osmolality was determined on a Fiske osmometer by the method of O'Brien? 8 Studies on the urine for the determination of chloride, sodium, potassium, calcium, phosphorus, and osmolality were done by methods similar to those used on the plasma. Determinations of creatine and creatinine, 39 and amino acid nitrogen 4~ were done on the urine of all infants who had sufficient urinary output. The nitroprusside test~" for urine acetone 'was used. ~Worthington Biochemical Corporation, Freehold, N. J. ~'Aeetest tablets, Ames Company, Inc., Elkhart, Ind.

Perinatal stress in the premature in[ant

365

No baby was continued in the study if his condition necessitated intravenous fluid administration or if it was felt that the minimal handling necessary for the study would in any way impair the infant's normal progress. The premature infant was placed on a metabolic frame 41 in an Isolette maintained at 88 to 89 ~ F. and 80 to 95 per cent humidity. 4z No oxygen was used unless indicated for respiratory distress, cyanosis, or apnea. Twenty-four hour urine specimens were collected in air-tight bottles fitted into iced Styrofoam~ containers. Stools were obtained in a Pedi-urine collectort sealed over the rectal area with colostomy paste. A gummed slit was left for the determination of rectal temperature. Isolette and body temperatures, respiratory and heart rates were recorded every 2 hours for the first 12 hours then every 6 hours throughout the study. Blood and plasma determinations as outlined were obtained at birth, 24, 48, 72, 108, and 144 hours of age. Electrocardiograms and blood pressure readings.43 were obtained at these same intervals. The infants were weighed daily. Nothing was given by mouth for the first 72 hours of life. For the next 24 hours 80 ml. per kilogram of 5 per cent dextrose in water was offered. During the fifth and sixth days pooled breast milk:~ was offered at the rate of 100 and 120 ml. per kilogram per 24 hours, respectively. The amount refused was measured and subtracted from each 24 hour intake. The observations were completed at 144 hours of age. Since numerical samples are occasionally quite small, Dr. Roscoe Dykman, head of the Division of Biostatistics, University of Arkansas School of Medicine, recommended that the values would have more significance if reported as medians with ranges representing the middle 60 per cent of the sample, rather than as means with standard deviations. In the presentation of data, any value

:§ Chemical Company. tSterilon Corporation, Buffalo 11, N. Y. :~Supplied by Ross Laboratories, Inc.

36 6

Beard et al.

September 1963

T a b l e I I . C l i n i c a l s u m m a r i e s of all cases s t u d i e d , r a n k e d a c c o r d i n g t o b i r t h w e i g h t

Sex

Birth weight (grams)

Mother's age (years)

1. BroB

M

1,0'00

28

G3, P~

Uneventful

2. Stiv

F

t,065

40

G~I, P10

Pre-eclampsia P1. P

S C~H,,

3. Broa

M

1,120

28

G3, P2

Uneventful

P

4. Wilk~

M

1,219

17

G~, P~

Eelampsia

SB Dem See Amy

5. MOOA

F

1,276

36

G3, P2

Uneventful

None

6. Blev

F

1,280

32

Gs, P4

Cervicitis

SB

7. Web

F

1,280

27

GT, P~ Abortions 2

Uneventful

SB Dem Phen Sp Nall

8. MooB

M

1,345

38

G~, Pz

Uneventful

None

9. Bel

M

1,403

14

G1, Po

Uneventful

SB Dem

10. L u n n

M

1,420

23

G4, P3

Uneventful

SB

11. For

M

1,453

31

G~, P6

Uneventful

None

12. H o u

F

1,480

34

G10, P9

Eclampsia

Amy Reserpine

13. H a d

M

1,580

36

G,, Pll Abortions 5

Uneventful

SB

14. DunB

F

1,602

27

GT, P1 Abortions 5

RHD

None

15. Ros

M

1,673

21

G4, P3

Uneventful

None

16. WilkA

M

1,680

17

G1, P0

Eclampsia

SB Dem See Amy

17. Phil

F

1,701

17

G.~, P1

Uneventful

SB Dem

18. Bev

M

1,720

29

Infant

Parity and gravidity

Pregnancy

Medication P

G~, P4 Toxemia Amy Abortions 3 Ab. P1, Abruptlo placentae; Amy, Amytal; Ap. Apgar; Aut, Autopsy; Aver, Avertine; Br, Breech; BS, Breath sound; C, Cyan0" Marginal sinus rupture; MST, Marginal sinus tear; Res, Resuscitations; RHD, Rheumatic heart disease; RD, Respiratory distreSS; membranes; S, Surital; SB, Saddle block; Seop, Scopolamine; Sp, Spinal; V, Vertex.

Volume 63

Number "J

L a b o r and delivery ......---

Pr. L

Br Cesarean section

Perinatal stress in the premature in[ant

367

Hospital course

C o n d i t i o n at birth

Ap 3 RD

RD with apnea. Died at 12 hours. Aut, CNS hemorrhage

Ap 3

Diarrhea, E. Coli 0119, and sepsis, E. coti, 6 days. Death 13 days. Aut, (1) CNS hemorrhage; (2) gastric ulcer

Pr. L

Br

Ap 7 Cry delayed

RD first 24 hours only. Aspiration pneumonitis 10 days. Died 11 days. Aut, pneumonia.

Pr. L Convulsion

Br

Ap 1 Breathing delayed 10 rain.

RD first 24 hours only. Duodenal atresia. Operation, died 7th day. Aut, duodenal atresia

PRM

V Ab. PI 10%

Ap 10

RD first 24 hours only. + Cord section. No treatment. Discharged well

PRM

V

Ap 1

RD and apnea first 24 hours. Removed from study. Failed to respond. Died l0 days. Aut, CNS hemorrhage

Pr. L

V

Ap 10

RD with apnea first 24 hours. X-ray 9 hours shows emphysema. Discharged well

PRM

V

Ap 7

RD first 3 days. Diarrhea and pneumonia. S t a p h . aureus, second week. Discharged well

PRM Pr. L

Pit ELF

Ap 10

+ Cord section. Treatment 5 days. Discharged well

V Ab. P1

Ap 10

RD with apnea at birth. Death at 45 hours. Removed from study. Aut, CNS hemorrhage

V

Ap I

RD from birth. Removed frmn study. Died at 5 days. Aut, subdural hemorrhage

V Ab. PI

Ap 1

RD from birth. Sclerema second day. Died at 52 hours. Aut, (1) intravenous and subdural hemorrhage, (2) pneumonia

V

Ap 10

+ Cord section. Treatment 5 days. Discharged well

Br

Ap 7

RD from birth. Sclerema second day. Removed from study. Died at 72 hours. Aut, (1) subarachnoid hemorrhage, (2) pneumonia

V

Ap 10

Uneventful

V

Ap 1

RD first 24 hours. Discharged well

V ELF MSR

Ap 1-3

Uneventful

PRM

PRM

Pr. L Convulsion

PRM

V Ap 8 Uneventful Ab. P1 ~is;Dem, Demerol; ELF, Elective low forceps; Ep, Epidural; HMD, Hyaline membrane disease; Intub, Intubated; Nan, Nalline; MSR, Pit, Pitocin induced; P, Pudendal; Phen, Phenergan; P1. P, Placenta previa; Pr. L, Prolonged labor; PRM, Premature rupture of

3 6 8 Beard et al.

September

1963

Table II. Cont'd

Infant

} Sex }

Birth weight ] Mother's age (years) (grams)

Parity and gravity

Pregnancy

Medication

19. Harr

M

1,758

17

G1, P0

Uneventful

SB

20. And

M

1,768

27

Gs~ PG

Uneventful

Dem Phen

Abortion 1 21. Bur

M

1,800

17

G2, P1

Uneventful

SB

22. Lips

M

1,800

16

G,.,, P1

Eclampsia

Dem Phen Ep

23. Ree

F

1,814

21

G3~ P2

Uneventful

SB

24. Mab

M

1,814

19

G4, P3

Uneventful

P

25. DUnA

M

1,857

27

GT, P1 Abortions 5

RHD

None

26. Syk

F

1,885

30

G,, P0

Eclampsia

Ep Reserpine Diuril

27. Dic

F

1,899

19

G2~ Pa

Uneventful

SB

28, Bat

M

1,914

25

G~, P~ Abortion 2

Uneventful

SB

29. Reev

F

1,920

41

G~, P5

P1. P

Abortion 1

Sp Aver

30. Scot

F

1,956

17

G1, P0

Uneventful

SB

31. Guin

M

1,956

18

G1, P0

Uneventful

SB

32. Cris

F

1,960

22

G~., P1

Uneventful

Dem Phen Scop

33. Will

F

1,985

19

637 Pl

Uneventful

Abortion 1

SB Oem

34. Knig~

M

1,985

35

G~, P4

Uneventful

35. All

F

1,999

20

G~, P2

Uneventful

SB

36. Pete

F

2,041

29

G6, P5

Uneventful

SB

37. Jon

M

2,050

33

Uneventful G1s, P4 Abortions 13

38. Gra

M

2,126

26

G~,, P4

Toxemia

SB Phen Reserpine Diuril

Abortion 1

39. Moor

M

2,130

24

G1, P0

Pulmonary tuberculosis. Vaginal bleeding at 1 89 7, 8 months of gestation

Sp Dem Phen

40. DickB

M

2,155

15

G1, Po

Uneventful

Ep Dem Phen

Volume 63

Number 3

Labor and delivery

Perinatal stress in the premature in[ant

t

Condition at birth

3 69

Hospital course

Br

Ap 9-10

Did well until convulsion and apnea at 48 hours. Died third day. Aut., acute hemorrhagic pneumonia

Br

Ap 1

Uneventful

V ELF MST

Ap 10

Uneventful

Pit

Br

Ap 1

Diarrhea twentieth day, E. Coli 0124. Discharged well

PRM

V ELF

Ap 9

Uneventful

PRM

V

Ap 10

RD first 24 hours only. Discharged well

Br

Ap 10

Uneventful

V

Ap 8

Uneventful

V

Ap 9

Uneventful

V ELF

Ap 4

RD first 36 hours. H M D by x-ray. Removed from study. Discharged well

Ap 6

RD first 2 days. Coli aerogenes, umbilicus fifth day, urine twentieth day. Discharged well

V

Ap 10

Uneventful

V

Ap 2 Intubated 38

Cesarean section

Uneventful min.

Pr. L

V

Ap 10

Uneventful

Pr. L

V

Ap 1,0

Diarrhea 13 days, nontypable E. coll. Discharged well

Br

Ap 9

Uneventful

V

Ap 10

Uneventful

V

Ap 10

Uneventful

V

Ap 8

Uneventful

V

Ap 10

Uneventful

V ELF

Ap 10

Uneventful

Br

Ap 1

Uneventful

PRM

PRM

Pit

370

Beard et al.

September 1963

Table II. Cont'd In[ant 41. Terr

Sex F

Birth weight (grams) 2,155

Mother's age Parity and (years) gravidity 31 G., Ps

Pregnancy Pre-eclampsia

Medication SB

Diuril 42. John

F

2,162

23

G~, P1 Abscess of left breast at 7 Abortion 1 months. Culture, D. pneumoniae

43. KnigA

M

2,197

35

Go,, P~

Uneventful

44. Sand

F

2,289

13

G1, P0

Toxemia

SB Dem Spor

SB

Reserpine 45. Coh

F

2,296

37

G~.~, P,

P1. P, spotting last 5 weeks. Hemoglobin 8.7 Gm.

46. Mel

F

2,476

17

G1, P0

Thyrotoxicosis. Jaundice first trimester, bleeding second. Treatment K perehlorate

representing less than four samples is so marked.'• R E S U L T S AND C O M M E N T S Analysis of the data was made according to major categories of perinatal complications: Apgar 1-3, respiratory distress, toxemia in the mothers, and breech deliveries. Because infants frequently had more than one complication (especially those in the lowest weight group) further subdivisions were made to isolate changes due to a single complication such as asphyxia or respiratory distress. T h e number of babies in some of the subdivisions were so small that only an evaluation of trends was possible. In addition, data are grouped according to traditional weight groups (1,000 to 1,500, 1,501 to 2,000, 2,001 to 2,500 grams). Clinical summaries of all cases are listed in order by weight in Table II. Distributions of complications and deaths are recorded in Tables I I I and IV. It is apparent that the lowest weight group with 12 infants had the greatest number of complications and deaths and the ~'The values for each infant studied, the mean and the ranges for each weight and clinical category evaluated can be obtained from the American Documentation Institute Auxiliary Publications Project, Photoduplieatlon Service, Library of Congress, Washington 25, D. C. For photoprlnt or 35mm. microfilm, make check or money order in the amount of $1.25 payable to: Chief, Photodupllcatlon Service, Library of Congress, Washington 25, D. (3. Mention Document No. 7518.

General SB Dem Phen

smallest number of infants from whom complete data were obtained. Only 5 infants completed the study. Although some of the infants died during the second week, the association of death with a low initial Apgar score, respiratory distress, and intracranial hemorrhage was common (Table I V ) . Twenty-three infants were in the 1,501 to 2,000 gram weight group and despite 2 deaths on the third day of life (Cases 14 and 19) the remainder were discharged in good condition. The 11 infants weighing over 2,000 grams had a minimum of complications and no deaths. CONTROLS WITHOUT COMPLICATIONS Results. By the criteria listed earlier, 15 babies were designated as control infants. Only one of the 15 control infants weighed less than 1,500 grams, whereas 9 were in the middle weight group (4 weighed over 1,950 grams) and 5 weighed over 2,000 grams; therefore, this "normal" group was drawn almost entirely from the two larger weight groups. Weight loss or gain; urine volume and osmolality (Figs. 1-3). Weight loss was relatively constant during the first 72 hours (about 40 grams per kilogram per 24 hours). With the administration of 80, then 100 ml. per kilogram per day of fluid containing calories there was a moderate weight gain (10

Volume 63

Number 3

P e r i n a t a l stress in t h e p r e m a t u r e

Labor and delivery

Condition at birth

infant

3 7 1

Hospital course

V

Ap 10

Uneventful

V ELF

Ap 10

Uneventful

V

Ap 10

Uneventful

V

Ap 2 Intubated 15 minutes

Uneventful

Ap 2

Uneventful

Ap 10

Mild transient hypothyroidism. Discharged well

Cesarean section V ELF

T a b l e I I I . F r e q u e n c y of c o m p l i c a t i o n s in infants who d i e d Central Case No.

1 2 3 4 6 10 11 12 14 19 Total 10

Weight (grams)

Age at death

1,000 1,065 1,120 1,219 1,280 1,420 1,453 1,480 1,602 1,758

24 13 11 7 10 45 5 3 3 3

nervous

In/ections

system

0 + + 0 + 0 0 0 + + 4-5

+

hours days days days days hours days days days days

Respira-tory distress

Respiratory distress 1, 3, 4, 5, 6, 7, 8,

10, 11, 12, 14, 16, 24, 28, 29

Apgar 1-3

Breech +

+ + 0

0 + 0

+

+

+

+

+ 0 + + 0 0

0 0 0 0 0 0

0 0 0 0 0

0

+ + + + + +

+

7

9

6

2

5

0 0 + + + + +

I

Toxemia

+ 0 +

+

T a b l e I V . D i s t r i b u t i o n of p a t i e n t s a m o n g categories (see T a b l e Respiratory distress t

1-3 Apgar

Breech

0 +

II)

I

Toxemia

Died

1, 4, 6, 11, 12, 16

1, 3, 4, 14

4, 12, 16

1, 3, 4, 6, 10, 11, 12, 14

1, 2, 4, 6, 11, 12, 16, 17, 20, 22, 31, 40, 44, 45

1, 4, 20, 22, 40

2, 4, 12, 16, 22, 44

1, 2, 4, 6, 11, 12

I, 4, 20, 22, 40

1, 3, 4, 14, 19, 20, 22, 25, 34, 40

4, 22

1, 3, 4, 14, 19

2, 4, 12, 16, 22,

4, 22

2, 4, 12, 16, 18, 22,

2, 4, 12

44 15, 21, 23, 27, 30,

26, 38, 41, 44 32 , 33, 35, 36, 37, 39, 42, 43

Apgar 1-3

1, 4, 6, 11, 12, 16 Breech

1, 3, 4, 14

Toxemia

4, 12, 16 Normal 9, 13,

3 7 2 Beard et al.

September 1963

Weight loss or gain A-- =1000-1500 e~=lBOI -2000 c~ =2001-2500

Weight loss or gain

Weight loss or gain

12 23 II

eL=control B.-=Resp. distress ~ ' " =Apgor I - 3 = Toxemia ~---=Breech

61t

15 14 14 I0 10

# = = Control ~= No RD ~,..-= Toxemia / p - = Toxemia ~.-.= Breech - - = Breech

Weight loss or gain 15 ~ = = 8 5 D-- = ~ = ~.,-.=

but Apgor I - 3

J,

~ Apgar ~ Apgor ~ Apgor

I-3 7-10 I-3 7-10

~.Apgor

Control RD ~ A p g a r RD ~ A p g o r

15 8 6

7-10 l-- 3

No RD but Apgor I - 3

8

~k"...

...g,'%:,

4O

~-Y

~z

\

~ . . . . . . . . . . .

§

ks " ........

JL.

\

20"~ 4O

z~

60 I

~,8

HOURS

Urine Volume Am, - 1000-1500

12 a ~ 9 IBOI - - 2 0 0 0 23 C-- - 2 0 0 1 - 2 5 0 0 ' l

I '72 ~e I~o 144 24 :~e HOURS

Urine Volume N~ i-t-b---

= Control = Rasp. distress = Apgar I - 3 = Toxemia 9 Breech

§

6B i~o HOURS

,I '96 I~o 144 HOURS

Urine Volume I5 14 14 I0 I0

Urine Volume

N ~ 9 Control 15 ~ . , , . = No RD but Apgor I - 3 8 &***,- Toxemia ~ Apgor 1-3 5 ~ 9 Toxemia ~ Apgor 7 - 1 0 5 e~,.,= Breech ~ Apgor I - 3 5 o - - - . Breech ~ A p g o r 7 - 1 0 5

80-

#m 9 ~= D..,~.,,,,-

Control RB ~. Apgar 7-10 RD E Apgar I - 3 NO RD but Apgor I - 3

15 8 6 8

A

60\

I

i**~, ~B '72

~ .

/

..,ZL:. /.

4o-

.....

200

2'4 48

7:> 9'6 HOURS

I I;)0 144 24 48

7'2 96 HOURS

I I:)0 144 24 48

yt""

#" "

I

72 96 HOURS

120 144 24 48

7'2 9'6 HOURS

120 144

Figs. 1-12. In all graphs, values in the first division represent infants grouped according to birth weight; in the second, according to major stress group; in the third and fourth, according to special subgroups (see text). Numerals after each group indicate number of infants. Numbers on graphs represent number of infants whenever it is less than 4.

to 20 grams per kilogram per day) over the next 48 hours. Urine volumes approximated 10 ml. per kilogram per 24 hours during the period of fluid and caloric deprivation, but increased gradually with oral intake. The osmolality increased to a m a x i m u m of 480 m O s m per liter at 72 hours (highest observed value 555 m O s m per liter), dropping to about 100 m O s m at 120 and 144 hours. Median values for serum osmolality in 5 infants are not depicted graphically, but were 261, 281, and 250 m O s m per liter at 24, 72, and 108 hours, respectively.

Urine sodium, potassium, chloride, and Na/k ratio (Figs. 4-7). Urinary sodium excretion fluctuated slightly around 0.5 mEq. per kilogram per 24 hours during the period of the study. Similarly, urinary chloride values ranged from 0.25 to 0.50 mEq. until after milk ingestion. Urinary potassium rose sharply during the second day to over 1.0 mEq. per kilogram per 24 hours and then leveled off at 0.5 to 0.6 mEq. Hence, it is apparent there is an increased excretion of sodium, chloride, and particularly potassium during the s~cond 24 hour period.

Volume 63 Number 3

Perinatal stress in the premature in[ant

Na (Urine).

No ( U r i n e ) N--- Control e,,,,. Na RD but Apgor &.,.,= Toxemia E Apgar ~--- 9 Toxemia g Apgor o . . . - Breech ~ Apgor 9 Breech ~ Apger

No (Urine)

A-- "

I 0 0 0 -1500 12 " 1501 - 2 0 0 0 23 C-- - 2001--2500 I I

IB

N ~ 9 Control l - - - Resp. distress .It.-- 9 Apgar I-5 9 Toxemia 9---- - Breech

14 14 I0 I0

Na (Urine) N1- Control 0 ~ - RD ~ Ap(Jor 7-10 0 , . = RD ~ Apgar I - 3 ~...~ No RD but Apgor I - 3

15 1-3 I-3 7-10 [-3 7-10

373

8 5 5 5 5

15 B 6 8

3

1.00 3 %

.~..,..

.75.

i

N

\

E

.50-

.25I

0

2'4

48

7'2 9'6 120

144

24

48

HOURS

Urine O s m o l a l i t v A-- = 1000-1500 1--=1501-2000 c~ =2001-2500

12014 j

7'2 9'6 HOURS

I

l

'20

'44

24

~ 9'6 ~o,44

48

HOURS

Urine O s m o l a l i t y 15 N= = Control 8 o - = RD r Apgor 7-10 5 =t--= RD ~ Apgor I - 3 ~.--= No RD but ApcJor I - 3

Urine O s m o l a l i t y N= = Control * - - = No RD but Apgar I - 3 A..-= Toxemia ~ Apgor I-3 ~ = Toxemia ~ Apgor 7-10 ~---= Breech Er Apgar I--3 ~ = Breech l: Apgar 7-10

#--=Control 15 1 - - = Resp. distress 14 i~..=Apgar I-3 14 k - - =Toxemia I0 : Breech IO

5?

~ 9~ HOURS

Urine O s m o l a l i f y 12 23 II

24 4'8

1 1

2

,oo] o

15 8 6 B

I

I

I

2'4 4s 7'2 9'6 I~0 144 2 4 , ~ HOURS

i2 96 HOURS

I

I;~0 144 2 4

K (Urine)

K (Urine)

72 9'6 HOURS

120 144 2 4

N ~ = Control ~...,. No RD but Apgar I - 3 & ..... Toxemia E Apgor I - 3 a---- 9 Toxemia ~ Ap(:Jar 7-10 o.,,.- Breech ~ Apgor I - 3 e--- 9 Breech ~ Apgor 7-10

15 14 14 I0 I0

48

7'2 96 HOURS

120

I

144

K ( Urine )

K (Urine)

N-- , Control l - - = Resp. distress e e - - 9 Apgar I - 3 9 Toxemia e~- 9 Breech

A-- 9 1 0 0 0 - 1 5 0 0 12 B-- 9 1 5 0 1 - 2 0 0 0 23 c-- = 2 0 0 1 - 2 5 0 0 I I

48

15 8 5 5 5 B

Nl 9 0--= [},... ~"'"

Control RD ~ Apgar 7-10 RD ~ Apqar 1 - 3 NO RD but Apgar I - 3

i

e

I5 8 6 8

~

t

1.00 -

"-.s~

.75\ L~ . 5 0 -

..,"

E

,,,

e

' ,,"

;

~, ~"/; B-,....,o'

,,

. : "%., "~t.~ ..............

I$

......... w.+,..,. ,o'W

.25.

o 2'4 4~

I

~

I

12. 9'6 m~014424 4~ ~2 ~6 120~424

HOURS

HOURS

The breast milk used contained 6.7 mEq. per liter of sodium, 14.7 mEq. per liter of potassium and 11.9 mEq. per liter of chloride. Following milk ingestion which was be-

4:8

I

72 9`6 HOURS

120

144 2 4

I

4'8

"r2 9'6 HOURS

120

144

gun at 96 hours, retention of chloride and potassium could be demonstrated, There was virtually no sodium retention during the same period. Urinary sodium/potassium ra-

3 7 4 Beard et al.

September 1963

CI ( U r i n e )

CI (Urine)

A-- = 1000-1500

12

e~ ~

23 II

= 1501 - 2 0 0 0 =2001-2500

Cl ( Urine ) N ~ = Control

CI ( U r i n e )

N = = Control m - - = R e s p , distress ~ , - - = A p g a r I-:~. ~-- :Toxemia

15

~=Breech

I0

N = = Control ~ - - - = N o RD but Apgar "~..-= Toxemia ~ A p g o r t~--= Toxemia ~ A p g o r

14 14 I0

~---= Breech

~ Apgor

~=

~ Apgor

Breech

15 I-3 I-3 7-10 [-3 7--10

8 5

e ~ - = RD ~ A p g a r 7-10 {::--= RD e A p g a r I-- 3 ~-.-,= No RD bul Apger I - 3

|

p.

1,00"

A .75"

\

,~e.,, 3

g

e

B

.....

i

,,C7"

e

,~

.50-

.25-

"

z:~ 4~

7~

,~o

~4424

:~B ~2

HOURS

I 144 z4 4B

No/K

A ~ 9 1000-1500

12

9 1501 - 2 0 0 0

23

C ~ C,- - 2 0 0 1 - 2 5 0 0

II

72

9B ~2o

I

~44,24

'4s

~2

HOURS

(Urine)

Na/K

N 1 , Control ~,.,.- No RD but Apgor I - 3 b...,, Toxemia ~ Apgor l - 3

15

s

E Apgor I - 3 E Apgor 7 - 1 0

(Urine)

Hi 9 [~--= D...= tP.,.,-

8

9 Toxemia ~ Apgar 7-10 - ~ , , . , Breech 9 Breech

'9~ lab I144

HOURS

(Urine)

No/K

N 1 9 Control I5 1 . - = Resp. distress 14 ~-= Apgor 1 - 3 14 k--- 9 Toxemia I0 6.--- 9 Breech I0

2.50-

N

"

HOURS

(Urine)

No/K

~B ,;,o

%

5 5 5 5

Control RE) E Apgar 7-10 RD E Apgar I - 3 No RD but Apgar I - 3

I5 8 6 B

\

2,00-

Z

"

1.50-

N

~ . s P""':::.~"J"'"'"~ 9

1.00-

,#e........

,,

"-,.jP .... .... o:.~'~., ' e.. o"

.50-

,,,

..... ,

3 0

24

4'8

7'2 HOURS

9'6

I:~0

114 0

2'4

48

7'2 9'6 HOURS

120

1/4 24 4'8

72

9'6

HOURS

120 144

I

24 48 Y2 9'6 ~o 144 HOURS

tios, which ranged between 0.50 and 1.50, were greatest in the first 24 hours and lowest at the second and third 24 hour periods, reflecting the greater sodium loss in the first period, the increased potassium loss in the second and third 24 hour periods.

cessful, either in groups or in individual babies, as might be illustrated by the finding of a CO2 content of 16.9 mEq. per liter in a control infant at a time when the pI-I was 7.41. However, most values for CO2 content were in the range of 19 to 21 mEq. per liter.

Plasma sodium, potassium, and chloride (Figs. 8-10). Plasma sodium values clustered

Plasma glucose, urine acetone, and bilirubin values. Because of technical complica-

around 145 to 150 mEq. per liter, being highest at 72 hours. Plasma potassium values ranged around 5 mEq. per liter throughout the study period, while plasma chloride values fluctuated between 103 and 109 mEq. per liter

tions, true blood glucose values for each time period were obtained for only the last 10 babies. Median values, representing both control infants and those under stress, were as follows: 40, 29.7, 29.5, 21.3, 43.4, 46.7 mg. per cent at birth, 24, 48, 72, 108, 144 hours of age, respectively. Serial urine acetone determinations were completed in 26 infants, 19 of w h o m had positive reactions at either 72 or 96 hours of age or both; 3 of these also had positive reactions at 48 hours. Six of the seven Apgar 1-3 babies had positive urine acetone reactions at one or more of the above periods,

Whole blood pH and plasma CO~ content (Figs. 11 and 12). Consistently higher blood p i t values were present in the control group over those seen in the other major groups. While initially 7.29, the pH rose to 7.4 at 24 hours and remained between 7.36 and 7~.:41 thereafter. Attempts to correlate CO2 content with blood pH values were unsuc-

Volume 63 ~umber 3

Perinatal stress in the premature in[ant

and 13 of the 19 babies with Apgar 7-10 showed similar reactions. No acetonuria was demonstrated during the first 24 hours. Serial total bilirubin determinations in 20 infants representing all groups revealed median levels of 10.4, 14.2, and 12.2 mg. per cent at 72, 96, and 120 hours. The highest individual level recorded was 18.2 mg. per cent at 120 hours. Comment. The control group was defined with care in order to eliminate as far as possible any stressful factor other than prematurity. Therefore, all 15 control infants were born in vertex presentation with no accompanying asphyxia, respiratory distress, infection, or postnatal complications. This group appears to be comparable to the group of 3 infants born by cesarean section, one inas "less premature" and to the 17 infants in the control group of Nicolopoulos and Smith, zs although this latter group included

No

3 infants born by cesarean section, one infant with tachycardia, and one with apneic spells. The 15 control infants in the present series lost 8.2 per cent of their birth weight the first 48 hours, compared to a loss of 8.4 per cent reported by Nicolopoulos and Smith z8 in premature infants and a loss of 9.3 per cent reported by McCance *~ in a group of normal term newborn infants from whom fluid and calories were similarly withheld. Weight loss for the first 72 hours was 12.9 per cent, approximately the same as that found for a group of "less premature" and term infants? s Urine volumes were greater during the second day of life, but averaged 11 ml. per kilogram per 24 hours for the period of deprivation, which is comparable to the 9 ml. reported by Hansen ~ for the "less premature" group and to the 13 ml. reported for a

Na ( P l a s m a )

(Plasma)

A-- = I000-1B00 g ~ =1501 - 2 0 0 0 r =;~001 - ~ 5 0 0

Na IPlasma) Na (Plasma) N= =Control 15 i . = Control ~----= No RD but Apgar I - 3 " 8 c~-= RD C Apgar 7-10 e,.,-= Toxemia ~ Apgar I-3 5 ~--= RD ~ Apgar I-- 3 - - = Toxemia t~ Apgar 7-10 " ~ . = Breech ~ Apgar 1-3 5 " .~-..-.= No RD but Apgar I - 3 ~ = Breech ~ Apgar 7-10 5 ,,,,"=~% 3 ,0.2 ,~,.,"" %% ,,o,'~

N - = Control 15 1--=Resp. distress 14 ~--=Apgar I - 3 14 A---=Toxemia ~0 = Breech [0

12 23 II

375

.S': ~

1601

--..

15 8 6 e

.,,,"\

.........

155 r

?"

"" 150. X

"::::::2; .............

=~i:::,:,:..,,,,,:,~::~.......... .

\

~145

140-

~'4 4'8 7'2

Id8

144I 0

2'4 4'8 72

1()8

14/

0

2'4 4'8

HOURS

HOURS

N= 11 ~e-/~ e--

A==looo-I$OO 12 N-lSOl2 0 0 0 23 r 2OOl-25oo ii

- Control = Resp. distress 9 Apgar I-3 9 Toxemia 9 Breech

108

I 14'~

0

24

HOURS

K(Plasma)

K (Plasma)

7'2

K Plasma) N ~ " Control ~,.-= NO RD but Apgar &,..,= Toxemia ~ Apgor &'~ 9 Toxemia ~ Apgor ~ , . . - Breech ~ Apgar ~ 9 Breech ~ Apgar

15 14 14 I0 I0

48 72 HOURS

168

[ 144

K (JPlasma) I-3 I-3 7-10 I-3 7-10

15 8 5 5 5 5

N~D---. E~..= ~'"~

Control I5 RD ~ Apgar 7-10 B RD E Apgar I - 3 6 NO RD but Apgar I - 3 8

% b

~-

5-

43

0

/4

4'8

-i2 HOURS

ib8

I 144

2'0

4'8

-t2 HOURS

168

I 144

0

2'4 4 ' 8

7'2 HOURS

1()8

I 144

o 2.4 ~

~'2 HOURS

I

16e 144

376

September 1963

Beard et al.

Cl (Plasma)

Cl (Plasma)

CI (Plasma)

# J = Cont roI i-=Resp distress ~--=ApQor I ~ = Toxemia = Breech

A-- = IO00-1BO0 ~2 e ~ = 1501 --~'000 23 ~ l =2001--2500 iI 120 115-/

but Apgat ~ Apg~r ~ Apgar ~ Apgor E Apgor

l-3 I-3 7-/0 I--3 7--10

15 8

W= = ~-= =P-= ~,---=

5 5

5

Control RD ~ Apgor 7-10 RD ~ Apgar 1-- 3 N o R D but Apgor t - 3

15 B 6 e

5 ?

/..__Z<.

A

,,o \

CI (Plasma)

~ l = Control I * - - = NO RD t,,.-= Toxem}~ l ~ = Toxemia ~---= Breech ~= Breech

15 14 14 10 I0

~

,."

105-

......~e 10095-

I 0

2'4

48

10

7'2 HOURS

r()8

0 2'4 48 7'2

f44

I 144

I08

HOURS

pH(Blood )

pH (Blood)

~.~

L2 23 LI

168

144

0

~4

4B

HOURS

N-- 9 Control

15 pH (Blood)

I~-Resp. distress ~ o - = Apgar ~-3 ~ 9 Toxemia ~ -Breech

14 14 I0

=

- 1000-1500 1501 - 2 O 0 0 C~'2001-2500

I

:~4 4~} 72

0

I0

I '44

~68

pH ( Blood )

~Control 15 ~..,,. NO RD but Apgar I - 3 8 &...,- Toxemia E Apgar I - 3 5 & ~ - Toxemia ~ Apgar 7 - 1 0 5 ~ , , . * Breech E Apgar I - 3 5 ~B r e r aegp A c 7-10. h l5 ~

7.5"

7~ HOURS

N1G~ . I~-.r ~

Control RD ~ Apgar 7-10 RD ~ Apgar I - 3 No RD but Apgar I - ~ ~

~

~

IS 8 6 8

c

7A-

~

7.3-

72" 7.1-

o

2'4 4'8 r~

108

I

144 0

HOURS

11

4;

71 HOURS

I;8

144

CO= Content (Plasma)

COz Content (Plasma) A-- =1000--1500 lira =1501-2000 r =2001-2~i00

?5-

24

12 23 II

0

:)4

48

72 HOURS

14 ,~--= NO RO but Apgor 14 IO A--= Toxemia ~ Apgor IO " ~ = Toxemia ~ Apgor ~---= Breech I~ Apgar

II= =Control

~=

15

Breech

~ Apgar

24

z~8 7'2 HOURS

108

144

CO= Content (Plasma)

15

N

,

144 0

COl Content (Plasma)

w==Control

i~-=Resp, distress 9~-- =Apgar r-3 J~---=Toxemia ~=Breech

23-

,

108

Ilm = Control

15

I-3 B m--= RD ~ 'Apgor 7-10 I-3 5 D--= RD E Apgar I-- 3 7 ~ 1 0 5"I'~..-.= No RD but Apgar I-3 I--3

/

7-10

8 6 B

~ t S .... 3

;J,;

1-

!-,

U~I917-

15-

12

2'4 4'8 i2 HOURS

ida

I 144 0

~4 4~ i2

Ida

HOURS

group of term infantsJ 4 Urine volumes reported by Nicolopoulos and Smith 1s are not comparable since fluids were not completely withheld. Urine osmolality was greatest at 72 hours and the median value of 441 mOsm. per liter compares closely with the figure obtained by others24, 42

14~, 0 r

~7~ HOURS

16B

I

144

0

24

4'B

"t2 HOURS

16B

H

144

Over a 6 day period, the total amounts of sodium, potassium, or chloride excreted by the control infants differed by less than 1 mEq. per kilogram. Urinary sodium and potassium excretion during the first 48 hours approximated that of Cart's 45 4 "good prematures," is slightly lower than figures of

Volume 63 Number 3

Perinatal stress zn the premature infant

Nicolopoulos and Smith, is and slightly higher than those reported by Osler 46 for "control prematures." The figures of Butterfield and associates47, 48 are not comparable since their infants were fed at 48 hours with milk of rather high sodium content and m u c h of their deficit represents stool sodium. Values for plasma sodium and potassium are comparable to those of others TM 24 and indicate no hypernatremia or hyperkaliemia in the control group during deprivation. Thus, no evidence of compromised homeostasis could be demonstrated in the control group as a result of fluid and caloric deprivation, although ketonuria and hypoglycemia occurred frequently and was most marked at 72 hours, reflecting demands on energy homeostasis. RESPIRATORY

DISTRESS

GROUP

Results. Seven of the 15 infants with respiratory distress had only initial or incomplete determinations, because of death or a deteriorating clinical condition. Six of these babies received 10 per cent glucose in a sodium bicarbonate solution intravenously after being removed from the study, but, despite occasional improvement, all but one died (Cases 6, 10, 11, 12, 14). Of the 8 premature infants with respira-

377

tory distress for whom the data are mo~e complete, 5 (Cases 3, 4, 5, 7, 8) weighed under 1,500 grams, 3 (Cases 16, 24, 29) between 1,501 and 2,000 grams. Only 2 were severely anoxic at birth (Cases 4, 16). The respiratory distress was mild as evidenced by the fact that only 2 babies had respiratory distress after 24 hours of age (Cases 8 and 29). Weight gain or loss, urine volume, and osmoIality (Figs. 1-3). Although the duration of respiratory distress ranged from less than 24 hours to 3 days, the weight loss was great a n d continued during the second 72 hour period (Table V ) . A similar loss was observed in the lowest weight group. The fact that the 3 infants with respiratory distress who weighed more than 1,500 grams lost an average of 40.1 grams during the second 72 hours suggests that such a weight loss m a y be characteristic of respiratory distress. Urine volume, in the respiratory distress and lowest weight groups, was only about two-thirds of that seen in the other groups during the second 72 hours. Urine osmo!ality, though paralleling the control values, was slightly higher at each period in the respiratory distress with normal Apgar (largest respiratory distress group). Table V demonstrates that the increased

Table V. Comparison of first and second 72 hour periods in regard to weight change, urine volume, body temperature, and respiratory rate. All figures represent median values First 72 hours Weight (Gm./ Kg./ 72 hr.) -119.0 -114.6

Urine volume (ml./ Kg./ 72 hr.) 32.9 31.9

Temper- Respiraature* tory (~ rater 94.5-97.2 44-60 93.5-95 36-54

Normal Respiratory distress Apgar 1-3 -122.7 41.8 93.7-96 38-49 Toxemia (whole) -112.7 25.1 94 -95.6 40-54 Nor. tox -111.0 19.8 95.2-96.2 40-51 Breech -114.3 31.3 94.3-96 46-54 1,000-1,500 -138.8 2 4 . 9 6 93.5-94.4 36-55 1,501-2,000 -109.6 36.3 94 -96.4 44-51 2,001-2,500 -117.5 3 8 . 6 1 94.4-97.3 40-56 *Highest and lowest rectal reading during each 72 hour period. tI-Iighest and lowest rate per minute for each 72 hour period.

Second 72 hours Weight (Gm./ Kg./ 72 hr.) +26.1 -35.5

Urine volume (ml./ Kg./ 72 hr.) 145.2 95.8

Respira-

+17.1 +24.57 +43 +42.7 -17.0 +17.4 +22.1

151.2 95 -96.8 1 4 5 . 2 96.4-96.8 148 96.4-97.4 115.7 95 -96.9 103.55 94 -94.8 148.2 94.6-95.8 1 4 2 . 5 6 96.2-96.2

Temperature* (~ 96 -96.8 94.2-95

tory rater 38-41 43-48 36-44 36-44 40-46 33-44 42-44 38-44 36-46

3 7 8 Beard et al.

weight loss noted in the respiratory distress group and the smallest weight group was associated with a tendency to lower body temperatures throughout the period of the study. Although respiratory rates are given in range of medians for the period depicted, no reflection of the degree of intercostal retraction and expiratory grunt which were present in all babies with respiratory distress is represented.

Urinary sodium, potassium, and chloride, Na/K ratios (Figs. 4-7, Table VI). Except for the first day, urinary potassium values were high throughout the period of the study. Similar values were found for the lowest weight group which contained most of the infants with respiratory distress. The one control infant (Case 9) who weighed under 1,500 grams did not reflect this tendency for the first 72 hours. The 2 infants with respiratory distress weighing over 1,500 grams (Cases 16 and 29) had elevated potassium values during the first 72 hours but thereafter they were similar to those of the control group. Urinary sodium and chloride values paralleled those seen in the group of controls without complications. N a / K ratios were generally lower for the respiratory distress group because of the increase in urinary potassium.

Plasma sodium, potassium, and chloride (Figs. 8-10). Plasma sodium values for the respiratory distress group as a whole tended to be in the low range of the control infants. Infants with respiratory distress with normal Apgar ratings had plasma sodium values 3 to 6 mEq. per liter lower than the uncomplicated controls at each test period. In the 2 infants with respiratory distress whose initial Apgar rating was 1-3, the plasma chloride values were 110 mEq. per liter or over at 48 hours and thereafter. No correlation between a decreased CO2 content and an elevated plasma chloride level could be demonstrated in any of the study infants. Median plasma potassium values above 6 mEq. per liter were demonstrated only in the respiratory distress groups and in babies weighing under 1,500 grams. Only 2 infants of the 1,000 to 1,500 gram weight group did

September 1963

not have respiratory distress (Cases 2 and 9) and in these babies the plasma potassium values were between 6.0 and 8.6 mEq. per liter at both 24 and 48 hours. T h e 3 infants weighing over 1,500 grams who had respiratory distress (Cases 16, 24, and 29) had plasma potassium values at 24 hours of 5185, 6.82, and 7.38 mEq. per liter, respectively (average 6.68 mEq. per liter).

Whole blood pH and plasma CO~ content (Figs. 11 and 12). Whole blood pH values for the respiratory distress group except for initial determinations were available only for those with less severe respiratory distress. After an initial value of 7.21, the pH values paralleled those of "uncomplicated" controls at 48 hours. However, in the second 72 hours, while the infants were clinically asymptomatic, the values fell to about 7.30 and remained at this level. Plasma CO2 content values mirrored those of the controls except for the 144 hour value, which was low. Comment. Although respiratory distress persisted for from less than 24 hours to 3 days and was not severe, these infants (all but 2 were in the lowest weight group) deviated from the control group in the following areas: greater total weight loss; tendency to lower body temperature; a urine volume two thirds that of the control group during the second 72 hours; tendency toward higher urinary osmolality especially during the second 72 hours; higher urinary potassium values; low N a / K ratios and higher plasma potassium levels at 24 hours with probable minimal lowering of the plasma sodium levels. Weight loss during the first 48 hours was 8.7 per cent compared with 8.2 per cent for the control infants during the same period. Nicolopoulos and Smith is reported an 8.8 per cent weight loss compared with 8.4 per cent for control infants. These figures do not lend support to Usher's 1~ statement that infants with respiratory distress under his care lost twice as much weight during the first 3 days as did the normal premature infants. It was particularly notable that weight loss continued into the second 72 hour period

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Table VI. Urinary excretion of sodium, potassium, and chloride during the first and second 72 hour periods

1,000-1,500 grams 1,501-2,000 grams 2,001-2,500 grams Normal Respiratory distress Respiratory distress with normal Apgar Breech Breech with normal Apgar Toxemia Uncomplicated toxemia Apgar 1-3

SodiUmhr 1st 72 2nd72 hr. . 1.99 2.40 1.30 1.49 1.34 1.60 1.52 1.87 1.66 1.69 2.11 2.02 1.10 .99 1.59 1.32 1.85

Total 4.39 2.79 2.94 3.39 3.35 4.13

Potassium 1st 72 2nd 72 hr. hr. 3.2I 2.64 1.61 2.13 1.49 1.27 1.87 1.74 2.94 2.66 3.46 3.27

Total 5.85 3.74 2.76 3.61 5.60 6.73

2.60 2.74 2.97 2.40 3.28

1.59 1.96 1.68 1.01 2.07

3.16 4.63 3.39 2.82 3.19

1.50 1.65 1.38 1.08 1.43

after all symptoms of respiratory distress had disappeared and calorie-containing fluids had been instituted. This over-all weight loss in the respiratory distress group was significant at the 5 per cent level when compared with all other major stress groups. It cannot be explained by increased renal water loss, since both the respiratory distress and lowest weight group actually excreted less urine than the control groups during the second 72 hours, coincident with a tendency to increased urine osmolality. As has been described, the urinary excretion of potassium was greater in the respiratory distress group and lowest weight group than in the control group throughout most of the study. This trend was seen in the work of CorP 9 whose 5 dyspneic infants excreted an average amount of potassium of 1.0 mEq. per kilogram per 36 hours, as well as in Nicolopoulos and Smith's 8 infants with respiratory distress whose average potassium excretion was 1.0 and 1.2 mEq. per kilogram during the first and second days. is Wilkerson ~~ reported on only one infant with respiratory distress; however, the amount of spiratory distress; however, the amount of potassium excreted was in the range of that in the normal control. Increased potassium excretion is usually indicative of increased protein catabolism and nitrogen excretion. From the work of

1.57 2.69 1.71 1.61 1.12

Chloride 1st 72 2nd 72 hr. hr. Total 1.10 2.03 3.13 1.16 1.44 2.60 0.86 1.58 2.44 , 1.15 1.71 2.86 1.15 1.45 2.60 1.21 1.51 2.72 1.24 1.24 1.05 .89 1.35

1.60 1.83 1.55 1.38 1.78

2.84 3.07 2.60 2.27 3.13

others, it appears that a normal premature infant, deprived of fluid and calories, will excrete between 60 and 105 mg. of nitrogen per kilogram per day? s, 24, 51 However, in infants with respiratory distress during the first 48 hours of life, Nicolopoulos and Smith is calculated that the amount of .nitrogen excreted may exceed these values by 50 to 75 per cent. In the present series, urinary potassium values continued to be high for the first 5 days of life without evidence of sodium retention or weight gain, suggesting that there was increased protein catabolism which persisted for several days past the period of respiratory distress. Since most of the infants with respiratory distress were in the lowest weight group, the influence of immaturity cannot be ascertained. These findings indicate that early provision of fluid and calories would be important as supportive measures in the management of respiratory distress in premature infants. A P G A R 1-3

Results. Of the 14 infants whose initial Apgar rating was 1-3, 6 weighed under t,500 grams. I n this Iow-welght group 5 had respiratory distress (Cases 1, 4, 6, 11, and 12), 2 came from toxemic mothers (Cases 4 and 12), and 2 were delivered by breech presentation (Cases 1 and 4). All infants from the lowest weight group subsequently died and

380

Beard et aI.

all but one (Case 4) had intracranial hemorrhage as part or all of the pathologic conditions described. Of the 8 infants weighing over 1,50,0 grams, none died; respiratory distress was present and mild in only one (Case 16). Three infants were born of toxemic mothers (Cases 16, 22, and 44) and 3 were delivered by breech presentation (Cases 20, 22 and 4O). T h e analgesic and anesthetic agents given to the mothers in both the control and the Apgar 1-3 groups are shown in Table V I I .

Weight loss or gain, urine volume, and osmolality (Figs. 1-3). Weight loss and gain approximated the values found in the control group. Urine volumes were slightly larger than those of the control group during both 72 hour periods. Urine osmolality paralleled the values for the controls without complications.

Urinary sodium, potassium, chloride, N a / K ratios (Figs. 4-7). T h e urinary sodium, potassium, and chloride excretion and N a / K ratios approximate the values found in the controls and the two largest weight group.s.

Plasma sodium, postassium, and chloride values (Figs. 8-10). Plasma sodium values over 155 mEq. per liter were seen at both 24 and 48 hours in the Apgar 1-3 group. The subgroups showed this same trend toward hypernatremia at 24 and 48 hours whether associated with respiratory distress, breech delivery, or toxemia in the mother. Plasma potassium and chloride values reflected the values found in the control infants, except for the 3 infants with respiratory distress with an initial Apgar rating of 1-3 who had high chloride values at 24 and 48 hours.

Blood p H and CO~ content (Figs. 11 and 12). Blood p H values were generally lower throughout the study than in any other group. Initial values were 7.11 and did not reach 7.3 or above until 144 hours. Comment. The outstanding differences that separate this group from the control group, aside from increased mortality rates, are: hypernatremia at 24 and 48 hours and low blood p H values throughout the first 5 days of life.

September 1963

Table V I I . Analgesic and anesthetic agents given to mothers in the control and Apgar 1-3 groups

Agent

Apgar 1-3 (14)

Controls (15)

Amytal intravenously Demerol alone Demerol and Phenergan Epidural block Saddle block Pudendal block

3 3 3 2 6 1

0 2 2 0 11 1

..

The magnitude of the increase in H § ion concentration compatible with survival has been documented by James, 2~ Karlberg, 22 Blystad, 19 and Miller. 23 T h a t such increase m a y be influenced by the inefficient utilization of glycogen in anaerobic metabolism is reflected chemically through documented accumulations of organic acids in the urine and serum 4, 6, 2o With improved oxygenation there is a rapid reversal of respiratory and metabolic acidosis leading usually within hours to an elevation of blood pH, COs content or buffer base, and 02 saturation. G' ~9, ~0 However, although the p H at 94 hours had increased to 7.28 in this series, acidosis persisted, as was evidenced by a drop at 48 hours to 7.20 and a persistence of this level until after fluid and caloric administration. This increase in acidosis during the second day of life and its persistence for several days is thus probably not related to continued anoxia as these infants were active and had no tachypnea or respiratory distress that persisted past the first 24 hours. The possibility that the increased hydrogen ion concentration reflected an increase in ketone bodies in the serum was considered, as it is well recognized that the glycogen stores in the newborn of some animal species are limited and rapidly depleted by anoxia or cold. s~-~4 Talbot and associates, ~ making similar deductions from values of the respiratory quotient in fasted newborn premature infants, found that by the third day of life about 8 per cent of the total energy expended was from carbohydrate, 92 per cent from fat. If the anoxic premature infant utilizes his available glycogen stores more rapidly than

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the control infant it would seem that blood glucose levels might be expected to drop more quickly and ketone bodies appear in the urine more profusely than in the control infant. However, true blood sugar values at 48 and at 72 hours of fluid and calorie deprivation have been found to be virtually identical in initially anoxic and in control premature infants. 56 Further Studies documenting the actual level of ketone bodies in the blood and defining the limits of available glycogen reserves and the interrelationships involved in their utilization are in progress. Hypernatremia (over 155 mEq. per liter) occurred during the first and second days of life in all groups undergoing stress with an initial Apgar rating of 1-3, and despite continued fluid and calorie deprivation tended toward "normal" at 72 hours. Weight loss and plasma osmolality determinations were not different from values observed in controls; thus greater dehydration cannot be implicated. Impairment of renal function occurs during acidosis; Nahas 57 correlated a reduced urine output with a fall in blood pH below 7.2 and Bohr ~8 reported that, with a drop in blood pH, a drop in para- aminohippuric acid excretion ratios occurs. Also, McCance 59 reported a reduced glomerular filtration rate and poor urea clearance in asphyxiated newborn infants. No specific tests of renal function were performed; however, initially asphyxiated infants exhibited urinary excretion patterns (volume, osmolality, electrolytes) entirely similar to those of the control infants, suggesting that renal mechanisms are not responsible for the observed hypernatremia. TOXEMIA

Results. Four infants had no other apparent stress than to have been born prematurely to a toxemic mother. Hence, these prematures serve to define the single effect of maternal toxemia (Cases 18, 26, 28, and 41), and constitute the group labeled "toxemia with Apgar 7-10." The remaining 6 infants (Cases 2, 4, 12, 16, 22, and 24), whose mothers had toxemia had in addition a variety of special problems, i.e., respiratory

Perinatal stress in the premature infant

38 1

distress, Apgar 1-3, infection, and breech delivery.

Weight loss or gain, urine volumes, urine osmolality (Figs. 1-3). Under the conditions of fluid and calorie administration outlined in the protocol, the over-all weight loss in the controls and the two largest weight groups during the whole study period was between 90 and 100 grams per kilogram. Conversely, the smallest weight group, the respiratory distress group and the group with toxemia plus other complications lost about 150 grams during the same period. The toxemia group without other complications and the breech infants had the smallest overall weight loss, 68 and 72 grams, respectively. Urine volume in the toxemia group without complications approximated that of the control group during the whole study period, although at 48 hours it was lower and urine osmolality was higher by 100 mOsm. than in any other group. Urine sodium, potassium, and chloride values, N a / K ratio (Figs. 4-7). Low sodium and chloride excretion for both the first and second 72 hour periods is seen in Table VI. However, this difference is not statistically significant. Potassium excretion approaches that seen in the largest weight group but is less than in the control group. Although the N a / K ratio is highest in all other groups at 24 hours, it is highest at 48 hours in the toxemia group without other complications. Plasma sodium, potassium a n d chloride values (Figs. 8-10). Plasma sodium, potassium, and chloride values for the toxemia group without complications mirrored the values found in the controls except for elevations of sodium at 48 and 72 hours. Hypernatremia with plasma sodium values comparable to those of the Apgar 1-3 group were seen in the toxemia group without complications (5 of 6 were also Apgar 1-3 infants). Plasma pH and COe content (Figs. 11 and 12). Despite rather complete data on all other determinations, the pFI values for the uncomplicated toxemia group are incomplete, but where evaluated are within the range of those of the control infants. The low pH values for the group as a whole reflect the

382

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large number of Apgar 1-3 babies in the toxemia group. Plasma CO2 content values generally fall within the range of those of the controls. Comment. Very little information is available concerning the infant of the toxemic mother other than reference to an association with premature delivery, 6~ subsequent hypoglycemia, 12 and increased mortality. 61 Clapp 62 and his group have shown that total body water and extracellular and intracellular water in 8 infants of toxemic mothers approximated that found in normal control prematures during the first 24 hours of life. However, in toxemic mothers, an expanded extracellular compartment 63 and a significantly larger mean sodium space TM 60 were found, when compared to values in either the normally pregnant woman or the hypertensive patient. What produces this affinity for increased total exchangeable sodium in the pre-eclamptic or toxemic woman is unknown. Steroid studies have been generally unrewarding in defining an abnormal hormone production; however, Frantz 66 and his group have shown that women with toxemia or eclampsia excrete significantly elevated amounts of 6 betahydroxycortisol over that in the normally pregnant woman in the third trimester of pregnancy. Aldosterone excretion in late pregnancy does not appear to be greater in toxemic than in nontoxemic women. 67 As has been described, infants born of toxemic mothers but otherwise without complications excreted less urine during the first 3 days of life, and had the smallest over-all weight loss of any of the groups studied. Excretion of sodium was less than in any other group, although the differences did not prove to be statistically significant. Thus it may be speculated that such infants, like their toxemic mothers, have operating within their bodies a factor which tends to retain sodium and water. BREECH PRESENTATION

Results. Seven of the 10 babies born by breech presentation were twins, 5 being the second delivered. The 5 with the lowest birth

weight died; 4 of these had respiratory distress. Only 2 infants delivered by breech presentation had no other stress factors (Cases 25 and 34), thus making a group too small for the evaluation of the single influence of breech delivery in premature infants. Where breech deliveries were associated with an initial Apgar 1-3 rating, the tendency to hypernatremia was definite; conversely, a tendency to hyponatremia was noted in the 5 infants with initial Apgar 7-10 ratings. Electrolyte excretions for the group as a whole mirrored the values in the two largest weight groups and the control group. However, in the subgroup of breech with normal Apgar the one infant (Case 3) who had respiratory distress also had high potassium excretions. The whole-blood pH values after 24 hours were 7.3 or above thoughout the study. Comment. Available metabolic data on infants delivered by breech presentation are scarce. Smith and others 6s include 2 infants delivered by breech presentation, one of whom was apparently without other complications and who excreted electrolyte and nitrogen in the middle range of the 10 infants reported. Nicolopoulos and Smith is had only one infant delivered by breech extraction who weighed 936 grams and died at 48 hours. DEATHS

Pertinent data concerning the infants who died either during the study or within the first 2 weeks are depicted in Table III. Postmortem examinations were performed on all; evidence of gross central nervous system hemorrhage was present in 70 per cent and was more often associated with an Apgar 1-3 rating and respiratory distress than with toxemia or breech delivery. Only 2 infants in this group had complete studies. One (Case 3 ) h a d respiratory distress initially and developed pneumonia at 10 days. The other infant (Case 2), who developed pyelonephritis and Escherich{a col{ sepsis during the second week of life, had had exceptionally large urinary losses of sodium and chloride during the period of study, with

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potassium excretion in the range of t h a t of other infants of the lowest weight group. SUMMARY

M e t a b o l i c d a t a on 46 p r e m a t u r e infants who received no fluid or calories d u r i n g the first 72 hours of life have been presented. T h e p e r i o d of study included the first 6 days of life. I n f a n t s w i t h o u t complications except t h a t of p r e m a t u r e delivery c o n s t i t u t e d the control group. Basic similarities in p a t t e r n s of change in all groups were r e m a r k a b l e . I n the areas m e a s u r e d , d e p r i v a t i o n of fluid a n d calories d i d not compromise the " c o n t r o l " infant, a l t h o u g h h y p o g l y c e m i a a n d acetonuria were f r e q u e n t l y observed. H o w e v e r , similar d e p r i v a t i o n in the infant w i t h A p g a r 1-3 was associated with p r o l o n g e d acidosis and early h y p e r n a t r e m i a ; in the i n f a n t of low birth weight with respiratory distress, increased weight loss a n d increased protein catabolism (as evidenced by p r o l o n g e d increased K excretion) persisted t h r o u g h o u t the 6 d a y period. T h e gravity of A p g a r 1-3 ratings a n d / o r respiratory distress in association with p r e m a t u r i t y is emphasized.

We wish to express our appreciation for the valuable work done on this project by Betty Hardister, medical technologist; Evelyn Cross, research technician; Anita Russell, research nurse; and Dr. Barbara Stinnett, student research fellow.

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Bauman, M. L., Makepeace, U. T., and Murayama, M.: Studies of acid base equilibrium in premature infants, Pediatrics 6: 753, 1950. 8. Bruck, E., and Weintraub, D. H.; Serum calcium and phosphorus in premature and full term infants, Am. J. Dis. Child. 90: 653, 1955. 9. Gittleman, I. F., Pincus, J. B., Schmerzler, E., and Saito, M.: Hypocalcemia occurring on the first day of life in mature and premature infants, Pediatrics 18: 721, 1956. 10. Craig, W. S.: Clinical signs of neonatal tetany: with especial reference to their occurrence in newborn babies of diabetic mothers, Pediatrics 22: 297, 1958. 11. ZetterstrSm, R., and Arnhold, R. G.: Impaired calcium phosphate homeostasis in newborn infants of diabetic mothers, Acta paediat. 47: 107, 1958. 12. Cornblath, M., Odell, G. B., and Levin, E. Y.: Symptomatic neonatal hypoglycemia associated with toxemia of pregnancy, J. PEDIAT. 55: 545, 1959. 13. Cornblath, M.: Hypoglycemia in newborn infants, Illinois M. J. 118: 332, 1960. 14. Norval, M. A.: Blood sugar values in premature infants, J. PEDIAT. 36: 177, 1950. 15. Usher, R. H.: Management of the metabolic changes in the respiratory distress syndrome of prematurity, A. M. A. J. Dis. Child. 100: 485, 1960. 16. Mann, T. P.: Neonatal injury, Brit. M. J. 2: 228, 1958. 17. Usher, R.: The respiratory.distress syndrome o f prematurity. I. Changes in potassium in the serum and the electrocardiogram and effects of therapy, Pediatrics 24: 562, 1959. 18. Nicolopoulos, D. A., and Smith, C. A.: Metabolic aspects of idiopathic respiratory distress (hyaline membrane syndrome) in newborn infants, Pediatrics 28: 206, 1961. 19. Blystad, W.: Blood gas determinations on premature infants. II. Investigations of premature infants with early neonatal dyspnea (the hyaline membrane syndrome), Acta paediat. 45: 103, 1956. 20. James, L. S.: Physiology of respiration in newborn infants and in the respiratory distress syndrome, Pediatrics 24: 1069, 1959. 21. James, L. S.: Acidosis of the newborn and its relation to birth asphyxia, Acta paediat. (suppl.) 122: 17, 1960. 22. Karlberg, P., Cook, C. D., O'Brien, D., Cherry, R. B., and Smith, C. A.: Studies of respiratory physiology in newborn infant; observations during and after respiratory distress, Acta paediat. 43 (suppl. 100): 397, 1954. 23. Miller, I-I. C., Behrle, F. C., Smull, N. W., ~nd Blim, R. D.: Studies of respiratory insufficiency in newborn infants. II. Correlation of hydrogen ion concentration, carbon dioxide tension, carbon dioxide content and oxygen saturation of blood with trend of respiratory rates, Pediatrics 19: 387, 1957. 24. Hansen, J. D. L., and Sm!th, C. A.: Effects

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60. Dunham, E.: Premature infants, ed. 2, New York, 1955, Hoeber-Harper, Inc., p. 22. 61. Dunham, E.: Premature infants, ed. 2, New York, 1955, Hoeber-Harper, Inc., p. 22. 62. Clapp, W. M., Butterfield, L. J., and O'Brien, D.: Body water compartments in the premature infant, with special reference to the effects of the respiratory distress syndrome and of maternal diabetes and toxemia, Pediatrics 29: 883, 1962. 63. Barter, F. C., Liddle, G. W., Duncan, L. E., Barber, J. K., and Delia, C.: The regulation of aldosterone secretion in man: The role of fluid volume, J. Clin. Invest. 35: 1306, 1956. 64. Plentl, A. A., and Gray, M. J.: Total body water, sodium space, a n d total exchangeable sodium in normal and toxemic pregnant women, Am. J. Obst. & Gynec. 78: 472, 1959.

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65. MacGillivray, I., Hytton, F. E., Taggart, N., and Buchanan, T. J.: The effect of a sodium diuretic on total exchangeable sodium and total body water in pre-eclamptic toxaemia, J. Obst. & Gynaec. Brit. Comm. 69: 458, 1962. 66. Frantz, A. G., Katz, F. H., and Jailer, J. W.: A quantitatively abnormal mode of hydrocortisone metabolism in pregnant and toxemic patients, Bull. Sloane Itosp. Women 7: 6, 1961. 67. Venning, E. H.: Endocrine aspects of toxemia, Clin. Obst. & Gynec. 1: 359, 1958. 68. Smith, C. A., Yudkin, S., Young, W., Minkowski, A., and Cushman, M.: Adjustment of electrolytes and water following premature birth, Pediatrics 3: 34, 1949.