Blood Transfusion Effect on the Respiratory Pattern of Preterm Infants

(1)

Blood

Transfusion

Effect

on the Respiratory

Pattern

of Preterm

Infants

Ashok

Joshi,

MD, Tilo Gerhardt,

MD, Patty

Shandloff,

RN, and

Eduardo

Bancalari,

MD

From the Department of Pediatrics, Division of Neonatology, University of Miami School of Medicine, Miami

ABSTRACT. Anemia may increase the risk of tissue hy-poxia in preterm infants. This could lead to respiratory center depression and an increased risk for apnea. Heart

rate and breathing pattern were recorded in 30 preterm infants (gestational age 30.0 ± 2.3 weeks, postnatal age 46.6 ± 20.8 days, and weight 1,438 ± 266 g) before and

after a transfusion of 10 mL/kg of packed RBCs. All infants were stable clinically, breathing room air, and free of prolonged apneic episodes. After transfusion, he-matocrit levels increased from 27.0% ± 2.5% to 35.8% ±

4.7%. Heart rate decreased from 157.2 ± 13.6 beats per

minute to 148.4 ± 13.9 beats per minute. There was no

change in respiratory rate or BP. The duration of periodic breathing decreased significantly, as did the duration of

the longest periodic breathing episode (P < .01). The number of respiratory pauses lasting 5 to 10 seconds and the number of pauses lasting 11 to 20 seconds also

de-creased significantly (P < .05). The total duration of respiratory pauses, excluding pauses during periodic breathing, were significantly lower after transfusion (P < .05), as was the number of episodes of bradycardia. These results indicate that preterm infants have a more irregular breathing pattern while anemic than after

cor-rection of the anemia. The irregular breathing pattern is

probably caused by mild hypoxic respiratory center

depression. Pediatrics 1987;80:79-84; anemia, apnea, breathing pattern, hematocrit, preterm infant.

Physiologic anemia develops earlier and is

fre-quently more pronounced in the preterm infant

than in the infant born at term.’3 This reduction

in hemoglobin concentration is caused by several

mechanisms48 and occurs when the breathing

pat-tern of the infants is still characterized by frequent

Received for publication Jan 27, 1986; accepted Oct 7, 1986.

Reprint requests to (E.B.) Department of Pediatrics (R-131),

University ofMiami School ofMedicine, P0 Box 016960, Miami, FL 33101.

American Academy of Pediatrics.

periodic breathing and apneic episodes. Most

in-fants tolerate the reduction in hemoglobin

concen-tration well, but in some cases, tachycardia,

tach-ypnea, and lethargy associated with the decrease in

oxygen-carrying capacity can be observed.4 When

available oxygen is insufficient to meet the

meta-bolic demands, CNS hypoxia may occur, leading to

respiratory center depression and an increase in

periodic breathing and apnea.9” The possibility

that anemia may predispose to apnea is supported

by the clinical experience of healthy, growing pre-term infants who have tachycardia, tire during

feed-ing, show lethargy, and, finally, have prolonged

apneic episodes associated with a progressive

de-crease in hematocrit level. The development of

prolonged apnea is associated with an increase in

episodes of periodic breathing and an increasing number of short apneic episodes.’#{176}’3 It is difficult

to document the development of prolonged apnea

and its correlation with a gradually decreasing

he-matocrit level because of the large day to day

van-ability in breathing pattern’4 and the maturational

changes of the CNS and respiratory center, which

tend to counteract this development. Also, the

many stimuli and support measures that are

initi-ated as apnea develops will alter the breathing

pattern.

This study takes advantage of the rapid change

in hematocnit level occurring in preterm infants

who receive transfusions to correct low hematocnit

levels, to study breathing patterns free of long-term

maturational and environmental changes. It is

hy-pothesized that an increase in hematocnit level in

anemic preterm infants will lead to a stabilization

in breathing pattern, ie, a reduction in incidence of

periodic breathing and a decrease in the number of

apneic episodes. This stabilization would indicate

(2)

INFANTS AND METHODS

Infants were selected for this study from the

preterm patients of the convalescent nursery at

Jackson Memorial Hospital. An infant was entered

into the study after the attending physician had

ordered a transfusion for him or her. The decision

to transfuse was based on the routine neonatal care

guidelines and was not influenced by the study. The

patient received 10 mL/kg of packed RBCs for two

to three hours when the hematocrit level had

de-creased to 25% to 28%. Infants with higher

hema-tocrit levels were given transfusions if they showed

lethargy, poor feeding, tachycardia, or an increasing

number of apneic episodes.

The anticoagulant used by the blood bank was

citrate, phosphate, dextrose. The RBCs transfused, which had an age of five days or less, were washed three times in saline and packed. If an antibody screening test or antiglobulin test was negative,

type 0, Rh-negative uncrossmatched cells were

used. A crossmatch was done only when antibodies were present.

Heart rate and breathing pattern before and after

transfusion were recorded for 38 infants who were

entered into the study. Eight infants were excluded

from the analysis because they were receiving

ami-nophylline (n = 6), supplemental oxygen (n = 1),

or continuous positive airway pressure (n = 1). This

resulted in a clinically homogenous study group of 30 preterm infants who were breathing room air, were free of acute cardiorespiratory disease, were receiving oral feedings, and were growing normally.

Clinical problems that the infants had during their hospital course included hyaline membrane

disease (n = 16), apnea of prematurity (n = 14),

respiratory depression at birth (n = 9), patent duc-tus arteriosus (n = 7), sepsis (n = 6), subependymal/

intraventricular hemorrhage (n = 4), ventricular

dilation (n = 3), necrotizing enterocolitis (n = 2),

and chronic lung disease (n = 1). All these

condi-tions had resolved at the time of the study. The physical characteristics of the infants are given in

Table 1.

TABLE 1. Characteristics of 30 Preterm Infants Who

Received Transfusions

Clinical Characteristics Mean ± SD Range

Gestational age (wk) 30.0 ± 2.3 26-35

Postnatal age when 46.6 ± 20.8 18-105 studied (d)

Birth wt (g) 1,040 ± 235 700-1,560

Wt when studied (g) 1,438 ± 266 900-2,000

Apgar score

1 mm 4.2 ± 2.6 1-9

5 mm 7.2 ± 1.4 1-9

Sex (male/female) 12/18

Before and after transfusion, the hematocrit level

was determined from blood samples obtained by heel stick. Arterial BP was measured using an

au-tomated oscillometer (Dinamap Neonatal Vital

Signs Monitor, Critikon Inc, Tampa, FL). Heart rate and breathing pattern were recorded

immedi-ately before and after transfusion with a

Corome-tnics Infant Monitor (Corometrics Medical Systems

Inc, Wallingford, CT).

Only periods of quiet breathing were analyzed.

Excluded from the analysis were periods of activity

evident from the tracing by an elevated fluctuating

heart rate and by frequent changes in the baseline

of the breathing pattern, with the ventilatory

ex-cursions exceeding the range of the tracing. The

recordings were analyzed for the following events:

duration of periodic breathing, longest episodes of

periodic breathing, number of apneic episodes of 5

to 10 seconds in duration, number of apneic

epi-sodes of 1 1 to 20 seconds in duration, number of apneic episodes of >20 seconds in duration, total duration of apneic pauses, total number of brady-cardic episodes, and number of bradycardic epi-sodes without apnea.

Periodic breathing was defined as three or more

episodes of apnea lasting >3 seconds, interrupted

by breathing episodes of <20 seconds. The number

of apneic episodes and duration of apneic episodes

did not include apnea observed during periodic

breathing.

Bradycardia was defined as a decrease in heart

rate 25% below baseline that persisted longer than

5 seconds. Baseline heart rate was heart rate

ob-served during quiet regular breathing. All

respira-tory pattern measurements, except for the longest

episode of periodic breathing, were related to 100

minutes of recording time.

The average value for heart rate was calculated

by taking measurements every four minutes throughout the total length of the recording and averaging them. The average respiratory rate was

obtained from determinations made every one to

two hours during the 12 hours before and after transfusion.

The interpretation of the recordings was done by

two investigators. They were not blinded to which

recording was done before and which after

trans-fusion.

The Committee for the Protection of Human

Subjects at the University of Miami did not

con-sider informed consent necessary for the study.

Both the transfusion of RBCs given for specific

indications and the monitoring of heart rate and respirations were part of the routine care of preterm infants.

(3)

rate, and hematocrit measurement was done by calculating mean ± SD and by using the paired t

test to determine significance of differences

ob-served in the measurements before and after

trans-fusion. Because the respiratory measurements did not have a normal distribution, nonparametric analysis was used.’5

RESULTS

The average duration of recording was 5.7 ± 1.7

hours before and 5.3 ± 1.8 hours after blood

trans-fusion. The duration of recording ranged from 3.1 to 8.8 hours before and 2.7 to 8.2 hours after

trans-fusion. Hematocrit levels ranged from 24% to 31% before and from 31% to 46% after transfusion. The mean increase of 8.8% in hematocrit level after transfusion was significant, but there was no

sig-nificant change in arterial BP (Table 2).

Heart rate decreased significantly by a mean of

8.8 beats per minute and respiratory rate remained unchanged (Table 2). The measurements of breath-ing and heart rate pattern changed significantly after transfusion (Table 3). The most striking changes are shown in Figs 1, 2, and 3. Duration of periodic breathing decreased in 22 of the 30 infants and increased in only one. No periodic breathing was present both before and after transfusion in

seven infants (Fig 1). The decrease in median value

of periodic breathing was significant

(P

< .01). The

longest episode of periodic breathing also decreased significantly after transfusion (Table 3).

The number of short apneic pauses lasting from

5 to 10 seconds decreased in 23 of 30 infants and

increased in seven (Fig 2). The median value of

short apneic pauses decreased significantly after transfusion (P < .05). The number of apneic pauses lasting 11 to 20 seconds, as well as the total duration

of respiratory pauses, also decreased after

transfu-sion. There were no respiratory pauses of more than 20 seconds’ duration before or after transfusion (Table 3).

The total number of bradycardic episodes

de-creased in 15 of the 30 infants and increased in four

after transfusion (Fig 3). There was no bradycardia

either before or after transfusion in 11 infants. The

decrease in median value of bradycardic episodes

was significant

(P

< .05). There was also a

signifi-cant decrease in bradycardic episodes not

associ-ated with apnea (Table 3).

None of the characteristics we measured (birth weight, gestational age, postnatal age, postnatal weight gain, hematocrit level, BP, or heart rate)

before and after transfusion could be identified as

more common among infants whose breathing

pat-tern did not improve after transfusion, compared

with those whose breathing pattern improved. There was no correlation between the severity of

anemia and the incidence of periodic breathing or

the number of apneic episodes. Also, the degree of

improvement after transfusion was not correlated

with initial hematocrit level. This finding is not

surprising because of the narrow range of

hemato-crit levels studied and the large interpatient

varia-tion in breathing pattern.

TABLE 2. Vital Signs and Hematocrit Levels Before and After Transfusion5

Before After P

Transfusion Transfusion Value

BP (mm Hg)

Systolic 73.6 ± 15.7 70.5 ± 12.6 NS

Diastolic 39.9 ± 10.8 40.1 ± 10.3 NS

Mean 52.2 ± 11.2 51.0 ± 10.5 NS

Heart rate (beats/mm) 157.2 ± 13.6 148.4 ± 13.9 .001

Respiratory rate (breaths/mm) 48.6 ± 12.2 49.8 ± 8.4 NS

Hematocrit (%) 27.0 ± 2.5 35.8 ± 4.7 .001

SResults are means ± SD.

TABLE 3. Respiratory Pattern Before and After Transfusion5

Respiratory Pattern Before After P

Transfusion Transfusion Value

Duration of periodic breathing (min/100 mm) 6.0 (0-35.1) 1.1 (0-24.3) .01

Longest episode of periodic breathing (mm) 3.1 (0-27.5) 1.4 (0-17.0) .01

No. of respiratory pauses 5-10 s/100 mm 9.0 (1.7-26.0) 5.0 (0-20.7) .05

No. of respiratory pauses 11-20 s/100 mm 0 (0-1.1) 0 (0-0.4) .05

No. of respiratory pauses >20 s/100 mm 0 0

Duration of respiratory pauses (min/100 mm) 0.9 (0.2-3.2) 0.4 (0-2.1) .05 No. of bradycardic episodes/100 mm 0.4 (0-4.8) 0.0 (0-3.2) .05 No. of bradycardic episodes without apnea/100 mm 0.3 (0-3.6) 0.0 (0-3.2) .01

(4)

min/100 mm

40_

3O_ z I I-4 Ui

U

0

Ui a. U. 0 z 0

4

10.

0-BEFORE AFTER

TRANSFUSION

Fig 1. Changes in duration of periodic breathing before and after transfusion of individual patients. Heavy line indicates median change (P < .01).

DISCUSSION

Anemia in the preterm infant may predispose to

tissue hypoxia because of reduced O2-carrying

ca-pacity of the blood. Tissue oxygenation may be further compromised because of the left shift of the 02 dissociation curve due to the presence of fetal hemoglobin. This makes the unloading of oxygen more difficult at the tissue level.4’6”7 The preterm

infant’s ability to compensate for hypoxia with an

increased cardiac output is limited,’8 and these in-fants frequently have impaired pulmonary function because of immature lungs or chronic lung disease.

In the present study, transfusion led to a signif-icant decrease in heart rate, suggesting that the increased heart rate before transfusion was a

re-sponse to the anemia, producing a compensatory increase in cardiac output.4

Hypoxia is an important cause of respiratory

depression in the newborn infant and is associated

with an increased incidence of periodic breathing

and apneic episodes.9”#{176}” Relieving hypoxia may stabilize the respiratory pattern and lead to a

re-duction in periodic breathing and apnea.’9 Anemia

severe enough to produce tissue hypoxia has been

associated with reduced central respiratory drive in animals2#{176} and with apnea in preterm infants.2”22

The infants studied here were a homogeneous

group of preterm growing infants, and all were in stable clinical condition without signs of distress or

evidence of prolonged apnea. However, they showed

an increased incidence of periodic breathing, short

apneic episodes, and bradycardia that improved

after transfusion. The findings suggest that before

transfusion these infants had some respiratory cen-ter depression, which was probably caused by mild CNS hypoxia.

More severe anemia than in the infants of this

No

/1

00 mm

30

C-) ‘U Cl) 0

I-I’)

C/) ‘U

0

-0 Cl) 0. ‘U

C-)

‘U

z

4

10-0

BEFORE

AFTER

TRANSFUSION

Fig 2. Changes in number of short apneic episodes

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crystalloid infusion is not clear. However, in the present study, there was no evidence of hypotension

before the transfusion and no BP increase

after-ward, suggesting that the infants were not

hypo-volemic.

Prolonged apneic episodes that may be triggered

by anemia can usually be detected by cardiorespi-ratory monitoring and terminated before severe tissue hypoxia occurs. The well-documented risks

of transfusion (transmission of viral diseases,

in-compatibility, and immunologic consequences)

need to be kept in mind and weighed against the

possible benefits of keeping a higher hematocrit

level in healthy preterm infants. Further work

needs to be done before a change in the indications

for blood transfusion in small preterm infants can

be recommended. No/100 mm 5 Cl) UI 0 0 Cl) a. UI C.) 0 4 C.) 0 4 U. 0 UI z 0 BEFORE AFTER TRANSFUSION

Fig 3. Changes in number of bradycardic episodes be-fore and after transfusion of individual patients. Heavy line indicates median change (P < .01).

study, an increased metabolic rate, reduced ability to increase cardiac output, or a mild hemoglobin desaturation may lead to more severe respiratory

center depression and prolonged apnea. This was

not seen in the infants studied here because we tried to keep their hematocrit levels above 25% and because infants with active medical problems were

excluded from the study.

It is possible that the painful stimulus of

insert-ing an IV catheter had some effect on respiratory

drive. It is, however, unlikely that this effect lasted

for more than two to three hours, by which time transfusion was completed and the pneumogram recording was started. The fact that heart rates decreased after transfusion also argues against the

possibility that breathing pattern improved because

of physical stimulation. Whether or not the same changes in breathing pattern might be obtained by

simple blood volume expansion using colloid or

ACKNOWLEDGMENT

This work was supported, in part, by the State of Florida, Department of Health and Rehabilitative

Serv-ices, Children’s Medical Services, and The University of Miami: Project Newborn.

REFERENCES

1. O’Brian RT, Pearson HA: Physiologic anemia of the new-born. J Pediatr 1971;79:132-138

2. Schulman J: Anemia of prematurity. J Pediatr 1959;54:663-672

3. Stockman JA III: Anemia of prematurity. Clin Perinatol

1977;4:239-257

4. Wardrop CAJ, Holland BM, Veale KEA, et al:

Nonphysio-logic anemia of prematurity. Arch Dis Child 1978;53:855-860

5. Bratteby LE, Garby L, Groth T: Studies on erytho-kinetics in infancy: XIII. The mean life span and the life span frequency function of red blood cells formed during foetal

life. Acta Paediatr Scand 1968;57:311-320

6. Bratteby LE: Studies on erythrokinetics in infancy: XI. The change in circulating red cell volume during the first five months of life. Acta Paediatr Scand 1968;57:215-224

7. Brown MS, Garcia JF, Phibbs RH, et a!: Decreased response of plasma immunoreactive erythropoietin to “available ox-ygen” in anemia of prematurity. J Pediatr 1984;105:793-798

8. Stockman JA III, Graeber JE, Clark DA, et a!: Anemia of

prematurity: Determinants of the erythopoietin response. J Pediatr 1984;105:786-792

9. Cross KW, Opp#{233}TE: The effect of inhalation of high and low concentrations of oxygen in the respiration of the pre-mature infant. J Physiol 1952;117:38-55

10. Rigatto H, Brady JP: Periodic breathing and apnea in

pre-term infants: II. Hypoxia as primary event. Pediatrics

1972;50:219-228

11. Rigatto H, Brady JP, de la Tone Verduzco R:

Chemorecep-tor reflexes in preterm infants: I. The effect of gestational

and postnatal age on the ventilatory response to inhalation

of 100% and 15% oxygen. Pediatrics 1975;55:604-613 12. Daily WJR, Klaus M, Meyer HBP: Apnea in premature

infants: Monitoring, incidence, heart rate changes, and an

effect of environmental temperature. Pediatrics 1969;43: 510-581

13. Steinschneider A: Prolonged sleep apnea and respiratory

instability: A discriminative study. Pediatrics

1977;59:962-970

14. Hunt CE, Brouillette RT, Lin K, et a!: Day to day

pneu-mogram variability. Pediatr Res 1985;19:174-177

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Sta-tistics. Danville, IL, Interstate Printers and Publishers Inc,

1959

16. Woodson RD: Physiologic significance of oxygen

dissocia-tion curve shifts. Crit Care Med 1979;7:368-373

17. Oski FA: Clinical implications of the oxyhemoglobin disso-ciation curve in the neonatal period. Crit Care Med 1979; 7:412-418

18. Romero TE, Friedman WF: Limited left ventricular

re-sponse to volume overload in the neonatal period: A corn-parative study with the adult animal. Pediatr Res 1979;

13:910-915

19. Rigatto H, Brady JP: Periodic breathing and apnea in

pre-term infants: I. Evidence for hypoventilation possibly due to central respiratory depression. Pediatrics 1972;50:202-218

20. Fagenholz SA, Lee JC, Downing SE: Association of anemia

with reduced central respiratory drive in the piglet. Yak J

Biol Med 1979;52:263-270

21. Wertharnrner J, Kelly DH, Shannon DC: Efficacy of blood

transfusion in reducing apnea in anemic premature infants, abstracted. Pediatr Res 1983;17:341A

22. DeMaio JG, Harris MC, Spitzer AR: The response of apnea of prematurity to transfusion therapy, abstracted. Pediatr Res 1986;20:389A

WHAT AMERICAN

CHILDREN

READ IN 1834 ABOUT

PAST INGRATITUDES

TOWARD

THEIR

PARENTS

The Reverend John S. C. Abbott of Worcester, Massachusetts, a respected

early nineteenth century author of books on family morals and duties, warned

children about past ingratitudes toward their parents as follows:

And when your mother dies, do you not think that you will feel remorse for every

unkind word you have uttered, and for every act of ingratitude? Your beloved parents must soon die. You will probably be led into their darkened chamber, to see them pale

and helpless on their dying bed. Oh, how will you feel in that solemn hour! All your past life will come to your mind, and you will think that you would give worlds, if you could

blot out the remembrance of past ingratitude. You will think that, if your mother or father should only get well, you would never do any thing to grieve them again. But the hour for them to die must come. You may weep as though your heart would break, but it will not recall the past, and it will not delay their death. They must die; and you will probably gaze upon their cold and lifeless countenances in the coffin. You will follow

them to the grave, and see them buried forever from your sight. Oh, how unhappy you will feel, if you then have to reflect upon your misconduct! The tears you will shed over their graves will be the more bitter, because you will feel that perhaps, your own

misconduct hastened their death.

REFERENCE

Noted by T.E.C., Jr, MD

(7)

1987;80;79

Pediatrics

Ashok Joshi, Tilo Gerhardt, Patty Shandloff and Eduardo Bancalari