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In Vivo 31P Nuclear Magnetic Resonance Measurement of Chronic Changes in Cerebral Metabolites Following Neonatal Intraventricular Hemorrhage


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In Vivo

31P Nuclear




of Chronic


in Cerebral








MD, Barbara


RN, PhD,



MD, Teresa


BS, Britton







From the Departments of Neurology, Pediatrics, and Biochemistry and Biophysics, School of Medicine and School of Nursing, University of Pennsylvania, and the Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia

ABSTRACT. The purpose of this study was to determine whether cerebral metabolic changes occur after intraven-tricular hemorrhage in the newborn. Five babies with bilateral grade 3 to 4 intraventricular hemorrhage were

compared with 15 preterm infants without intraventric-ular hemorrhage. Cerebral high-energy phosphorus me-tabolites and intracellular pH were measured with in vivo

3sP nuclear magnetic resonance spectroscopy. Spectra

were collected initially within the first 2 weeks of life, and then every other week until discharged from the hospital. The phosphocreatine to inorganic phosphate ratio and the phosphocreatine to adenosine triphosphate ratio were significantly lower in the group with intraven-tricular hemorrhage, but differences in intracellular pH were not significant. Differences between babies with and without intraventricular hemorrhage varied with postconceptional age: in those with intraventricular hem-orrhage, the phosphocreatine to adenosine triphosphate ratio was decreased at all postconceptional ages, and the phosphocreatine to inorganic phosphate ratio was lower in babies with intraventricular hemorrhage and younger than 30 weeks. Results of this study confirm the presence of chronic metabolic changes following intraventricular

hemorrhage which may exacerbate neurologic damage

after intraventricular hemorrhage in the newborn. Pedi-atrics 1988;82:331-336; nuclear magnetic resonance, cer-ebral metabolite, neonate, intraventricuk.zr hemorrhage.

Received for publication July 21, 1987; accepted Oct 6, 1987. Presented, in part, to the American Academy of Neurology, New York, April 1987, and the Society for Pediatric Research, Ana-heim, CA, April 1987.

Views expressed herein are those of the author, and no official endorsement of the Robert Wood Johnson Foundation is in-tended or should be inferred.

Reprint requests to (DY.) Division of Neurology, Children’s Hospital of Philadelphia, 34th & Civic Center Blvd,

Philadel-phia, PA 19104.

PEDIATRICS (ISSN 0031 4005). Copyright © 1988 by the

American Academy of Pediatrics.

Intraventicular hemorrhage occurs in

approxi-mately 45% of infants born weighing less than 1,500 g’ and is associated with an increased incidence of long-term neurodevelopmental problems.2 The pathogenesis ofthese problems is unknown but may

involve both hemorrhagic cerebral infarction and metabolic changes.3’7 If infarction is the only cause of neurologic abnormalities, then there is nothing other than optimal neonatal care that can be done to improve outcome after intraventricular hemor-rhage. However, if cerebral metabolic changes are also involved in the pathogenesis of postintraven-tricular hemorrhage neurologic problems, then in-terventional therapy could potentially improve out-come. The purpose of this study was to determine whether there are changes in cerebral metabolism after intraventricular hemorrhage in the newborn

and to compare the time course of metabolic

changes in babies with intraventricular hemorrhage to those without. Cerebral high-energy phosphorus metabolites were measured with 31P nuclear mag-netic resonance (NMR) spectroscopy which allows

noninvasive determination of cerebral

phospho-creatine, inorganic phosphate, adenosine

triphos-phate, phosphorylated diesters, phosphorylated monoesters, and intracellular pH.




All babies born at the hospital of the University


neonatologist thought the baby was stable and could be transported safely to the spectroscopy suite (approximately 30 m [100 ft]), the parents

were asked for permission to include their child in

the study. The study was approved by the Univer-sity of Pennsylvania’s Committee on Investigations Involving Human Beings, and informed consent

was obtained from the parents.

Babies with and without intraventricular hem-orrhage were studied concurrently. Obstetric,

deliv-ery room, and neonatal care of the two groups was

comparable. We did not try to control for factors

other then birth weight and intraventricular hem-orrhage.

After babies were discharged from the hospital, maternal and neonatal records were reviewed for

the presence of several other variables which may

have had impact on neurologic outcome (Table 1). These variables included obstetric factors (pre-eclampsia, perinatal vaginal bleeding, abnormali-ties in fetal heart rate patterns indicative of fetal distress, type of delivery, meconium-stained am-niotic fluid), delivery room factors (Apgar score at one and five minutes, resuscitation with intubation and bagging only, resucitation with intravenous medications), neonatal factors (birth weight, esti-mated gestational age, small or large for gestational

age, initial and lowest arterial blood gas values [P02,

Pco2, pH] in the first 48 hours, hypotension,

hy-pertension, hypoglycemia, time on mechanical yen-tilator, pneumothorax), and associated medical

di-agnosis (meconium aspiration, respiratory distress

syndrome, bronchopulmonary dysplasia, seizures, sepsis).

Cranial real time ultrasound examination was

performed on days 1, 3, and 7 of life.

Intraventric-ular hemorrhage was graded using the scale

re-ported by Papile et al.’ Babies with grade 1 or 2 intraventricular hemorrhage were not included in this study, because neurologic problems in these

babies are usually absent or minimal.46 In addition,

to eliminate metabolic abnormalities caused by

hemorrhagic infarction,8’9 we excluded babies with parenchymal hemorrhage in the NMR region. Six infants with grade 3 or 4 intraventricular hemor-rhage were compared with 15 preterm infants

with-out evidence of intraventricular hemorrhage (Table


Four of the babies with intraventricular

hemor-rhage had the initial 31P NMR spectroscopy study

within the first week of life; the fifth baby had the

initial study at 9 days of age (Table 2). Seven of

the babies without intraventricular hemorrhage had

the initial 31P NMR study within the first week of life; six had the initial study between 1 and 2 weeks,

and two babies had the initial study after 2 weeks

(19 and 57 days). In both groups, subsequent 31P

NMR studies were performed approximately every

other week until discharge. Those with

intraven-tricular hemorrhage had an average of 5.8 31P NMR

studies; those without had a mean of 3.8 studies. 31P NMR data were collected concurrently in the

two groups.

31p NMR Studies

3’P NMR spectroscopy was performed as previ-ously described.” When babies were clinically

sta-TABLE 1. Comparison of Babies With and Without Intraventricular Hemorrhage*

Characteristic Intraventricula r Hemorrhage P Value

With Without

No. of babies 5 15

Birth wt (mean g ± SEM) 915 ± 133 1,121 ± 43 NS

No. of 3,P nuclear magnetic 5.8 ± 0.5 3.8 ± 0.7 NS

resonance studies (mean ± SEM)t

Apgar score (mean ± SEM)

1 mm 3.6 ± 1.6 6.0 ± 0.7 NS

5 mm 5.6 ± 1.4 8.1 ± 0.3 <.02

Time on ventilator (mean d ± SEM) 50.6 ± 34.1 8 ± 4.2 <.05

No. of infants intubated and 3 9 NS

ventilated in delivery room

Estimated gestational age 26.8 ± 1.2 30.0 ± 0.4 <.01

(mean wk ± SEM)

Posteonceptional age at first 35P 3.60 ± 1.3 14.9 ± 3.9 NS

nuclear magnetic resonance (mean d ± SEM)

* Signficance was based on t test or x2 analysis. Babies were also compared on 20 other

variables, including obstetric complications, delivery room factors, neonatal factors, and associated medical diagnoses. Groups were not significantly different for any of these


t Number of times babies were studied. Most babies had two spectra (right and left




2. Clinical Characteristics of ntricular Hemorrhage

Infants With

Infant No.

Birth Estimated Intraventricular Wt Gestational Hemorrhage

(g) Age (wk) Grade*

Age (d) at First Nuclear Magnetic Resonance Study 1 2 3 4 5

946 29 3L;3R

1,070 28 3L; 3R

1,300 29 3L; 3R

719 25 4L;4R 540 23 3L;3R


3 9

4 1

N Based on four-category scoring system of neonatal

intraventricular hemorrhage (Papile et al’#{176}).

ble and could be safely moved, they were

trans-ported from the nursery to the NMR spectroscopy suite, which is located in the intensive care nursery.

After arriving in the spectroscopy suite, the baby

was removed from the transport isolette, swaddled in an infant blanket, and placed on a heated mat-tress in the spectroscopy isolette. The baby was stabilized in the supine position with a 4-cm

di-ameter radio frequency surface coil touching the

scalp just above the ear. The surface coil samples

an approximately hemispherical region of the

tern-poral-parietal cortex under the coil. The baby and isolette were then positioned in the magnet, so that

the cerebral region of interest was located in the

center of the magnet’s homogeneous field. NMR examinations were performed at 1.5 Tesla using a Phospho Energetics spectrometer (PE 80-250). The magnetic field homogeneity was optimized by shim-ming on the proton-free induction delay.

Phospho-rus spectra were collected for 16 minutes using a pulse width of 50 rns and a pulse delay of 4 seconds (sum of 240 free induction decay). After collecting

spectral data from the temporal-parietal region of

one hemisphere, the spectroscopy isolette was

re-moved from the magnet, the baby was repositioned to collect spectra data from the contralateral

hem-isphere, and the 31P NMR procedure was repeated.

After spectra from both hemispheres were collected,

the baby was transported back to the nursery. The

entire procedure usually required less than one

hour. Heart rate, respiratory rate, and skin temper-ature were monitored throughout the NMR study; when necessary, oxygen saturation was measured intermittently with a pulse oximeter (Nellcor).

Spectra were analyzed using a

computer-gener-ated curve-fitting program.’2 Intracellular pH was

calculated from the chemical shift of inorganic

phosphate relative to phosphocreatine.’3



T tests were used to examine the differences in mean metabolite ratios between the two groups of babies (Tables 1, 3, and 4).


analysis was used to

TABLE 3. Metabolit

Without Intraventricu

e Ratios for Babies W

lar Hemorrhage* ith and Ratio Intraventricular Hemorrhage P Value With Without PCr/Pi PCr/ATP PME/ATP PDE/ATP Intracellular pH PCr/(PDE + PME)


Postconceptional age

at study No. of spectra

0.78 ± 0.04 0.93 ± 0.04

0.52 ± 0.02 0.66 ± 0.02 1.75 ± 0.06 1.75 ± 0.05

2.48 ± 0.07 2.31 ± 0.06

7.22 ± 0.02 7.19 ± 0.02 0.12 ± 0.01 0.17 ± 0.01 0.25 ± 0.01 0.26 ± 0.01

34.1 ± 0.6 33.8 ± 0.3

49 93 <.01 <.0001 NS <.05 NS <.0001 NS NS

* Results are means ± SEM, except No. of spectra.

Ab-breviations: ATP, adenosine triphosphate; PCr, phospho-creatine; Pi, inorganic phosphate; PME, phosphorylated monoester; PDE, phosphorylated diester. Means were calculated by averaging all spectra obtained from babies

with and without intraventricular hemorrhage.

compare clinical variables between the groups

(Ta-ble 1). 31P NMR results were grouped by estimated

postconceptual age at the time of NMR study (30,

30.5 to 32, 32.5 to 34, 35.5 to 36, 36.5 to 38 weeks).

One-way analysis of variance was performed to measure the effect of postconceptional age on

me-tabolite ratios (Table 4).


The group of babies with intraventricular

hem-orrhage had significantly lower, estimated

gesta-tional age and five-minute Apgar score and required

a longer period of mechanical ventilation (Table 1).

The groups did not differ with respect to several

other variables including birth weight;

postconcep-tional age when the first 31P-NMR spectra were

collected; obstetric complications; need for

intuba-tion, bagging, or medications in the delivery room;

lowest arterial blood gas results; presence of

sei-zures and anticonvulsant drug treatment; major

medical complications; and length of


Results of each to the


NMR spectra were

combined to calculate mean 31P NMR results for

babies with and without intraventricular

hemor-rhage. Those with intraventricular hemorrhage had

significantly lower phosphocreatine to inorganic

phosphate (P < .01), phosphocreatine to adenosine

triphosphate (P <


and phosphorylated

diester to adenosine triphosphate (P < .05) ratios.

Phosphorylated monoester to adenosine triphos-phate ratio and intracellular pH were not signifi-cantly different between the groups. The mean

postconceptional age at the time of the study did

not differ between groups.

To evaluate age-related differences in metabolite


TABLE 4. 3,P


Nuclear Magnetic Resonance Studies in

Hemorrhage at Different Postconceptional

Infants With and Without



Age (wk) Phosphocreatine Phosphocreatine

No. of to Inorganic to Adenosine

Studies Phosphate Triphosphate

Ratio Ratio

Phosphorylated Phosphorylated

Monoester to Diester to

Adenosine Adenosine Triphosphate Triphosphate

Ratio Ratio

With Without With Without With Without With Without With Without

30.0 7 8 0.59 0.4 0.46 0.68

(0.08)#{176}(0.02) (0.06y’ (0.08)

1.82 1.76 2.45 2.08

(0.08) (0.11) (0.24) (0.29)

30.5-32.0 8 22 0.77 0.95 0.51 0.67

(0.06) (0.08) (0.04)#{176}(0.04)

2.00 1.81 2.29 2.21

(0.19) (0.11) (0.10) (0.13)

32.5-34.0 12 26 0.82 0.84 0.52 0.68

(0.09) (0.06) (006)b (0.04)

1.74 1.89 2.28 2.50

(0.17) (0.07) (0.15) (0.10)

34.5-36.0 5 23 0.72 0.99 0.46 0.61

(0.17) (0.07) (0.06r (0.02)

1.81 1.65 2.52 2.20

(0.10) (0.10) (0.26) (0.10) 36.5-38.0 17 14 0.85 1.02 0.56 0.69

(0.05) (0.11) (0.05’ (0.07)

1.60 1.53 2.70 2.39

(0.09) (0.08) (0.08) (0.18)

* Metabolic ratios are means (±SEM). Mean values were calculated from all spectra

obtained from babies with and without intraventricular hemorrhage. Postconceptional age at the time of each study was calculated by adding estimated gestational age at birth and

age since birth. Results of t test: GJ < .05; bp < .02. One-way analysis of variance was used to measure the effect of postconceptional age on metabolite ratios in babies with and without intraventricular hemorrhage. Metabolite ratios at different postconceptional ages did not differ significantly.

groups based on estimated postconceptional age at the time of the study (Table 4). Babies with and without intraventricular hemorrhage were analyzed

separately. Metabolite ratios obtained at different

postconceptional ages did not differ significantly in

either group of babies.

Differences between infants with and without

intraventricular hemorrhage varied with

postcon-ceptional age (Table 4). In each of the age groups,

babies with intraventricular hemorrhage had

sig-nificantly lower phosphocreatine to adenosine

tn-phosphate ratios. In the youngest age group (30

weeks), babies with intraventnicular hemorrhage

had significantly lower phosphocreatine to

inor-ganic phosphate ratios, but the phosphocreatine to

inorganic phosphate ratio in the four older groups

was not different. None of the age groups had

different phosphorylated monoester to adenosine

tniphosphate on phosphorylated diester to

adeno-sine tniphosphate ratios in infants with and without

intraventnicular hemorrhage.


Intraventnicular hemorrhage is a major neuro-logic problem in low birth weight infants. Although survivors of intraventnicular hemorrhage have an increased risk for long-term neurodevelopmental abnonmalities,2”416 little is known about the pathophysiology of these problems. Most authoni-ties suggest that late neurologic sequelae are sec-ondary to structural injury from hemorrhagic

cer-ebral infarction.7 Our data indicate the presence of

prolonged metabolic changes following

intraven-tnicular hemorrhage, suggesting that alterations in metabolism may be involved in the pathogenesis of late neurologic sequelae. Between 28 and 38 weeks postconceptional age, the brain undergoes rapid

growth and development with neuronal layering,

alignment, and orientation; dendnitic and axonal

growth; synapse formation; and glial proliferation.7

If cerebral metabolism is altered throughout this

period, it is possible that these processes will not

proceed normally. Therefore, chronic changes in

cerebral metabolism may cause neurologic

abnor-malities beyond those related to structural changes. Several investigators have reported changes in

cerebral blood flow following neonatal

intraventnic-ular hemorrhage. Ment and co-workers12’17 demon-strated significant differences in the hemispheric

flow ratios one to two days after intraventnicular

hemorrhage and lower cerebral blood flow at four to six days.12”7 Volpe and colleagues18 reported a

two- to fourfold reduction in cerebral blood flow

throughout the affected hemisphere in five- to

17-day-old babies with intraventnicular hemorrhage.

At a mean age of 34 days, babies with

posthemor-rhagic hydrocephalus had higher lactate to pyruvate

ratios and lower CSF glucose concentrations,

sug-gesting anaerobic glycolysis with increased glucose requirements.16 Our results agree with these stud-ies, indicating that changes in cerebral blood flow

and metabolism exist for several weeks after

intra-ventricular hemorrhage.

The exact cause of the biochemical changes is


et al’9 reported lower phosphocreatine to inorganic phosphate ratios in severely asphyxiated babies.

The babies in the intraventricular hemorrhage

group had lower Apgar scores; therefore, some of

the metabolic changes may be directly related to cerebral injury from peninatal asphyxia. Another possibility is that dilated ventricles may cause rel-ative cerebral ischemia with increased anaerobic glycolysis and decreased phosphocreatine concen-tration. This may be a major factor soon after intraventricular hemorrhage and may account for

the lower phosphocreatine to inorganic phosphate

ratio in babies less than 30 weeks’ postconceptional

age. Biochemical changes caused by CNS

matura-tion may also be involved. Tofts and Wray1#{176}re-ported maturational increases in the phosphocrea-tine to inorganic phosphate ratio in rat brain and similar changes may exist in humans.8 Because the intnaventnicular hemorrhage group had a lower es-timated gestational age, differences in brain matu-ration may account for part of the metabolic differ-ence. However, the initial 31P NMR spectra were collected at similar postconceptional ages, and met-abolic differences persisted when the groups were compared at the same postconceptional age; there-fore, difference in estimated gestational age cannot

completely explain the difference. The decreased

phosphocreatine concentration may be related to decreased brain creatine which could result from a combination of cerebral injury in the babies with intnaventnicular hemorrhage and decreased crea-tine uptake in newborn brain.20 Although babies with intraventnicular hemorrhage required a longer period of mechanical ventilation, we do not think that cerebral metabolic differences between the groups were caused by alterations in arterial blood gases during the 31P NMR study. In newborn ani-mals, cerebral metabolites do not change until Pa02 decreases to less than 33 mm Hg.2’ None of the babies had bradycardia, cyanosis, or other clinical

signs of significant hypoxia during spectroscopy.

The lower phosphocreatine concentration

mdi-cates that the brain is severely stressed for several weeks following intraventnicular hemorrhage. Chance et al22’23 have demonstrated that the phos-phocreatine to inorganic phosphate ratio is related

to V/Vmax, where V represents adenosine

tniphos-phatase activity and Vmax is the maximum rate of adenosine tniphosphate synthesis. In babies with-out intraventnicular hemorrhage, V/Vmax was 0.6; however, between 31 and 37 weeks, the babies with intraventnicular hemorrhage had a V/Vmax of ap-proximately 0.7. In mature animals, feedback con-trol of oxidation phosphorylation begins to fail at levels this high and cerebral bioenergetics become unstable.23 It is unknown whether a similar re-sponse occurs in babies; however, the high V/Vmax

ratio in the babies with intraventnicular hemor-rhage suggests that they are in a marginally stable state and that only small metabolic changes might result in large alterations in phosphocreatine to

inorganic phosphate ratio, anaerobic glycolysis,

in-tracellular acidosis, loss of cerebral adenosine

tn-phosphate, and further neuronal injury.

The composition of the phosphorylated

monoes-ten and phosphorylated diester peaks and their

rel-evance to cerebral metabolism have generated

con-siderable interest. Phosphorylethanolamine is the

major component of the phosphorylated monoester

peak with phosphorylcholine and sugar phosphates

making a smaller contribution.24 The increased

con-centration of phosphorylethanolamine in newborn

brain may be related to its role as a precursor of

myelin and phospholipids. Because of this, it has also been suggested that the phosphorylated mon-oester peak can be used as a marker of anabolic activity in the brain.25 The phosphorylated diester

peak is mainly due to phosphatidylcholine and

phosphatidylsenine, with smaller contributions from phosphatidylethanolamine, phosphatidylino-sitol, and sphyngomyelin.26 The phosphonylated diester peak may be useful as a marker of brain

catabolic activity. Babies with intraventniculan

hemorrhage had increased phosphonylated diester to adenosine tniphosphate ratios, suggesting the possibility of increased catabolic functions.

These results may have important clinical nami-fications. If further studies confirm the presence of prolonged metabolic changes after intraventniculan

hemorrhage, and if these changes correlate with

neurodevelopmental outcome, then 31P NMR

meas-urements will allow us to select babies at greatest

neurologic risk, to design therapeutic interventions

for these children, and possibly to improve

neuro-logic prognosis.


This work was supported by National Institutes of

Health grant SBIR HD 18540. Dr Younkin is the

recipi-ent of Teacher Investigator Development Award NIH

NS-00774. Dr Medoff-Cooper is a Robert Wood Johnson

Clinical Nurse Scholar.

The authors thank Linda Cella for her secretarial



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and Maria Delivoria-Papadopoulos

Donald Younkin, Barbara Medoff-Cooper, Ronnie Guillet, Teresa Sinwell, Britton Chance

Cerebral Metabolites Following Neonatal Intraventricular Hemorrhage

P Nuclear Magnetic Resonance Measurement of Chronic Changes in


In Vivo


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and Maria Delivoria-Papadopoulos

Donald Younkin, Barbara Medoff-Cooper, Ronnie Guillet, Teresa Sinwell, Britton Chance

Cerebral Metabolites Following Neonatal Intraventricular Hemorrhage

P Nuclear Magnetic Resonance Measurement of Chronic Changes in


In Vivo


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