Electronic Supplementary Material

Dopamine therapy promotes cerebral flow–metabolism coupling in preterm infants

Supplementary Methods

Subjects

Babies were studied whilst receiving care in the Neonatal Intensive Care Unit at Monash Medical Centre, Melbourne, Australia, over a 20-month period. Infants were excluded if they had major congenital abnormalities. Management of neonatal hypotension was based upon the recommendation of The Joint Working Group of the British Association of Perinatal Medicine[1] that the mean arterial blood pressure (MAP) in mmHg should be maintained at or greater than the gestational age in weeks.

Physiological variables

Arterial blood pressure was continually measured from an peripheral or umbilical arterial catheter connected to a transducer monitoring system zeroed at the mid-maxillary line (Abbott Critical Care Systems Transpar IV, Abbott Australasia, Kurnell, New South Wales, Australia). The arterial pressure waveform and numerical values of MAP were recorded (Agilent CMS 2000, Component Monitoring System, Agilent Technologies Inc, Andover, MA) along with transcutaneous partial pressure of carbon dioxide (PaCO2, Viridia CMS 2000 series, Hewlett-Packard, Waltham, MA).

Cerebral fractional oxygen extraction (CFOE) and cerebral metabolic rate of oxygen consumption (CMRO2)

Values of SpO2 averaged over 10 sec immediately before the paired estimates of CBF/CSvO2 were used for calculations of cerebral metabolic rate of oxygen consumption (CMRO2). We employed the standard equations:

CMRO2 = CBF x [Hb] x (SpO2 - CSvO2) x 1.39

CFOE = (SpO2 - CSvO2) / SpO2

where CBF is ml.100g-1.min-1, CDO2 and CMRO2 are ml oxygen.100g-1.min-1,[Hb] = haemoglobin concentration (g.ml-1), and 1.39 = the stoichiometric oxygen capacity of hemoglobin (ml.g-1).

Measurement protocol and data analysis

For each infant, replicate, paired measurements of CBF and CSvO2 were performed over 2 hr. Measurements were then pooled and averaged over each 30 min period. For each infant, a median value of the 30 min averages was calculated for the entire 2 hr study period. Group median values were then calculated from the individual median values of each infant.

Precision of measurements

To assess variability of CBF, CSvO2, MAP and PaCO2 measurements, coefficients of variation were calculated from replicates within 30 min periods.

Supplementary Results

Precision of measurements

The coefficient of variation of replicate measurements within 30 min periods [median (IQR)] was 13.2% (9.2-21.8%) for CBF, 6.1% (3.1-8.8%) for CSvO2, 2.7% (1.7-4.6%) for MAP and 3.2% (1.6-6.8%) for PaCO2 respectively.

Relationship of cerebral blood flow and cerebral venous saturation with perinatal variables

Univariate analysis for the entire group of infants (n=26) showed that CBF was positively correlated with postnatal ageand PaCO2.Multiple linear regression analysis showed that postnatal age and PaCO2 remained independent predictors of CBF (ESM Table 3). CSvO2 showed a weak positive correlation with postnatal age but not with other perinatal variables.

After correcting the values of CBF and CSvO2 for postnatal age and PaCO2, the differing relationships between cerebral haemodynamics and oxygenation between the Control and the DOPA groups (Fig 1 and 2) remained unchanged (ESM Table 4).

References

1.BAPM (1998) Guidelines for good practice in the management of neonatal respiratory distress syndrome. Report of the second working group of the British Association of Perinatal Medicine

ESM Table 1 Perinatal characteristics and physiological variables of Control and Dopamine-treated (DOPA) infants.

Control (n=16) / DOPA (n=10) / P
Gestational age, wk / 27 (25-29) / 26 (25-27) / 0.3
Birth weight, g / 930 (678-1116) / 882 (744-899) / 0.4
Antenatal steroids*, number (%) of infants / 14 (88) / 8 (80) / 0.6
Postnatal age at study, hr / 10 (7-20) / 20 (12-40) / 0.1
Mean arterial pressure (MAP), mmHg / 33.9 (32.0-37.2) / 32.6 (30.4-34.2) / 0.2
Arterial oxygen saturation(SpO2), % / 90.5 (89.3-92.5) / 90.9 (89.1-92.3) / 0.7
Partial pressure of carbon dioxide, mmHg / 41.5 (37.4-49.2) / 44.3 (39.5-46.8) / 1.0
Haemoglobin, g.dl-1 / 15 (13-16) / 14 (13-16) / 0.8
Incidence of grade 2-4 IVH, number (%) of infants / 3 (19) / 1 (10) / 1.0

Values are median (IQR), except for Infants who received antenatal steroid and Incidence of grade 2-4 intraventricular hemorrhage (IVH).

* Includes infants who received complete and incomplete course of antenatal steroid

Infants (Gestational age, week) / Possible cause of the hypotension / Echocardiographic finding(within the first 3 postnatal days) / Lowest MAP before receiving dopamine (mmHg) / Maximum dosage of dopamine
(µg.kg-1.min-1)
1 (26) / E.Coli sepsis, persistent pulmonary hypertension of newborn / Large PDA / 19 / 20
2 (26) / Sepsis due to chorioamnionitis / NA / 25 / 6
3 (30) / Fetal distress, delivered via emergency caesarian section / NA / 24 / 10
4 (27) / Bilateral pneumothorax / Large PDA / 25 / 6
5 (24) / unclear / No PDA / 22 / 10
6 (26) / unclear / moderate PDA / 24 / 10
7 (24) / Staph sepsis, pneumothorax / moderate PDA / 22 / 14
8 (26) / unclear / moderate PDA / 20 / 10
9 (29) / Maternal pre-eclampsia / NA / 23 / 10
10 (25) / Cord prolapse, suspected perinatal hypoxic-ischaemia / Large PDA, biventricular dysfunction / 14 / 12

ESM Table 2 Clinical details of the Dopamine-treated (DOPA) infants in the first 3 postnatal days

MAP, mean arterial pressure; NA, not available; PDA, patent ductus arteriosus

ESM Table 3Regression ofCBF and CSvO2, with perinatal variables.

Gestational age, wk
R2 P / Postnatal age, hr
R2 P / PaCO2, mmHg
R2 P / MAP, mmHg
R2 P
CBF, ml.100g-1.min-1, n=26 / 0.06 / 0.22 / 0.38 / 0.001* / 0.26 / 0.01* / 0.00 / 1.0
CSvO2, %, n=26 / 0.01 / 0.63 / 0.17 / 0.04* / 0.02 / 0.5 / 0.01 / 0.6

*P<0.05

CBF, cerebral blood flow; CSvO2, cerebral venous oxygen saturation; PaCO2, partial pressure of carbon dioxide; MAP, mean arterial pressure

ESM Table 4 Correlation between cerebral haemodynamics and oxygenationusing original measurements (refer to Fig 1 and 2), and using measurements corrected for postnatal age and partial pressure of carbon dioxide (corrected measurements). Note all correlations retain the same statistical relationships after the correction.

Control (n=16) / DOPA (n=10)
Regression using original measurements / Regression using corrected measurements / Regression using original measurements / Regression using corrected measurements
R2 / P / R2 / P / R2 / P / R2 / P
CBF vs CMRO2 / 0.02 / 0.56 / 0.01 / 0.38 / 0.62 / 0.01* / 0.46 / 0.02*
CFOE vs CBF / 0.65 / <0.001* / 0.3 / 0.015* / 0.003 / 0.88 / 0.02 / 0.34
CSvO2 vs CBF / 0.56 / <0.001* / 0.27 / 0.02* / 0.01 / 0.81 / 0.01 / 0.7

* P<0.05

DOPA, dopamine-treated; CBF, cerebral blood flow; CSvO2, cerebral venous oxygen saturation;CMRO2, cerebral metabolic rate of oxygen consumption; CFOE, cerebral fractional oxygen extraction

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