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Effects of Phenobarbital on Cerebral Blood Flow Velocity After Endotracheal Suctioning in Premature Neonates
Gary H. Burgess, MD;
William Oh, MD;
Benjamin S. Brann IV, MD;
Ann-Mari Brubakk, MD;
Barbara S. Stonestreet, MD
Arch Pediatr Adolesc Med. 2001;155:723-727.
ABSTRACT
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Objective To examine the effect of phenobarbital administration on anterior cerebral
artery blood flow velocity before and after endotracheal suctioning in premature
neonates.
Design Transcutaneous PO2 (TcPO2), heart rate, mean arterial
blood pressure (MABP), and Doppler velocimeter blood flow of the left anterior
cerebral artery were measured before and immediately after 3 consecutive endotracheal
suctioning procedures in premature neonates. Intravenous phenobarbital (20
mg/kg) was administered immediately after the first procedure.
Setting Neonatal intensive care unit.
Patients Nine neonates with a mean birth weight of 807 g (range, 620-1060 g)
and a mean gestational age of 27 weeks (range, 25-30 weeks) were studied at
age 8 to 12 hours.
Results Transcutaneous PO2 decreased in response to endotracheal
suctioning at each of the suctioning procedures before and after phenobarbital
was given (P<.001). Changes in heart rate were not observed.
There were increases in MABP and area under the velocity curve (AUVC) per
minute in response to endotracheal suctioning before but not after phenobarbital
administration (P= .046). Use of phenobarbital lowered the overall
peak systolic blood flow velocity in response to endotracheal suctioning (P = .02, analysis of variance, interactions for the effect of phenobarbital
therapy on the response to suctioning). Changes in end-diastolic blood flow
velocity were not observed. There were decreases in the differences before
and after endotracheal suctioning for MABP at 2 and 4 hours and for AUVC and
peak systolic blood flow velocity 4 hours after phenobarbital was given (P = .04).
Conclusions In very low-birth-weight neonates, endotracheal suctioning is associated
with decreases in TcPO2 and increases in MABP and AUVC. Treatment
with phenobarbital attenuates the increases in MABP and AUVC but not the decreases
in TcPO2 after endotracheal suctioning.
INTRODUCTION
PHENOBARBITAL is used for treatment of seizures and sedation in low-birth-weight
neonates. Concern has been raised regarding treatment with phenobarbital because
it has been shown to decrease cerebral blood flow during hypertension1 and hypotension2 in
newborn piglets. In normotensive newborn piglets, phenobarbital exposure has
been shown to result in transient dose-dependent decreases in mean arterial
blood pressure (MABP) and cerebral blood flow; MABP and cerebral blood flow
returned to baseline values within 60 minutes of administration.3
In human neonates, no effects on MABP or cerebral blood flow velocity were
observed after administration of an intravenous dose of phenobarbital, 20
mg/kg.4
Endotracheal suctioning increases MABP and cerebral blood flow velocity
in human neonates.5 The objective of this study
was to examine the effect of phenobarbital treatment on the responses of MABP
and cerebral blood flow velocity to endotracheal suctioning in very low-birth-weight
neonates.
PATIENTS, MATERIALS, AND METHODS
This study was approved by the institutional review board of Women and
Infants Hospital of Rhode Island, Providence, and informed consent was obtained
from the legal guardians of the newborns. Consecutive neonates were recruited
after informed consent had been obtained and according to investigator availability.
Only 1 neonate could be studied at a time. Neonates were enrolled from March
23, 1984, through December 30, 1984. The study had not been published previously
because at the time of the original study, measures were made by tracing the
velocimeter curves using a handheld device. To improve on the accuracy of
our findings, we had to wait until computerized techniques became available,
and, as outlined later, the tracings were then reanalyzed by digitalizing
the original velocimeter tracings.
Nine neonates with a mean ± SEM birth weight of 807 ±
54 g and a gestational age range of 25 to 30 weeks were studied. All neonates
were intubated, receiving conventional ventilatory support, and had 3.5F umbilical
arterial catheters (Argyle; Sherwood Medical Industries, St Louis, Mo) placed
in the descending aorta at the level of the 8th to 10th thoracic vertebra
for clinical monitoring of arterial blood gases and blood pressure. None of
the neonates were paralyzed or treated with surfactant replacement therapy.
Neonates were studied at age 8 to 12 hours.
Exclusion criteria included (1) maternal antenatal barbiturate therapy;
(2) neurologic abnormalities, including seizures, microcephaly, and chromosomal
or genetic syndromes with brain abnormalities; and (3) development of any
severe complications before or during the study period, such as pneumothorax
or prolonged bradycardia.
MEASUREMENT PROCEDURES
All neonates had normal cranial ultrasound findings before enrollment
in the study. Transcutaneous PO2(TcPO2) (model 632;
Kontron, Zurich, Switzerland) was monitored in all neonates. Continuous descending
aortic blood pressure and heart rate were monitored through the umbilical
arterial catheter, which was connected to a pressure transducer (model P 23ID;
Gould Statham, Oxnard, Calif) and a polygraph recorder (model 7D; Grass Instruments
Co, Quincy, Mass). Arterial blood samples were obtained for measurement of
serum phenobarbital concentrations and hematocrit values. Intermittent arterial
blood gas determinations correlated with simultaneously obtained TcPO2 values.
Although Doppler blood flow velocity measurements do not equal absolute
blood flow, Hansen et al6 previously demonstrated
a linear correlation between cerebral blood flow measured by radionuclide-labeled
microspheres and area under the velocity curve (AUVC). Therefore, Doppler
blood flow velocity can be used to provide a noninvasive estimate of cerebral
blood flow in very low-birth-weight human infants.
In the present study, our intent was not to measure absolute changes
in cerebral blood flow before and after endotracheal suctioning; rather, we
used cerebral blood flow velocity as an estimate of cerebral blood flow and
expressed the data as changes with reference to a procedure (endotracheal
suctioning) and an intervention (treatment with phenobarbital). Doppler blood
flow velocity measurements were performed on the left anterior cerebral artery
with a continuous–wave form bidirectional Doppler velocimeter (model
BV 318; Sonicaid, Fredericksburg, Va). Doppler blood flow velocity tracings
were taken over the anterior fontanel by applying ultrasound transmission
gel (Aquasonic; Parker Laboratories Inc, Orange, NJ) to the scalp and using
a handheld 8-MHz pencil probe. The probe was directed on the parasagittal
plane and adjusted to allow maximal audiometric output determined with earphones.
Recordings were made just before and immediately after 3 consecutive endotracheal
suctioning procedures spaced 2 hours apart. Ten cardiac cycles taken within
30 seconds of any given period with the highest peak systolic velocity tracings
were analyzed to determine AUVC, peak systolic blood flow velocity (PSBFV),
and end-diastolic blood flow velocity (EDBFV).
At the time of the original study, measures were made by tracing the
velocimeter curves using a handheld device. After computerized techniques
had become available, the tracings were reanalyzed by digitalizing the original
velocimeter tracings to improve on the accuracy of our original findings.
Each cardiac cycle tracing was digitalized into 300-dpi images in ".pcx" format
using a scanner (MFS-6000CS Flatbed Image Scanner; Mustek Inc, Irvine, Calif)
and imaging software (Picture Publisher, version 4.0ak; Micrografx, Richardson,
Tex). The images were then calibrated and further digitalized (UN-SCAN-IT
software; Silk Scientific Inc, Orem, Utah) into data by manually tracing the
velocimeter tracings with points placed in the middle of each curved line.
Between 199 and 314 points were manually placed for each tracing. The AUVC
was measured using the trapezoidal rule of area measurement and then corrected
to square centimeters per minute using the heart rate determined for each
cardiac cycle imaged. The PSBFV was measured in centimeters per second as
the highest Y-value on the velocimeter curve, and the EDBFV was measured in
centimeters per second as the lowest Y-value at the end of each cardiac cycle.
The measurements obtained from the 10 cardiac cycle tracings for each period
were then averaged. These means were then used for the statistical analysis.
To test the reproducibility of the digitalization and measuring procedures
of the Doppler blood flow velocity curve tracings, one cardiac cycle was scanned
24 separate times, evenly distributed among the other cycles that were scanned.
The mean AUVC for the test tracings was 78.5 cm2/min (range, 77.6-79.1
cm2/min). The coefficient of variation for the intrareliability
of the Doppler velocity digitalization and measuring procedures was 0.12%.
INTERVENTION PROCEDURES
Consistency of the endotracheal suctioning was maintained by one of
us (G.H.B. or B.S.B.) performing the procedure. One milliliter of sterile
isotonic sodium chloride solution was placed into the endotracheal tube. The
neonate's head was turned to the right; 5 insufflations were given with 100%
oxygen through a ventilation bag, and a suction catheter was used to suction
the endotracheal tube for approximately 5 seconds. This procedure was then
repeated with the head turned to the left.
Immediately before and after the suctioning procedure, TcPO2,
heart rate, MABP, and left anterior cerebral artery blood flow velocity were
measured. Immediately after the first suctioning procedure and measurements,
arterial samples were obtained for determination of hematocrit values. Thereafter,
phenobarbital, 20 mg/kg body weight, was given intravenously. The endotracheal
suctioning procedure and the measurements before and after suctioning described
above were repeated 2 and 4 hours after phenobarbital administration. Immediately
after the last suctioning procedure and measurements, arterial blood samples
were obtained for measurement of serum phenobarbital concentrations and hematocrit
values.
STATISTICAL ANALYSIS
Repeated-measures analysis of variance (ANOVA) with 2 repeated factors
was used to analyze the effects of endotracheal suctioning and treatment with
phenobarbital on changes in TcPO2, heart rate, MABP, AUVC, PSBFV,
and EDBFV during the studies. When a significant difference was found by ANOVA,
the Newman-Keuls post hoc test was used to identify specific differences.
To determine the modulating effect of phenobarbital on the MABP, AUVC, PSBFV,
and EDBFV on changes before and after endotracheal suctioning, the values
after suctioning were subtracted from those before suctioning for each procedure;
the differences at the 3 periods were then compared by ANOVA for repeated
measures. When a significant difference was found by ANOVA, the Newman-Keuls
post hoc test was used to detect differences among the 3 suctioning procedures.
All values are expressed as mean ± SEM. Differences were considered
statistically significant at P<.05.
RESULTS
The 9 neonates had a mean hematocrit of 0.44 ± 0.02. Changes
in hematocrit values were not observed during the study. The serum phenobarbital
level achieved 4 hours after administration was within the therapeutic range
(21.4 ± 1.6 mg/dL).
As shown in Figure 1, TcPO2 decreased in response to endotracheal tube suctioning before and after
treatment with phenobarbital (P<.001, ANOVA, main
effects for endotracheal suctioning). There were no changes in heart rate
during the study (P = .72, ANOVA, main effects for
endotracheal suctioning)). Mean arterial blood pressure increased after endotracheal
suctioning before but not after phenobarbital was administered (P = .01, ANOVA, interactions for the effect of phenobarbital treatment
on the response to suctioning). Mean arterial blood pressure was higher after
endotracheal suctioning before treatment with phenobarbital than after treatment.
As shown in Figure 2, there was
a statistically significant increase in AUVC per minute in response to suctioning
before but not after treatment with phenobarbital (P
= .03, ANOVA, interactions for the effect of phenobarbital treatment on the
response to suctioning). Phenobarbital treatment lowered the overall PSBFV
response to endotracheal suctioning (P = .02, ANOVA,
interactions for the effect of phenobarbital treatment on the response to
suctioning). There were no significant changes in the EDBFV values during
the study (P = .13, ANOVA, main effects for endotracheal
suctioning).
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Figure 1. Mean ± SEM values for transcutaneous
PO2 (A), heart rate (B), and mean arterial blood pressure (MABP)
(C) before and after 3 endotracheal suctioning procedures in 9 premature neonates.
Administration of phenobarbital, 20 mg/kg, was at time 0. Asterisk indicates P<.05 compared with before endotracheal suctioning; dagger, P<.05 compared with baseline values before phenobarbital administration
and after endotracheal suctioning.
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Figure 2. Mean ± SEM values for area
under the velocity curve per minute (A), peak systolic blood flow velocity
(B), and end-diastolic blood flow velocity (C) before and after 3 endotracheal
suctioning procedures in 9 premature neonates. Administration of phenobarbital,
20 mg/kg, was at time 0. Asterisk indicates P<.05 compared
with before endotracheal suctioning; dagger, F = 5.4; P= .02,
analysis of variance, interactions for the effect of phenobarbital treatment
on the response to suctioning.
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To demonstrate the modulating effect of phenobarbital therapy on the
values before and after endotracheal suctioning, the values after suctioning
were subtracted from those before suctioning for each procedure. As shown
in Figure 3, there was a decrease
in the differences for MABP 2 and 4 hours after treatment with phenobarbital
(F = 6.20; P = .01, ANOVA). There were decreases
in the differences for AUVC (P = .04, ANOVA) and
PSBFV (P = .03, ANOVA) 4 hours after treatment with
phenobarbital compared with the differences before phenobarbital had been
given. The EDBFV differences did not change after phenobarbital administration
(P = .59, AVOVA) (data not shown).
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Figure 3. Mean ± SEM differences
in mean arterial blood pressure (MABP) (A), area under the velocity curve
per minute (B), and peak systolic blood flow velocity (C) in 9 premature neonates
during the study periods. Values were calculated at each period by subtracting
the measurements after suctioning from those before suctioning. Administration
of phenobarbital, 20 mg/kg, was at time 0. Asterisk indicates P<.05
compared with before phenobarbital therapy.
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COMMENT
The purpose of our study was to examine the effects of phenobarbital
administration on changes in anterior cerebral artery blood flow velocity
resulting from endotracheal tube suctioning in ventilated very low-birth-weight
neonates. We found that (1) endotracheal suctioning was associated with decreases
in TcPO2 and increases in MABP and AUVC per minute and (2) treatment
with phenobarbital attenuated the increases in MABP, AUVC per minute, and
PSBFV but not the decreases in TcPO2 after endotracheal suctioning.
Therefore, phenobarbital therapy modulates the response of anterior cerebral
artery blood flow velocity to endotracheal suctioning in very low-birth-weight
neonates.
Our findings are consistent with those of previous studies that demonstrated
that suctioning of the endotracheal tube in ventilated premature infants5 and dogs7 results in
significant increases in MABP and decreases in arterial oxygen tension. However,
the reductions in TcPO2 after endotracheal suctioning were not
in the hypoxic range, most likely because our suctioning procedures were standardized.
Endotracheal suctioning was performed in a controlled fashion by the investigators,
and 100% oxygen was administered via bag ventilation, thus potentially limiting
the reductions in systemic oxygenation in response to suctioning. Others also
found that administration of supplemental oxygen attenuates hypoxia during
tracheobronchial hygiene.8
Our findings are also consistent with those of previous studies that
have shown that phenobarbital administration temporarily abolishes the hypertensive
peaks in arterial blood pressure in stressed premature infants9
and attenuates the rise in mean aortic blood pressure in response to routine
nursery procedures.10 However, phenobarbital
treatment did not attenuate the reductions in TcPO2 in response
to suctioning.
Consistent with previous findings,5 endotracheal
suctioning was associated with a 21% increase in anterior cerebral Doppler
blood flow velocity (AUVC) before phenobarbital was administered.
The mechanism for the increase in cerebral blood flow velocity with
suctioning cannot be ascertained with certainty from our study. Although the
increase in blood flow velocity was associated with an increase in MABP and
a decrease in TcPO2 during endotracheal suctioning, it is unlikely
that the changes in these variables account for the increase in cerebral blood
flow velocity with suctioning in our very low-birth-weight neonates. Autoregulation
of brain blood flow is an important homeostatic mechanism by which perfusion
is maintained relatively constant over a wide range of systemic blood pressures
in adults.11 Consequently, cerebral blood flow
increases in response to changes in systemic blood pressure only when the
cerebral circulation becomes pressure passive.11, 12
Although the range of autoregulation is relatively narrow in the premature
fetal lamb12 and newborn,13
the precise range of autoregulation in very low-birth-weight infants is not
known. Nevertheless, the increase in MABP that we observed after suctioning
was most likely within the range of autoregulation for low-birth-weight neonates,
and the mean increase in blood pressure from 32 to 38 mm Hg was most likely
not sufficient to exceed the autoregulatory range of these neonates.13
The reduction in TcPO2 from a mean of 9.6 to 6.8 kPa in response
to suctioning did not reach the hypoxic range. In the early neonatal period
(age 8-12 hours), this level of oxygenation was most likely sufficient to
provide the neonates with adequate systemic oxygenation. Nevertheless, the
cerebral circulation is sensitive to changes in arterial oxygen content.14 The suctioning-related decreases in TcPO2
might have been sufficient to reduce the arterial oxygen content such that
cerebral blood flow, reflected by AUVC, increased to maintain cerebral oxygen
delivery constant.14 Although the modest increases
in MABP, per se, most likely did not exceed the autoregulatory range in these
neonates, we cannot rule out the possibility that the decreases in TcPO2 with potential secondary effects on cerebral blood flow velocity,
along with the increases in MABP, might have impaired cerebral autoregulation
in these very low-birth-weight neonates.
Several other mechanisms might have accounted for the suctioning-related
increases in Doppler blood flow velocity in our very low-birth-weight neonates.
Endotracheal suctioning might have shifted the behavioral state of our neonates
to a more alert state. In the perinatal period, state-related increases in
brain blood flow have been reported.15 In addition,
endotracheal suctioning also simulates sympathoexcitatory receptors in the
large airways and results in increased sympathetic activity.16
Treatment with phenobarbital attenuated the increases in MABP and Doppler
blood flow velocity but did not affect the reductions in TcPO2
associated with endotracheal suctioning. As outlined earlier, it is unlikely
that the increase in MABP resulted in a pressure-passive increase in Doppler
blood flow velocity in our neonates. Consequently, the decrease in MABP after
phenobarbital treatment and endotracheal suctioning cannot account for the
lack of increase in anterior cerebral Doppler blood flow velocity (AUVC) after
phenobarbital therapy and endotracheal suctioning.
The mechanism(s) by which phenobarbital attenuated the increases in
Doppler blood flow velocity in response to endotracheal suctioning cannot
be determined by our study. Nonetheless, several mechanisms might have accounted
for the decreases in blood flow velocity after phenobarbital treatment. Phenobarbital
has been shown to decrease cerebral oxygen consumption in newborn piglets,3 to decrease brain glucose utilization in adult humans,17 and to increase smooth muscle vascular tone in vitro.18 In addition, reductions in cerebral blood flow and
metabolic rate of oxygen have been demonstrated in adult humans during deep
sleep.19 Thus, the sedative effect of phenobarbital
also might have affected blood flow velocity by altering the sleep-wake state
in our very low-birth-weight neonates19 and/or
by attenuating alert/awake state-related increases in brain blood flow15 that might have been associated with suctioning and/or
increased sympathetic activity.16
Although these studies were performed before surfactant replacement
was routinely used in low-birth-weight infants, the physiologic responses
of cerebral blood flow velocity to phenobarbital administration after endotracheal
suctioning are most likely still relevant because changes in cerebral hemodynamics
seem to correlate more with changes in MABP than surfactant administration
in infants with respiratory distress syndrome.20
We conclude that endotracheal suctioning of very low-birth-weight neonates
results in significant deceases in TcPO2and increases in MABP and
anterior cerebral blood flow velocity. Phenobarbital treatment modulates these
changes by abolishing the effects of endotracheal suctioning on MABP and anterior
cerebral blood flow velocity.
AUTHOR INFORMATION
Accepted for publication January 13, 2001.
This study was supported by the Pediatric Department Fund at Women and
Infants Hospital of Rhode Island, Providence.
From the Department of Pediatrics, Brown University School of Medicine,
Women and Infants Hospital of Rhode Island, Providence.
Corresponding author and reprints: Barbara S. Stonestreet, MD, Department
of Pediatrics, Brown University School of Medicine, Women and Infants Hospital
of Rhode Island, 101 Dudley St, Providence, RI 02905-240 (e-mail: bstonest{at}wihri.org).
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