Original Paper 1611009
Dev Pharmacol Ther 1992;19:10-18
Developmental Pharmacology and Perinatal Research Unit, McGill University-Montreal Children’s Hospital Research Institute, Montreal, Canada
KeyWords Phénobarbital Cerebral blood flow Anticonvulsants Newborn
Presented in part at the 2nd European Workshop on Neonatology. Klingenthal. France. June 1991.
Effects of Phénobarbital on Cerebral Blood Flow in the Newborn Piglet
Abstract To determine the neonatal cerebrovascular effect of a thera peutic dose and a high dose of phénobarbital (Pb), the effect of Pb on cerebral blood flow (CBF) and total brain oxygen con sumption (CMR02) was studied in three groups of awake newborn piglets (aged 1-3.5 days). Group I (control n = 9) received normal saline solution, group II (n = 9) received a therapeutic dose of Pb (15 mg/kg i.v.) and group III (n = 9) received a high Pb dose (45 mg/kg i.v.). Four CBF measure ments per piglet using radioactive microspheres (141 Ce, 85Cr, 95Nb, 46Sc), arterial blood gases, CU content, hematocrit and plasma glucose were obtained at 0, 15, 30, 60 min after saline or Pb injections. In all groups, pH, PaCb, PaCC>2, blood pres sure, heart rate, temperature and plasma glucose remained unchanged excepta 14% decrease (p < 0.01) in blood pressure and an increase (p < 0.05) in PaCC>2, 60 min after drug injec tion in groups II and III. Total CBF in group II decreased by 14% (p < 0.05) 15 min after drug injection and was signifi cantly lower (p < 0.05) than control (group I) but returned to baseline after 30 min. High Pb dose progressively lowered CBF by 11 % 15 min after drug injection and produced a sig nificant decrease by 20% (p < 0.01) 30 min after drug injec tion with return to baseline after 60 min. Similar effects were noted in different brain regions (cerebrum and thalamus). CMR02 remained unchanged in the control group; however, it was decreased by 35% (< 0.01 p > 0.05) 15 min after drug injection and returned to baseline after 60 min. In group III, high Pb dose lowered CMR02 by 31 % 30 min (p = 0.02) after drug injection. Data indicate that Pb exerts a minimal but transient dose-dependent effect on CBF and CMR02.
Emmanuel Scalais, MD Department of Pediatrics. Pediatric Neurology Entité Hospitalière CH St-Joseph-EspéranceRocourt Clinique St-Vincent, rue Fr. Lefèbvre. 207 B-4000 Liège (Rocourt) (Belgium)
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Emmanuel Scalais Kay Beharry Apostolos Papageorgiou Michel Bureau Jacob V. Aranda
© 1992 S. Karger AG. Basel 0379-8305/92/ 0191 —0010$2.7 5/0
Materials and Methods Twenty-seven male Yorkshire farm-bred piglets, aged 1-3.5 days and weighing from 0.780 to 1.400 kg, were studied. They were divided into three groups: group I (n = 9) received a placebo (saline solution) to serve as control; group II (n = 9) received a therapeutic dose of Pb (15 mg/kg i.v.), and group III (n = 9) received a high dose of Pb (45 mg/kg i.v.). All piglets were anesthetized with (0.6-0.9%) halo thane for insertion of polyethylene catheter (umbilical catheter size 3.5 mm ARGYLE Division of Sherwood Medical, St. Louis, Mo.) into the abdominal aorta via the right femoral, into the internal jugular vein and into the left ventricle via the right axillary artery. The ventricular location of the catheter for microspheres infusion was identified by pressure tracing using a strain gauge transducer attached to a Beckman Re corder (Grass Model 7 Polygraph). The location of the catheter tip was confirmed at postmortem in all ani mals. The catheters were then flushed with heparin
ized physiological saline solution (50 U/ml). All proce dures were performed under a radiant warmer with control of temperature. When all the surgical proce dures were accomplished, halothane was withdrawn and the incisions were closed. The mean time of anes thesia was 22.5 min (range 15-35). The animals were allowed to recover from anesthesia for at least 3.5 h before the experiments were initiated. The following physiological measurements were made in order to monitor postoperative recovery: body temperature, respiratory rate, suction reflex, plasma glucose concentration and arterial blood gases [pH, arterial oxygen tension (PO2), and arterial carbon dioxide tension (PC02)]. Four measurements of CBF were performed in each study: during the baseline period and at 15, 30, and 60 min after Pb or saline solution injection. After the first blood flow determi nation, the drug was injected for 5 min. Prior to each blood flow measurement, arterial blood gases, hemato crit, heart rate, mean systemic arterial blood pressure, arterial and venous oxygen content, and plasma glu cose concentration were determined. Arterial PaO?, PaCCF and pH were measured using an IL Blood gas machine (Radiometer, Copenhagen). Arterial and in ternal jugular oxygen content was measured with an TL 282 Co-oximeter’. Arterial plasma Pb levels were determined prior to and after Pb administration in group II and III and only during the baseline period in group I. CBF was measured by radionuclide-labelled microspheres [15, New England Nuclear, Boston, Mass.] as described by Heymann et al. [16]. Micro spheres labelled with 141Ce, 85Sr, 95Nb, 46Sc were used. The isotope sequence was assigned at random for the blood flow determination. At each blood flow determi nation, approximately 3 X 105 microspheres, sus pended and continuously agitated in 0.5 ml of a solu tion of 10% tween were administered within 30 s into the left ventricle and flushed with 2 ml of saline solu tion for a total of 70 s. A reference sample of blood from the femoral artery was removed continuously beginning 10 s before the injection of microspheres at a withdrawal rate of 1.2 ml/min using a Harvard with drawal pump (Harvard Apparatus). Blood samples were replaced after each blood flow measurement with blood from a donor piglet of the same litter. At the end of the experiments, the animal was killed with an over dose of Pb. The brain was divided into sections repre senting frontal, occipital, parieto temporal lobes, thala mus, cerebellum, brain stem (from the superior colli culus to the spinal cord) and all the organs were weighed and placed in counting vials. Organ radioac tivity was measured by a y-spectrometer (Beckman, Calif.). Counting window widths were selected to give
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Phénobarbital (Pb) has been used for many years to treat neonatal seizures. It has also been used for the possible prevention of intra ventricular hemorrhage (IVH). But its effi cacy in decreasing the occurrence of IVH par ticularly when given postnatally remains a matter of debate [1-9]. Pb has been shown to attenuate systemic hemodynamic changes due to stress [10], to prevent IVH secondary to rapid systemic blood pressure changes in newborn beagle puppies [11] and to attenuate cerebral blood flow (CBF) increases during hypertension induced by phenylephrine in newborn beagles [12] or during seizures [13]. Suggestions have been made to use Pb monotherapy at higher dose before adding a second drug in the treatment of neonatal sei zure [14]. Anesthetic doses of Pb decrease CBF and total brain oxygen consumption (CMR02) [15] and Pb decreases CBF in ma ture animals and in adults under the influence of anesthesia. We, therefore, tested the hy pothesis that Pb exerts a dose-dependent ef fect on CBF and metabolism during the awake state.
Table 1. Arterial blood gas variables, systemic mean arterial blood pressure, heart rate, hematocrit, tempera ture, and plasma glucose at each blood flow determination
pH
PO2, Torr
PCO2, Torr
Control (n = 9), min postplacebo
Therapeutic dose (n = 9), min postdrug
baseline
baseline
15
30
7.44 ±0.02
7.45 ±0.01
7.44
7.44
±0.01
±0.02
73.8 ±5.1
76.1 ±4.8
76.3 ±3.4
71.6 ±4.9
34.2
32.6 ±1.5
32.3 ±1.4
31.8
±1.2
Pressure
Heart rate beats/min Hematocrit, %
60
15
30
60
7.42
7.41
±0.02
±0.02
7.43 ±0.01
7.40 ±0.03
69.0 ±3.1
68.3 ±2.9
69.2 ±1.9
69.0 ±69
±1.6
35.3 ±1.4
36.5 ± 1.5+’*
±1.1
38.0 ± 1.9+-*
56.2 ±2.4
57.0 ±2.4
±1.8
51.6 ±2.4
51.6 ±2.4
47.4 ±2.5**
177 ±7
146
152
150
161
±8
±8
±10
29.8 ±1.6
32.4 ±3.2
58.4
56.0
±2.1
±2.6
167
178
171
±8
±8
±20
30.0 ±1.4
Temperature, °C
Plasma glucose levels, ml/1
38.6
55.2
38.4 ±0.2
±0.2
38.6 ±0.7
38.6 ±0.3
38.3 ±0.1
4.8 ±0.5
4.7 ±0.7
4.5 ±0.5
5.1 ±0.3
3.8 ±0.4
Mean ± SEM. + p * ±4.9
22.8
22.0
21.8
±1.7
±1.5
±1.4
15
30
60
49.6 ±2.7
p < 0.01, compared to baseline; * p < 0.05, compared to control.
Scalai s/Beharry/Papageorgiou/Bureau/ Aranda
Effects of Phénobarbital on Cerebral Blood Flow
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base- 15 line
Therapeutic dose (n = 9) min postdrug
t test and an analysis of variance. Changes in CBF within the groups were also analyzed for each flow measurement after the drug or placebo treatment and compared to the control predrug values.
baseline
15
30
60
7.44 ±0.01
±0.02
7.44
7.45
±0.01
±0.01
66.5 ±3.3
65.5
69.2
±2.1
±2.8
36.6 ±1.7
36.7
38.5
±2.8
±0.8*
±1.6**
55.8 ±2.3
59.2 ±2.9
58.1 ±3.4
56.3 ±3.0
182 ±14
194 ±11
190 ±15
196 ±4
29.1 ±1.9
7.40
68.1 ±3.0 39.4
28.1
38.9 ±0.1
38.7
38.6
38.8
±0.1
±0.1
±0.2
4.8 ±0.3
5.1 ±0.5
4.4 ±0.3
4.6 ±0.3
maximum efficiency as well as good separation for each of the isotopes. Although a relatively narrow range was chosen for each isotope, perfect separations of the different isotopes could not be achieved and crossover was corrected for by resolving simultaneous equations. Organ blood flow was calculated from the equation: flow =
organ radioactivity X reference sample radioactivity reference sample withdrawal rate (ml/min)
Blood flow was expressed as ml/min/100 g.
Data Analysis CBF values from the Pb group treated were com pared to the control placebo group using a Student
Results Table 1 shows the arterial blood gas vari ables, systemic mean arterial blood pressure, heart rate, hematocrit, temperature and se rum glucose data measured in the three groups immediately before each cerebral blood flow determination. The pH and the PO2 did not change significantly in the three groups throughout the study. Intragroup vari ation in PCO2 was noted. In the control group, there was a gradual decrease in the PCO2. In the therapeutic dose group, the PCO2 increased significantly by 3-7% (p < 0.05) 15 and 60 min after drug injection and was significantly higher than the control group (p < 0.05). In the high Pb group, there was a gradual increase in PCO2 (7%) which was significantly higher than the control group 30 min (p < 0.05) and 60 min (p < 0.01) after drug injection. In all groups, blood pressure, heart rate, hematocrit, temperature and plasma glucose levels remained stable except a 14% decrease (p < 0.01) in blood pressure 60 min after drug injection. Table 2 shows total brain blood flow and Pb plasma concentrations in the three groups. Plasma Pb concentrations were 22.0 pg/ml in the therapeutic dose group and 50 (ig/ml in the high Pb dose group. Total CBF (TCBF) remained stable in the control group through out the study. However, in the therapeutic group, TCBF decreased significantly (p < 0.05) by 14% 15 min after drug injection, was significantly (p < 0.05) lower than the control group and returned to baseline after 30 min. High Pb dose lowered progressively TCBF by 11% 15 min after drug injection and pro-
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High dose (n = 9), min postdrug
Table 3. TCBF and regional CBF as a percentage of change from time 0 Control (n = 9) min postplacebo
Total brain
7.4
30 3.3
±11.0
Cerebrum
9.8 ±13.7
2.8
Thalamus
2.0 ±5.4
5.1 ±7.2
Brain Stem
1.5 ±7.1
2.2
6.3 ±7.1
7.5 ±9.0
Cerebellum
Mean ± SEM. + p < 0.05,
High dose (n = 9) min postdrug
15
60
60
15
30
60
±3.3
-14.0++ ±4.7 ++
-5.3 ±4.5
3.7 ±5.2
-11.5 ±6.3
0.7 ±3.5
-14.6 ±5.2
-6.7 ±5.1
2.9 ±6.3
-12.0
1.9 ±4.6
-15.1 ±5.5+-*
-5.2 ±5.2
3.3 ±4.8
-12.9
-20.4
-12.9
-4.9
4.4 ±5.2
-9.3 ±9.9
-11.6 ±6.7
0.5 ±15.6
6.8
-13.8
±6.2
±6.2
3.8 ±13.7
1.1
±5.9
±49+,* ±5i
3.6 ±3.9
-8.1 ±5.6
3.3 ±4.6
8.1
p < 0.01, compared to baseline; * p < 0.05,
duced a significant decrease by 20% (p < 0.01) 30 min after drug injection with return to baseline values 60 min afterwards. Table 3 summarizes the total and regional CBF to cerebrum, cerebellum, thalamus, and brain stem as a percentage of change from time 0. In the control group, the total and regional CBF remained stable. In the thera peutic Pb group, there was a significant de crease of 8-15% in TCBF and regional CBF for cerebrum, thalamus, and brain stem (p < 0.05) 15 min after drug injection with return to baseline after 30 min. This reduction was statistically significant (p < 0.05) in compar ison with control group (thalamus, brain stem). In the high Pb-treated group, there was a decrease of 20-23% in TCBF and regional CBF to cerebrum and thalamus (p 0.05; ** p = 0.02, versus control.
Sixty minutes after administration of the ther apeutic dose of Pb the mean systemic blood pressure was significantly reduced. But CBF was unchanged at that time suggesting that Pb does not alter autoregulation in the physiolog ical range of blood pressure. These changes in blood pressure at the end of the experiment are unclear and no varia tion in blood pressure at the higher dose of Pb was observed. In the newborn beagles, intra venous administration of Pb lowered blood pressure without altering resting CBF [22], However, in contrast to the present study where CBF was evaluated during the first 60 min after drug injection, Goddard-Finegold et al. [22] measured CBF 24-48 h after drug administration. Regional blood flow to cere brum, thalamus, and brain stem decreased significantly by 8-15% 15 min after drug injection with return to baseline thereafter. In the high Pb gorup, Pb arterial plasma concentrations were above the therapeutic range usually considered anticonvulsant in newborn humans. With this dose and plasma concentrations, 15 min after injection Pb low ered CBF progressively and produced a signif icant decrease at 30 min but returned to base line after 60 min. A comparison with the con trol group showed a significant variation in the PCO2 values. These changes in PCO2 val ues may have affected the results of cerebral determinations as in the therapeutic group.
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limited to the anesthetic barbiturates. The major effect is to depress neuronal function, which results in a decrease in CMR02 with a concomitant decrease in CBF [15, 17], The metabolic-suppressant effect has been used to provide a degree of protection for the brain in the event of transient incomplete ischemia or hypoxia [17], Other hypotheses for the protec tive actions of barbiturates include a decrease in catecholamine release [18] and antioxidant effects by scavenging free radicals [19]. How ever, the free radical scavenging is probably not an important mechanism of protection [17], Anesthesia induces perturbations in CBF and metabolism [20], and the cerebral metabolic and vascular effects of an anes thetic depend on their individual functional effects. We studied the effect of Pb on CBF in awake newborn piglets and found that thera peutic doses of phénobarbital produced plasma concentrations considered thera peutic in newborn humans [21] and also caused a transient reduction in CBF 15 min after drug injection with return to the baseline after 30 min. Fifteen and 60 min after Pb injection, the PCCF values were significantly altered probably because of a depressed respi ratory function due to barbiturates; however, barbiturates do not interfere with CCb reac tivity or autoregulation [20]. Moreover, these changes in carbon dioxide tension may have attenuated the direct reduction of CBF by Pb.
Table 5. Early studies on pre- and postnatal Pb prophylaxis of periventricular and intraventricular hemor rhage in neonates Authors
Ref. No.
Donn et al.
n
60
Criteria of inclusion
Time h
BW < 1,500 g
< 6
Dose mg/kg
Level mg/1
Time course days
20
20-30
7
10-26
One dose
20 l.m., ì.v.
14-27
One dose
2X10
12-26
6
(5)
Morgan et al.
2
60
BW < 1,250 g or BW 1,250-1,500g+MV
1-22
l.m.
Whitelaw et al.
5
60
BW < 1,500 g or GA < 31 weeks
Dev Pharmacol Ther 1992;19:10-18
Developmental Pharmacology and Perinatal Research Unit, McGill University-Montreal Children’s Hospital Research Institute, Montreal, Canada
KeyWords Phénobarbital Cerebral blood flow Anticonvulsants Newborn
Presented in part at the 2nd European Workshop on Neonatology. Klingenthal. France. June 1991.
Effects of Phénobarbital on Cerebral Blood Flow in the Newborn Piglet
Abstract To determine the neonatal cerebrovascular effect of a thera peutic dose and a high dose of phénobarbital (Pb), the effect of Pb on cerebral blood flow (CBF) and total brain oxygen con sumption (CMR02) was studied in three groups of awake newborn piglets (aged 1-3.5 days). Group I (control n = 9) received normal saline solution, group II (n = 9) received a therapeutic dose of Pb (15 mg/kg i.v.) and group III (n = 9) received a high Pb dose (45 mg/kg i.v.). Four CBF measure ments per piglet using radioactive microspheres (141 Ce, 85Cr, 95Nb, 46Sc), arterial blood gases, CU content, hematocrit and plasma glucose were obtained at 0, 15, 30, 60 min after saline or Pb injections. In all groups, pH, PaCb, PaCC>2, blood pres sure, heart rate, temperature and plasma glucose remained unchanged excepta 14% decrease (p < 0.01) in blood pressure and an increase (p < 0.05) in PaCC>2, 60 min after drug injec tion in groups II and III. Total CBF in group II decreased by 14% (p < 0.05) 15 min after drug injection and was signifi cantly lower (p < 0.05) than control (group I) but returned to baseline after 30 min. High Pb dose progressively lowered CBF by 11 % 15 min after drug injection and produced a sig nificant decrease by 20% (p < 0.01) 30 min after drug injec tion with return to baseline after 60 min. Similar effects were noted in different brain regions (cerebrum and thalamus). CMR02 remained unchanged in the control group; however, it was decreased by 35% (< 0.01 p > 0.05) 15 min after drug injection and returned to baseline after 60 min. In group III, high Pb dose lowered CMR02 by 31 % 30 min (p = 0.02) after drug injection. Data indicate that Pb exerts a minimal but transient dose-dependent effect on CBF and CMR02.
Emmanuel Scalais, MD Department of Pediatrics. Pediatric Neurology Entité Hospitalière CH St-Joseph-EspéranceRocourt Clinique St-Vincent, rue Fr. Lefèbvre. 207 B-4000 Liège (Rocourt) (Belgium)
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Emmanuel Scalais Kay Beharry Apostolos Papageorgiou Michel Bureau Jacob V. Aranda
© 1992 S. Karger AG. Basel 0379-8305/92/ 0191 —0010$2.7 5/0
Materials and Methods Twenty-seven male Yorkshire farm-bred piglets, aged 1-3.5 days and weighing from 0.780 to 1.400 kg, were studied. They were divided into three groups: group I (n = 9) received a placebo (saline solution) to serve as control; group II (n = 9) received a therapeutic dose of Pb (15 mg/kg i.v.), and group III (n = 9) received a high dose of Pb (45 mg/kg i.v.). All piglets were anesthetized with (0.6-0.9%) halo thane for insertion of polyethylene catheter (umbilical catheter size 3.5 mm ARGYLE Division of Sherwood Medical, St. Louis, Mo.) into the abdominal aorta via the right femoral, into the internal jugular vein and into the left ventricle via the right axillary artery. The ventricular location of the catheter for microspheres infusion was identified by pressure tracing using a strain gauge transducer attached to a Beckman Re corder (Grass Model 7 Polygraph). The location of the catheter tip was confirmed at postmortem in all ani mals. The catheters were then flushed with heparin
ized physiological saline solution (50 U/ml). All proce dures were performed under a radiant warmer with control of temperature. When all the surgical proce dures were accomplished, halothane was withdrawn and the incisions were closed. The mean time of anes thesia was 22.5 min (range 15-35). The animals were allowed to recover from anesthesia for at least 3.5 h before the experiments were initiated. The following physiological measurements were made in order to monitor postoperative recovery: body temperature, respiratory rate, suction reflex, plasma glucose concentration and arterial blood gases [pH, arterial oxygen tension (PO2), and arterial carbon dioxide tension (PC02)]. Four measurements of CBF were performed in each study: during the baseline period and at 15, 30, and 60 min after Pb or saline solution injection. After the first blood flow determi nation, the drug was injected for 5 min. Prior to each blood flow measurement, arterial blood gases, hemato crit, heart rate, mean systemic arterial blood pressure, arterial and venous oxygen content, and plasma glu cose concentration were determined. Arterial PaO?, PaCCF and pH were measured using an IL Blood gas machine (Radiometer, Copenhagen). Arterial and in ternal jugular oxygen content was measured with an TL 282 Co-oximeter’. Arterial plasma Pb levels were determined prior to and after Pb administration in group II and III and only during the baseline period in group I. CBF was measured by radionuclide-labelled microspheres [15, New England Nuclear, Boston, Mass.] as described by Heymann et al. [16]. Micro spheres labelled with 141Ce, 85Sr, 95Nb, 46Sc were used. The isotope sequence was assigned at random for the blood flow determination. At each blood flow determi nation, approximately 3 X 105 microspheres, sus pended and continuously agitated in 0.5 ml of a solu tion of 10% tween were administered within 30 s into the left ventricle and flushed with 2 ml of saline solu tion for a total of 70 s. A reference sample of blood from the femoral artery was removed continuously beginning 10 s before the injection of microspheres at a withdrawal rate of 1.2 ml/min using a Harvard with drawal pump (Harvard Apparatus). Blood samples were replaced after each blood flow measurement with blood from a donor piglet of the same litter. At the end of the experiments, the animal was killed with an over dose of Pb. The brain was divided into sections repre senting frontal, occipital, parieto temporal lobes, thala mus, cerebellum, brain stem (from the superior colli culus to the spinal cord) and all the organs were weighed and placed in counting vials. Organ radioac tivity was measured by a y-spectrometer (Beckman, Calif.). Counting window widths were selected to give
11
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Phénobarbital (Pb) has been used for many years to treat neonatal seizures. It has also been used for the possible prevention of intra ventricular hemorrhage (IVH). But its effi cacy in decreasing the occurrence of IVH par ticularly when given postnatally remains a matter of debate [1-9]. Pb has been shown to attenuate systemic hemodynamic changes due to stress [10], to prevent IVH secondary to rapid systemic blood pressure changes in newborn beagle puppies [11] and to attenuate cerebral blood flow (CBF) increases during hypertension induced by phenylephrine in newborn beagles [12] or during seizures [13]. Suggestions have been made to use Pb monotherapy at higher dose before adding a second drug in the treatment of neonatal sei zure [14]. Anesthetic doses of Pb decrease CBF and total brain oxygen consumption (CMR02) [15] and Pb decreases CBF in ma ture animals and in adults under the influence of anesthesia. We, therefore, tested the hy pothesis that Pb exerts a dose-dependent ef fect on CBF and metabolism during the awake state.
Table 1. Arterial blood gas variables, systemic mean arterial blood pressure, heart rate, hematocrit, tempera ture, and plasma glucose at each blood flow determination
pH
PO2, Torr
PCO2, Torr
Control (n = 9), min postplacebo
Therapeutic dose (n = 9), min postdrug
baseline
baseline
15
30
7.44 ±0.02
7.45 ±0.01
7.44
7.44
±0.01
±0.02
73.8 ±5.1
76.1 ±4.8
76.3 ±3.4
71.6 ±4.9
34.2
32.6 ±1.5
32.3 ±1.4
31.8
±1.2
Pressure
Heart rate beats/min Hematocrit, %
60
15
30
60
7.42
7.41
±0.02
±0.02
7.43 ±0.01
7.40 ±0.03
69.0 ±3.1
68.3 ±2.9
69.2 ±1.9
69.0 ±69
±1.6
35.3 ±1.4
36.5 ± 1.5+’*
±1.1
38.0 ± 1.9+-*
56.2 ±2.4
57.0 ±2.4
±1.8
51.6 ±2.4
51.6 ±2.4
47.4 ±2.5**
177 ±7
146
152
150
161
±8
±8
±10
29.8 ±1.6
32.4 ±3.2
58.4
56.0
±2.1
±2.6
167
178
171
±8
±8
±20
30.0 ±1.4
Temperature, °C
Plasma glucose levels, ml/1
38.6
55.2
38.4 ±0.2
±0.2
38.6 ±0.7
38.6 ±0.3
38.3 ±0.1
4.8 ±0.5
4.7 ±0.7
4.5 ±0.5
5.1 ±0.3
3.8 ±0.4
Mean ± SEM. + p * ±4.9
22.8
22.0
21.8
±1.7
±1.5
±1.4
15
30
60
49.6 ±2.7
p < 0.01, compared to baseline; * p < 0.05, compared to control.
Scalai s/Beharry/Papageorgiou/Bureau/ Aranda
Effects of Phénobarbital on Cerebral Blood Flow
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base- 15 line
Therapeutic dose (n = 9) min postdrug
t test and an analysis of variance. Changes in CBF within the groups were also analyzed for each flow measurement after the drug or placebo treatment and compared to the control predrug values.
baseline
15
30
60
7.44 ±0.01
±0.02
7.44
7.45
±0.01
±0.01
66.5 ±3.3
65.5
69.2
±2.1
±2.8
36.6 ±1.7
36.7
38.5
±2.8
±0.8*
±1.6**
55.8 ±2.3
59.2 ±2.9
58.1 ±3.4
56.3 ±3.0
182 ±14
194 ±11
190 ±15
196 ±4
29.1 ±1.9
7.40
68.1 ±3.0 39.4
28.1
38.9 ±0.1
38.7
38.6
38.8
±0.1
±0.1
±0.2
4.8 ±0.3
5.1 ±0.5
4.4 ±0.3
4.6 ±0.3
maximum efficiency as well as good separation for each of the isotopes. Although a relatively narrow range was chosen for each isotope, perfect separations of the different isotopes could not be achieved and crossover was corrected for by resolving simultaneous equations. Organ blood flow was calculated from the equation: flow =
organ radioactivity X reference sample radioactivity reference sample withdrawal rate (ml/min)
Blood flow was expressed as ml/min/100 g.
Data Analysis CBF values from the Pb group treated were com pared to the control placebo group using a Student
Results Table 1 shows the arterial blood gas vari ables, systemic mean arterial blood pressure, heart rate, hematocrit, temperature and se rum glucose data measured in the three groups immediately before each cerebral blood flow determination. The pH and the PO2 did not change significantly in the three groups throughout the study. Intragroup vari ation in PCO2 was noted. In the control group, there was a gradual decrease in the PCO2. In the therapeutic dose group, the PCO2 increased significantly by 3-7% (p < 0.05) 15 and 60 min after drug injection and was significantly higher than the control group (p < 0.05). In the high Pb group, there was a gradual increase in PCO2 (7%) which was significantly higher than the control group 30 min (p < 0.05) and 60 min (p < 0.01) after drug injection. In all groups, blood pressure, heart rate, hematocrit, temperature and plasma glucose levels remained stable except a 14% decrease (p < 0.01) in blood pressure 60 min after drug injection. Table 2 shows total brain blood flow and Pb plasma concentrations in the three groups. Plasma Pb concentrations were 22.0 pg/ml in the therapeutic dose group and 50 (ig/ml in the high Pb dose group. Total CBF (TCBF) remained stable in the control group through out the study. However, in the therapeutic group, TCBF decreased significantly (p < 0.05) by 14% 15 min after drug injection, was significantly (p < 0.05) lower than the control group and returned to baseline after 30 min. High Pb dose lowered progressively TCBF by 11% 15 min after drug injection and pro-
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High dose (n = 9), min postdrug
Table 3. TCBF and regional CBF as a percentage of change from time 0 Control (n = 9) min postplacebo
Total brain
7.4
30 3.3
±11.0
Cerebrum
9.8 ±13.7
2.8
Thalamus
2.0 ±5.4
5.1 ±7.2
Brain Stem
1.5 ±7.1
2.2
6.3 ±7.1
7.5 ±9.0
Cerebellum
Mean ± SEM. + p < 0.05,
High dose (n = 9) min postdrug
15
60
60
15
30
60
±3.3
-14.0++ ±4.7 ++
-5.3 ±4.5
3.7 ±5.2
-11.5 ±6.3
0.7 ±3.5
-14.6 ±5.2
-6.7 ±5.1
2.9 ±6.3
-12.0
1.9 ±4.6
-15.1 ±5.5+-*
-5.2 ±5.2
3.3 ±4.8
-12.9
-20.4
-12.9
-4.9
4.4 ±5.2
-9.3 ±9.9
-11.6 ±6.7
0.5 ±15.6
6.8
-13.8
±6.2
±6.2
3.8 ±13.7
1.1
±5.9
±49+,* ±5i
3.6 ±3.9
-8.1 ±5.6
3.3 ±4.6
8.1
p < 0.01, compared to baseline; * p < 0.05,
duced a significant decrease by 20% (p < 0.01) 30 min after drug injection with return to baseline values 60 min afterwards. Table 3 summarizes the total and regional CBF to cerebrum, cerebellum, thalamus, and brain stem as a percentage of change from time 0. In the control group, the total and regional CBF remained stable. In the thera peutic Pb group, there was a significant de crease of 8-15% in TCBF and regional CBF for cerebrum, thalamus, and brain stem (p < 0.05) 15 min after drug injection with return to baseline after 30 min. This reduction was statistically significant (p < 0.05) in compar ison with control group (thalamus, brain stem). In the high Pb-treated group, there was a decrease of 20-23% in TCBF and regional CBF to cerebrum and thalamus (p 0.05; ** p = 0.02, versus control.
Sixty minutes after administration of the ther apeutic dose of Pb the mean systemic blood pressure was significantly reduced. But CBF was unchanged at that time suggesting that Pb does not alter autoregulation in the physiolog ical range of blood pressure. These changes in blood pressure at the end of the experiment are unclear and no varia tion in blood pressure at the higher dose of Pb was observed. In the newborn beagles, intra venous administration of Pb lowered blood pressure without altering resting CBF [22], However, in contrast to the present study where CBF was evaluated during the first 60 min after drug injection, Goddard-Finegold et al. [22] measured CBF 24-48 h after drug administration. Regional blood flow to cere brum, thalamus, and brain stem decreased significantly by 8-15% 15 min after drug injection with return to baseline thereafter. In the high Pb gorup, Pb arterial plasma concentrations were above the therapeutic range usually considered anticonvulsant in newborn humans. With this dose and plasma concentrations, 15 min after injection Pb low ered CBF progressively and produced a signif icant decrease at 30 min but returned to base line after 60 min. A comparison with the con trol group showed a significant variation in the PCO2 values. These changes in PCO2 val ues may have affected the results of cerebral determinations as in the therapeutic group.
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limited to the anesthetic barbiturates. The major effect is to depress neuronal function, which results in a decrease in CMR02 with a concomitant decrease in CBF [15, 17], The metabolic-suppressant effect has been used to provide a degree of protection for the brain in the event of transient incomplete ischemia or hypoxia [17], Other hypotheses for the protec tive actions of barbiturates include a decrease in catecholamine release [18] and antioxidant effects by scavenging free radicals [19]. How ever, the free radical scavenging is probably not an important mechanism of protection [17], Anesthesia induces perturbations in CBF and metabolism [20], and the cerebral metabolic and vascular effects of an anes thetic depend on their individual functional effects. We studied the effect of Pb on CBF in awake newborn piglets and found that thera peutic doses of phénobarbital produced plasma concentrations considered thera peutic in newborn humans [21] and also caused a transient reduction in CBF 15 min after drug injection with return to the baseline after 30 min. Fifteen and 60 min after Pb injection, the PCCF values were significantly altered probably because of a depressed respi ratory function due to barbiturates; however, barbiturates do not interfere with CCb reac tivity or autoregulation [20]. Moreover, these changes in carbon dioxide tension may have attenuated the direct reduction of CBF by Pb.
Table 5. Early studies on pre- and postnatal Pb prophylaxis of periventricular and intraventricular hemor rhage in neonates Authors
Ref. No.
Donn et al.
n
60
Criteria of inclusion
Time h
BW < 1,500 g
< 6
Dose mg/kg
Level mg/1
Time course days
20
20-30
7
10-26
One dose
20 l.m., ì.v.
14-27
One dose
2X10
12-26
6
(5)
Morgan et al.
2
60
BW < 1,250 g or BW 1,250-1,500g+MV
1-22
l.m.
Whitelaw et al.
5
60
BW < 1,500 g or GA < 31 weeks
