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Propofol administration to the maternal-fetal unit improved fetal EEG and influenced cerebral apoptotic pathway in preterm lambs suffering from severe asphyxia.

Seehase M, Jennekens W, Zwanenburg A, Andriessen P, Collins JJ, Kuypers E, Zimmermann LJ, Vles JSh, Gavilanes AW, Kramer BW - Mol Cell Pediatr (2015)

Bottom Line: UCO resulted in global asphyxia and cardiac arrest.Propofol increased levels of anti-apoptotic B-cell lymphoma-extra large (Bcl-xL) and phosphorylated STAT-3 and reduced the release of cytochrome c from the mitochondria and the protein levels of activated cysteinyl aspartate-specific protease (caspase)-3, -9, and N-methyl-d-aspartate (NMDA) receptor.The underlying mechanism is probably the reduction of glutamate-induced cytotoxicity by down-regulation of NMDA receptors and an inhibition of the mitochondrial apoptotic pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Paediatrics, Maastricht University Medical Center, P. Debyelaan 25, 6202 AZ, Maastricht, The Netherlands. matthias.seehase@med.uni-goettingen.de.

ABSTRACT

Background: Term and near-term infants are at high risk of developing brain injury and life-long disability if they have suffered from severe perinatal asphyxia. We hypothesized that propofol administration to the maternal-fetal unit can diminish cerebral injury in term and near-term infant fetuses in states of progressive severe asphyxia.

Methods: Forty-four late preterm lambs underwent total umbilical cord occlusion (UCO) or sham treatment in utero. UCO resulted in global asphyxia and cardiac arrest. After emergency cesarean section under either maternal propofol or isoflurane anesthesia, the fetuses were resuscitated and subsequently anesthetized the same way as their mothers.

Results: Asphyctic lambs receiving isoflurane showed a significant increase of total and low-frequency spectral power in bursts indicating seizure activity and more burst-suppression with a marked increase of interburst interval length during UCO. Asphyctic lambs receiving propofol showed less EEG changes. Propofol increased levels of anti-apoptotic B-cell lymphoma-extra large (Bcl-xL) and phosphorylated STAT-3 and reduced the release of cytochrome c from the mitochondria and the protein levels of activated cysteinyl aspartate-specific protease (caspase)-3, -9, and N-methyl-d-aspartate (NMDA) receptor.

Conclusions: Improvement of fetal EEG during and after severe asphyxia could be achieved by propofol treatment of the ovine maternal-fetal unit. The underlying mechanism is probably the reduction of glutamate-induced cytotoxicity by down-regulation of NMDA receptors and an inhibition of the mitochondrial apoptotic pathway.

No MeSH data available.


Related in: MedlinePlus

Study design and time course of experiments. Lambs were born at 89% of gestation. The ewes carrying the gestational age control group were euthanized and their offspring was delivered by cesarean section and subsequently euthanized. The ewes of the other groups underwent the cesarean section while being sedated with the same anesthetic as their offspring later on intensive care unit. Two groups were exposed to an average time of total umbilical cord occlusion (UCO) of 11 min. The cutoff for the occlusion was a MABP below 30 mmHg for exactly 2 min. This protocol always led to severe bradycardia (HR < 30/min) or even cardiac arrest.
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Fig1: Study design and time course of experiments. Lambs were born at 89% of gestation. The ewes carrying the gestational age control group were euthanized and their offspring was delivered by cesarean section and subsequently euthanized. The ewes of the other groups underwent the cesarean section while being sedated with the same anesthetic as their offspring later on intensive care unit. Two groups were exposed to an average time of total umbilical cord occlusion (UCO) of 11 min. The cutoff for the occlusion was a MABP below 30 mmHg for exactly 2 min. This protocol always led to severe bradycardia (HR < 30/min) or even cardiac arrest.

Mentions: We used the same experimental protocol as published previously [12]. In brief, the pregnant ewes were intubated and general anesthesia was maintained with isoflurane (1% to 2%) or propofol (25 mg/kg/h) during the cesarean section. Both anesthesia types were supplemented by continuous remifentanil infusion (3 μg/kg/min). After a lower midline incision, the fetus was carefully extracted through a small incision of the uterus. The fetus was instrumented with an endotracheal tube and an arterial catheter in the femoral and umbilical artery and a venous catheter in the external jugular vein. The umbilical cord was gently extracted through the incision of the uterus, and a vascular occluder (OC16HD, 16 mm, IN VIVO METRIC, Healdsburg, California, USA) was placed around the umbilical cord. The umbilical cord was occluded until the mean arterial blood pressure (MABP) dropped below 30 mmHg. From that time point onwards, the occlusion was continued for exactly 2 min (Figure 1). After these 2 min, occlusion was stopped regardless of whether the lambs suffered from bradycardia only or from cardiac arrest. After the end of the occlusion, the lambs stayed in utero for 20 s experiencing reperfusion. Then, they were delivered, the umbilical cord was cut, and resuscitation was started while the fetus was brought to an open, heated incubator (IW930 Series CosyCot™ Infant Warmer, Fisher & Paykel Healthcare). The incubator maintained the lamb’s body temperature of 38.5°C. When the lambs were delivered and when their umbilical cord was cut, they were initially ventilated with a resuscitator bag via the endotracheal tube with room air (60/min). Heart massage was started with around 120 compressions per minute. The fetus was brought to the incubator with one medical operator doing the heart massage while the other one was ventilating the lamb. After arrival at the incubator, the lamb was connected to a ventilator Servo 900C (Siemens-Elema, Solna, Sweden), put into plastic foil to prevent cooling effects, and adrenaline was administered via the venous catheter in augmented doses from 30 μg, to 60 μg, to 0.1 mg. In addition, a volume bolus of ringer lactate of 10 ml/kg BW was administered after the first shot of adrenaline. The lambs were administered with pressure-regulated ventilation using a ventilator with initial settings as follows: FiO2 = 1, positive end-expiratory pressure, 5 cmH20, peak inspiratory pressure 30 cmH20, frequency 60/min, and I:E 1:2. Thereafter, inspiratory pressure was adjusted to achieve a targeted volume of 3.0 L/min and a PaCO2 of 35 to 45 mm Hg. The ventilation and sedation was continued for 8 h after delivery. The sedation was maintained either with isoflurane (0.5% to 1.0%) or propofol (1 to 3 mg/kg/h) and supplemented with remifentanil (3 μg/kg/min) in both groups. All cord-occluded lambs developed a spontaneous HR (>150/min) and a sufficient MABP (>50 mmHg) within 10 min after starting resuscitation with the exception of two lambs, which were excluded from the study.Figure 1


Propofol administration to the maternal-fetal unit improved fetal EEG and influenced cerebral apoptotic pathway in preterm lambs suffering from severe asphyxia.

Seehase M, Jennekens W, Zwanenburg A, Andriessen P, Collins JJ, Kuypers E, Zimmermann LJ, Vles JSh, Gavilanes AW, Kramer BW - Mol Cell Pediatr (2015)

Study design and time course of experiments. Lambs were born at 89% of gestation. The ewes carrying the gestational age control group were euthanized and their offspring was delivered by cesarean section and subsequently euthanized. The ewes of the other groups underwent the cesarean section while being sedated with the same anesthetic as their offspring later on intensive care unit. Two groups were exposed to an average time of total umbilical cord occlusion (UCO) of 11 min. The cutoff for the occlusion was a MABP below 30 mmHg for exactly 2 min. This protocol always led to severe bradycardia (HR < 30/min) or even cardiac arrest.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4530565&req=5

Fig1: Study design and time course of experiments. Lambs were born at 89% of gestation. The ewes carrying the gestational age control group were euthanized and their offspring was delivered by cesarean section and subsequently euthanized. The ewes of the other groups underwent the cesarean section while being sedated with the same anesthetic as their offspring later on intensive care unit. Two groups were exposed to an average time of total umbilical cord occlusion (UCO) of 11 min. The cutoff for the occlusion was a MABP below 30 mmHg for exactly 2 min. This protocol always led to severe bradycardia (HR < 30/min) or even cardiac arrest.
Mentions: We used the same experimental protocol as published previously [12]. In brief, the pregnant ewes were intubated and general anesthesia was maintained with isoflurane (1% to 2%) or propofol (25 mg/kg/h) during the cesarean section. Both anesthesia types were supplemented by continuous remifentanil infusion (3 μg/kg/min). After a lower midline incision, the fetus was carefully extracted through a small incision of the uterus. The fetus was instrumented with an endotracheal tube and an arterial catheter in the femoral and umbilical artery and a venous catheter in the external jugular vein. The umbilical cord was gently extracted through the incision of the uterus, and a vascular occluder (OC16HD, 16 mm, IN VIVO METRIC, Healdsburg, California, USA) was placed around the umbilical cord. The umbilical cord was occluded until the mean arterial blood pressure (MABP) dropped below 30 mmHg. From that time point onwards, the occlusion was continued for exactly 2 min (Figure 1). After these 2 min, occlusion was stopped regardless of whether the lambs suffered from bradycardia only or from cardiac arrest. After the end of the occlusion, the lambs stayed in utero for 20 s experiencing reperfusion. Then, they were delivered, the umbilical cord was cut, and resuscitation was started while the fetus was brought to an open, heated incubator (IW930 Series CosyCot™ Infant Warmer, Fisher & Paykel Healthcare). The incubator maintained the lamb’s body temperature of 38.5°C. When the lambs were delivered and when their umbilical cord was cut, they were initially ventilated with a resuscitator bag via the endotracheal tube with room air (60/min). Heart massage was started with around 120 compressions per minute. The fetus was brought to the incubator with one medical operator doing the heart massage while the other one was ventilating the lamb. After arrival at the incubator, the lamb was connected to a ventilator Servo 900C (Siemens-Elema, Solna, Sweden), put into plastic foil to prevent cooling effects, and adrenaline was administered via the venous catheter in augmented doses from 30 μg, to 60 μg, to 0.1 mg. In addition, a volume bolus of ringer lactate of 10 ml/kg BW was administered after the first shot of adrenaline. The lambs were administered with pressure-regulated ventilation using a ventilator with initial settings as follows: FiO2 = 1, positive end-expiratory pressure, 5 cmH20, peak inspiratory pressure 30 cmH20, frequency 60/min, and I:E 1:2. Thereafter, inspiratory pressure was adjusted to achieve a targeted volume of 3.0 L/min and a PaCO2 of 35 to 45 mm Hg. The ventilation and sedation was continued for 8 h after delivery. The sedation was maintained either with isoflurane (0.5% to 1.0%) or propofol (1 to 3 mg/kg/h) and supplemented with remifentanil (3 μg/kg/min) in both groups. All cord-occluded lambs developed a spontaneous HR (>150/min) and a sufficient MABP (>50 mmHg) within 10 min after starting resuscitation with the exception of two lambs, which were excluded from the study.Figure 1

Bottom Line: UCO resulted in global asphyxia and cardiac arrest.Propofol increased levels of anti-apoptotic B-cell lymphoma-extra large (Bcl-xL) and phosphorylated STAT-3 and reduced the release of cytochrome c from the mitochondria and the protein levels of activated cysteinyl aspartate-specific protease (caspase)-3, -9, and N-methyl-d-aspartate (NMDA) receptor.The underlying mechanism is probably the reduction of glutamate-induced cytotoxicity by down-regulation of NMDA receptors and an inhibition of the mitochondrial apoptotic pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Paediatrics, Maastricht University Medical Center, P. Debyelaan 25, 6202 AZ, Maastricht, The Netherlands. matthias.seehase@med.uni-goettingen.de.

ABSTRACT

Background: Term and near-term infants are at high risk of developing brain injury and life-long disability if they have suffered from severe perinatal asphyxia. We hypothesized that propofol administration to the maternal-fetal unit can diminish cerebral injury in term and near-term infant fetuses in states of progressive severe asphyxia.

Methods: Forty-four late preterm lambs underwent total umbilical cord occlusion (UCO) or sham treatment in utero. UCO resulted in global asphyxia and cardiac arrest. After emergency cesarean section under either maternal propofol or isoflurane anesthesia, the fetuses were resuscitated and subsequently anesthetized the same way as their mothers.

Results: Asphyctic lambs receiving isoflurane showed a significant increase of total and low-frequency spectral power in bursts indicating seizure activity and more burst-suppression with a marked increase of interburst interval length during UCO. Asphyctic lambs receiving propofol showed less EEG changes. Propofol increased levels of anti-apoptotic B-cell lymphoma-extra large (Bcl-xL) and phosphorylated STAT-3 and reduced the release of cytochrome c from the mitochondria and the protein levels of activated cysteinyl aspartate-specific protease (caspase)-3, -9, and N-methyl-d-aspartate (NMDA) receptor.

Conclusions: Improvement of fetal EEG during and after severe asphyxia could be achieved by propofol treatment of the ovine maternal-fetal unit. The underlying mechanism is probably the reduction of glutamate-induced cytotoxicity by down-regulation of NMDA receptors and an inhibition of the mitochondrial apoptotic pathway.

No MeSH data available.


Related in: MedlinePlus