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Maternal and fetal effects of propofol anaesthesia in the pregnant ewe
The Veterinary Journal The Veterinary Journal 170 (2005) 77–83 www.elsevier.com/locate/tvjl
Maternal and fetal effects of propofol anaesthesia in the pregnant ewe A. Andaluz *, O. Trasserras, F. Garcı´a
*
Departament de Medicina I Cirurgia Animals, Facultat de Veterina`ria, edifici V, Universitat Auto`noma de, Barcelona, 08193 Bellaterra, Spain
Abstract The objective of this study was to determine the effects of propofol (PRF) on maternal and fetal cardiopulmonary function during the last trimester of pregnancy. Six pregnant 2–3 year-old Ripollesa sheep, each weighing 78 ± 8 kg were used in the study and prepared by placing catheters in the maternal jugular vein and carotid artery. A catheter was also placed in the fetal femoral artery. Twenty-four hours later the sheep were anaesthetized with PRF (6 mg/kg intravenous (IV) followed by a continuous infusion at a rate of 0.4 mg/kg/min for 60 min) and cardiopulmonary data collected. Further data were collected for 105 min following termination of the infusion. The maternal mean arterial pressure (MAP) and diastolic arterial pressure (DAP) were significantly decreased (P < 0.05) during the first 15 min of the infusion period, while the maternal pH was also significantly decreased. Maternal PaCO2 and PaO2 were significantly increased throughout the total infusion period. It was further observed that the fetal pH decreased significantly, throughout the infusion period, whereas the fetal MAP, DAP and PaCO2 were significantly increased during the first 15 min of the infusion, after which time all parameters returned to control values. No differences in either maternal or fetal parameters were observed between control and recovery times. Ó 2004 Elsevier Ltd. All rights reserved. Keywords: Propofol; Infusion; Sheep; Cardiovascular effects; Fetus
1. Introduction Propofol (PRF) is an injectable anaesthetic agent that is widely used both for the induction and maintenance of general anaesthesia. In human anaesthesia, it has gained popularity because it produces a smooth induction and a rapid recovery, owing to its pharmacokinetic characteristics (Langley and Heel, 1988). It is a small lipophilic molecule which is rapidly metabolised, chiefly in the liver. Because of these characteristics, PRF has become a widely used anaesthetic agent in obstetrical anaesthesia (Valtonen et al., 1989). However, the effects of PRF on the fetus are unclear. In women undergoing caesarean section, PRF readily crosses the placenta and *
Corresponding authors. Tel./fax: +34 935811512. E-mail addresses: [email protected] (A. Andaluz), [email protected] (F. Garcı´a). 1090-0233/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tvjl.2004.02.006
neonatal depression may occur, although the significance of this depression is unknown (Bacon and Razis, 1994; Jauniaux et al., 1998). The most important effects of PRF are on the cardiovascular and respiratory systems. After an intravenous (IV) bolus administration, hypotension and a reduction in cardiac output may occur but heart rate usually remains unaffected. Apnoea can also occur with respiratory depression caused by a decrease in tidal volume and respiratory rate (Taylor et al., 1986; Thurmon et al., 1996; Grim et al., 2001). Pain on injection is common in humans but appears to be rare in small animals (Paddleford, 1999). Adverse neurological effects, such as convulsions and involuntary movements, have been described after PRF administration in humans (Cochran et al., 1996) and studies have indicated transitory signs of excitement in 8.1–11% of dogs and cats (Davies, 1991; Duke, 1995).
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Several studies have been performed to evaluate the pharmacokinetics and cardiovascular effects of PRF in sheep (Runciman et al., 1990; Correia et al., 1996; Lin et al., 1997). Moreover, pregnant ewes have been used as models for studies of placental transfer and fetal exposure to different anaesthetics such as lidocaine (Guay et al., 1992), remifentanil (Kan et al., 1998), halothane and isoflurane (Palahniuk and Shnider, 1974) and ketamine (Levinson et al., 1973). Alon et al. (1993) studied the effects of PRF in pregnant ewes and their fetuses during PRF infusion. They used a combination of PRF and a succinylcholine dose for the induction and nitrous oxide (N2O) during the experimental study. No adverse effects on maternal and fetal variables were found, with the exception of transient maternal bradycardia after succinylcholine administration. The authors attributed all adverse effects reported to succinylcholine use at induction, not to PRF. The objective of our study was to determine the effects of PRF on fetal and cardiopulmonary function during the last trimester of pregnancy in sheep.
2. Material and methods 2.1. Animals Six pregnant Ripollesa ewes, between days 105 and 135 of gestation were used. Their mean weight was 78.8 ± 8.09 kg and the ewes were between 2 and 3 years of age.
catheters were advanced and then sutured in place using silk. The incision was closed using reabsorbable sutures. The left jugular catheter was used for fluid and drug administration. The left carotid artery was used for blood sampling and recording of maternal blood pressure and heart rate. Through a hysterotomy incision, the fetal hindlimb was exposed and the femoral artery catheterised using a 16 G polypropylene catheter (Cavafix, B. Braun) for blood sampling and recording of fetal blood pressure and heart rate. The hind limb was replaced and 0.9% NaCl warmed solution was injected to replace the estimated amount of amniotic fluid lost during the surgical preparations. The placenta and the uterus were closed with an inverting pattern. The fetal catheter exited through the left side of the motherÕs flank and was protected using small plastic bags sutured to the abdominal wall. The ewesÕ temperature, heart rate, respiratory rate, end-tidal carbon dioxide, arterial blood pressure, pulse and electro cardiogram were monitored throughout surgery using a Datex Ohmeda Cardiocap II monitor. Cardiovascular variables of the fetuses were recorded once the fetal catheter had been placed in position. When the ewes had regained their reflexes, they were returned to their box for a minimum of 24 h. During this period, the dam and fetus venous and arterial catheters were flushed with heparinised saline (0.9% saline with 5 U heparin/mL) every 8 h to avoid clotting. The animals were checked every 3 h for signs of pain. Every 12 h, the animals received 0.01 mg/kg subcutaneously buprenorphine and the antibiotic cefalexine, 20 mg/kg IV, every 12 h.
2.2. Surgical procedure 2.3. Animal treatments The surgical procedure followed that reported by Capece et al. (2001) with some modification. Before anaesthesia, food was withheld from all the animals for 12 h but water was freely available until just before induction. The ewes were premedicated with 0.2 mg/kg IV midazolam (Dormicum, Roche Laboratories) and 0.01 mg/kg IV buprenorphine (Buprex, Schering-Plough Laboratories) using a catheter positioned in the right jugular vein. Fifteen minutes after tranquillisation, the animals were allowed to breathe spontaneously while inhaling 5% isofluorane in 100% oxygen, delivered by mask until anaesthesia was induced. The trachea was intubated with a 10 mm endotracheal tube, and anaesthesia maintained with isofluorane (vaporizer setting 2%) in 100% oxygen, at a flow rate of 25 mL/kg/min, though a semi-closed circular system. Throughout anaesthesia, 10 mL/kg/h of warmed Lactated RingerÕs solution was administered through the right jugular catheter. In each animal, a catheter was placed in the left jugular vein and a second in the left carotid artery. The
Following a stability period of 60 min, each ewe was positioned in right lateral recumbency. Maternal and fetal heart rate, arterial blood pressure and maternal pulse-oximetry and respiratory rate were recorded at 0, 5, 10, 15, 30, 45 and 60 min Arterial blood gases were determined at 30 min using an IRMA Blood Analysis System Series 2000 (Diametrics, Medical Inc.). At the end of the stabilizing period, a dose of 6 mg PRF/kg IV over 90 s was given, followed by an IV infusion of 0.4 mg PRF/kg/min for 1 h administered via the left jugular vein. The infusions were performed using a Medfusion 2010 Syringe Pump. PRF-Lipuro 1% supplied by Braun Medical (Spain). During the study period, the ewesÕ tracheas were intubated and 100% oxygen was administered at a flow rate of 25 mL/kg/h via the endotracheal tube. The cardiorespiratory parameters of the ewes and the fetuses were recorded at 5, 10, 15, 30, 45 and 60 min of the PRF infusion. Arterial blood gases, for both, ewes and fetuses, were determined at 15 and 45 min after starting
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the PRF infusion. Cardiopulmonary parameters were recorded 5, 10, 15, 30, 45, 60, 75, 90 and 105 min after the termination of the infusion. Arterial blood gases were collected at 15 and 60 min. The tracheas were extubated when the swallowing reflex returned (5.7 ± 1.2 min after the cessation of the PRF infusion). Throughout the experimental procedure, maintenance fluid therapy was administered using warmed Lactated RingerÕs solution at 10 mL/kg/h IV. At the end of the study all animals were euthanased using an IV dose of sodium pentobarbital.
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the effects of PRF reported in other studies (Robertson et al., 1992; Correia et al., 1996). All procedures were approved by the Ethical Commission of Animal and Human Experimentation (Spanish Government, Authorization Number DARP 2074) under the auspices of the Ethical Commission of the Autonomous University of Barcelona.
3. Results 3.1. Maternal cardiovascular variables
2.4. Statistical analysis Statistical Analysis was performed using SAS v8.0 software and validation of all parameters was undertaken to localise missing or incorrect values. The variable response was analysed using a mixed model for repeated measurements. The variable ‘‘time’’ was chosen as a fixed effect, in addition to the other variables specified in the model. When possible, an unstructured correlation matrix was used. In other cases an autoregressive structure was assumed. Cardiac variables, in both the mothers and fetuses were grouped in different periods; while all parameters registered during the control period were grouped in the same period. For the analysis, the infusions of PRF at 5, 10 and 15 min were grouped in period I1, and for those at 30, 45 and 60 min in the period I2. The parameters recorded during the recovery were grouped in two periods, period R1 at 5, 10 and 15 min and period R2 at 30, 45, 60, 75 and 90 min of recovery. These estimations were applied based on the duration of
During I1, maternal MAP and DAP decreased significantly (P < 0.05) in relation to the control values whereas in I2 these variables returned to control values. Maternal MAP and DAP remained at control values throughout the rest of the study and recovery period (Table 1). The maternal heart rate remained close to control values throughout the study (Table 1). 3.2. Maternal acid–base status, oxygenation, O2 saturation There were significant differences between controls at 15 and 45 min of the infusion for pH, pCO2 and pO2. There was a significant decrease in maternal mean pH, and a significant increase in maternal mean PaCO2 and PaO2 during the infusion period (Table 2) but during recovery all these parameters returned to control values. In the infusion period, the maternal mean HCO3 increased significantly at 45 min. There were significant
Table 1 Maternal cardiovascular and respiratory variables (mean values ± SD) Control
HR (beats/min) SAP (mmHg) DAP (mmHh) MAP (mmHg)
Infusion
146 ± 6 142 ± 3 101 ± 4 115 ± 3
Recovery
I1
I2
R1
R2
120 ± 12 107 ± 14 63 ± 5* 78 ± 5*
139 ± 11 117 ± 8 79 ± 9 93 ± 9
149 ± 6 138 ± 2 94 ± 5 115.1 ± 3
133 ± 4 138 ± 5 97 ± 7 113 ± 7
HR = heart rate, SAP = systolic arterial pressure, DAP = diastolic arterial pressure, MAP = mean arterial pressure. * Significant changes. Table 2 Maternal acid–base variables (mean values ± SD) Control
Infusion
Recovery
I1 pH PaCO2 (mmHg) PaO2 (mmHg) BEecf HCO3 (mEq/L) *
Significant changes.
7.44 ± 0.03 31.5 ± 7.3 93.5 ± 12.7 2.8 ± 1.0 21.4 ± 1.1
I2 *
7.23 ± 0.04 56.5 ± 8.0* 219.8 ± 12.7* 3.0 ± 1.2 23.9 ± 1.1
R1 *
7.19 ± 0.04 75.6 ± 8.8* 232.4 ± 13.9* 1.4 ± 1.2 26.7 ± 1.2*
7.52 ± 0.08 39.0 ± 16.5 94.4 ± 20.9 0.9 ± 2.0 21.4 ± 1.8
R2 7.46 ± 0.04 32.2 ± 8.8 96.0 ± 12.7 0.06 ± 1.2 23.6 ± 1.2
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Table 3 Fetal cardiovascular and respiratory variables (mean values ± SD)
HR (beats/min) SAP (mmHg) DAP (mmHh) MAP (mmHg)
Control
Infusion
Recovery
I1
I2
R1
R2
180 ± 9 75 ± 2 50 ± 3 61 ± 2
251 ± 2* 98 ± 8 62 ± 3* 77 ± 4*
222 ± 11 77 ± 3 53 ± 2 63 ± 2
225 ± 10 77 ± 3 55 ± 3 64 ± 2
215 ± 11 73 ± 3 53 ± 2 60 ± 2
HR = heart rate, SAP = systolic arterial pressure, DAP = diastolic arterial pressure, MAP = mean arterial pressure. * Significant changes. Table 4 Fetal acid–base variables (mean values ± SD) Control
pH PaCO2 (mmHg) PaO2 (mmHg) BEecf HCO3 (mEq/L) *
7.39 ± 0.04 47.1 ± 8.3 23.5 ± 4.6 3.2 ± 2.3 28.3 ± 2.0
Infusion
Recovery
I1
I2
R1
R2
7.18 ± 0.04* 70.7 ± 8.3* 49.6 ± 4.4 2.2 ± 2.3 26.1 ± 2.0
7.13 ± 0.04* 83.7 ± 9.0* 29.9 ± 7.0 2.2 ± 2.4 26.9 ± 2.1
7.42 ± 0.06 38.4 ± 16.3 20.2 ± 0.3 3.1 ± 3.2 27.6 ± 3.02
7.34 ± 0.04 49.2 ± 9.0 22.3 ± 8.0 1.1 ± 2.4 27.1 ± 2.1
Significant changes.
differences in maternal mean base excess between the recovery period and the infusion period although there were no significant differences when compared to the control values (Table 2). Maternal respiratory rate, pulse-oximetry and blood electrolyte concentration remained stable throughout the study. 3.3. Fetal cardiovascular variables Fetal MAP, DAP and heart rate increased significantly during I1 but remained close to the control values during I2. In the recovery period all cardiovascular parameters were normal (Table 3). 3.4. Fetal acid–base variables There was a significant decrease in pH and PaCO2 values compared to the control period at 15 and 45 min of infusion (Table 4). All other variables remained unchanged.
4. Discussion The anaesthetic and surgical techniques used were those described by Capece et al. (2002) with some minor modifications. Short-acting anaesthetic agents with a rapid metabolism were chosen, including midazolam and isoflurane, so that the anaesthetic requirements for the surgical procedures would have minimal effects on the fetus and the eweÕs recovery would be relatively safe and rapid (Thurmon et al., 1996; Paddleford, 1999).
We used the femoral artery instead of the carotid artery because it permitted less exposure of the fetus. Laparotomy was performed at a paramedial site to preserve the integrity of the mammary vessels. The PRF dosages used for the induction and maintenance of the anaesthesia and the times chosen for recording all the variables, were similar to those described in previous studies of non-pregnant ewes by Lin et al. (1997) and by Correia et al. (1996) and were considered adequate for the performance of the experimental procedures in our ewes. 4.1. Maternal findings The induction and maintenance of anaesthesia with PRF are associated with cardiovascular and respiratory depression. This depression is higher during induction, particularly, if PRF is administered rapidly (Grounds et al., 1985; Branson and Gross, 1994; Short and Bufalari, 1999). In the present study, it was observed that the maternal heart rate decreased during the infusion from 146.1 ± 6.8 beats/min to 120.8 ± 12.1 beats/min, however, these changes were not significant. The decrease in maternal MAP observed in our study did not differ from results previously obtained in both animal and human patients (Grounds et al., 1985; Short and Bufalari, 1999) undergoing PRF anaesthesia. Grounds et al. (1985) described a reduction in the arterial blood pressure of between 20% to 40% of preinduction values following IV administration in humans. Similar results have been obtained in human females undergoing caesarean section (Moore et al., 1989). Alon et al. (1993) studied the effects of PRF on maternal and fetal cardiovascular variables in pregnant
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ewes, using succinylcholine for the intubation of the animals and nitrous oxide (N2O) during the study period. In the study performed by Alon et al. (1993) a severe bradycardia and a slight decrease in the arterial blood pressure was observed and attributed to the administration of succinylcholine for intubation in the presence of PRF. The cardiovascular changes in animals given succinylcholine remain unclear. Succinylcholine may cause vagal or sympathomimetic effects depending on whether muscarinic or sympathetic receptors are activated (Klein, 1987). Cardiovascular changes in animals given succinylcholine are variable. Arterial blood pressure frequently increases, and both bradycardia and tachycardia have been observed following succinylcholine injection (Hildebrand, 1992; Thurmon et al., 1996). Furthermore, paralysis of the larynx is not necessary for successful intubation in sheep and its use is currently unacceptable because of the high risk of aspiration of regurgitated rumen contents if the intubation is not performed rapidly (Hildebrand, 1992; Carroll and Hartsfield, 1996). In the study performed by Alon et al. (1993), the cardiovascular effects of PRF would be masked by the use of succinylcholine. Nitrous oxide is infrequently used for ruminant anaesthesia since it accumulates in gas filled compartments and may promote tympany and hypoxaemia, especially during lateral or dorsal recumbency. The accumulation of gas in the sheepÕs rumen may increase arterial and pulmonary blood pressure. Lunn et al. (1977) studied the effects of N2O in bovines, observing that its use in concentrations >30% in unanaesthetized calves, resulted in a significant increases in cardiac output and in the mean aortic, pulmonary and right atrial pressures. Our results differed from those reported by Runciman et al. (1990) undertaken on non-pregnant ewes; who reported a significant increase in heart rate and MAP during PRF anaesthesia in sheep. Nevertheless, several studies, have reported the hypotensive effects of PRF after its administration (Correia et al., 1996). In the present study, the maternal acid–base status varied significantly from values obtained in the control period. It was observed that the maternal pH decreased significantly during the infusion time as a result of the increase in PaCO2. Respiratory depression has been widely described in both humans and animals undergoing PRF anaesthesia (Taylor et al., 1986; Thurmon et al., 1996). During the study period, the respiratory rate did not change significantly from the control period. However, three of the six ewes were apnoeic after the IV administration, a condition which lasted for 1.4 ± 1.1 min This transient period of apnoea following IV. PRF has previously been reported in sheep (Correia et al., 1996), dogs and cats (Smith et al., 1993; Thurmon et al., 1996) and in humans (Taylor et al., 1986).
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During the study period, the tracheas of all the animals were intubated and they received 100% oxygen, so that the PaO2 increased significantly during the infusion period until the recovery time when the tracheas were extubated and the administration of 100% oxygen ceased. The extubation time in our study (5.7 ± 1.2 min) was longer than that described by Correia et al. (1996) in non-pregnant ewes. However, our PRF dose was slightly higher and there was no-surgical stimulus, which may explain the prolongation of the extubation time. The cardiovascular and acid–base changes observed during PRF anaesthesia in pregnant ewes in our study, are similar to those described by Palahniuk and Shnider (1974) during halothane and isoflurane anaesthesia. However, the acid–base changes observed in our study were slight higher than those described by Palahniuk and Shnider (1974) for inhalational anaesthetics. 4.2. Fetal findings During the study period, fetal cardiovascular and acid–base status showed a significant variation from the control period values. The fetal arterial heart rate and arterial blood pressure, increased significantly during the infusion period I1 possibly reflecting a fetal response to maternal stress associated with the induction of anaesthesia and/or fetal distress caused by a reduction in the uterine blood flow. Although in the present study, the uterine blood flow was not monitored, the increase in fetal heart rate and arterial blood pressure as a result of fetal distress, was as described for other anaesthetic agents such as ketamine (Fisher and Paton, 1974). Alon et al. (1993) did not observe any change in the uterine blood flow during PRF anaesthesia in pregnant sheep but the use of N2O and succinylcholine may have interfered with the results obtained in their study. N2O diffuses rapidly across the placenta and may produce hypoxaemia in the fetus and newborn (Blechner et al., 1969). The PaO2 values recorded in AlonÕs study were, however, similar to those we recorded. Polvi et al. (1996), in a study performed in pregnant women at full term, showed that maternal and fetal central vascular resistance were decreased by 30% N2O inhalation. Since uterine blood flow is inversely proportional to uterine vascular resistance (Thurmon et al., 1996), the combination of different anaesthetics in the study performed by Alon et al. (1993) may have masked the real effects produced by PRF alone. In our study PRF only was used so there could be no interaction with other anaesthetic agents. The acidosis and the increase in fetal PaCO2 observed could be secondary to a rise in maternal PaCO2. This effect on the fetus may reflect a decrease in the uteroplacental perfusion and in uterine blood flow. The fetal acidosis found in our study was similar to that reported after an IV administration of several anaesthetic agents
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to a pregnant ewe (Palahniuk and Shnider, 1974; Levinson et al., 1973). These workers described a significant fetal acidosis during moderate and deep levels of anaesthesia (1.5 and 2.0 of the Minimum Alveolar Concentration (MAC) value respectively), using halothane and isoflurane; whereas Levinson et al. (1973) described a sight rise in fetal PaCO2 during ketamine anaesthesia. During the recovery period all of the fetal variables returned to control values. This rapid recovery from PRF anaesthesia has been described during caesarean section in human patients (Valtonen et al., 1989; Sanchez-Alcaraz et al., 1998). In these studies the blood gas analyses of neonates were within the normal range and the neonatal viability (assessed by Apgar Score), were well preserved. However, other authors have described evidence of neonatal depression due to PRF administration to the mother (Celleno et al., 1989; Gin et al., 1991). We conclude that PRF has no adverse effects on the pregnant ewe other than those described following its use in non-pregnant animals and humans or in pregnant ewes undergoing inhalational anaesthesia. However the effects of PRF on fetuses may be important in other circumstances, such as in prolonged infusion periods in the hypoxaemic fetus; in the fetus with cardiac disease or during a caesarean section.
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Maternal and fetal effects of propofol anaesthesia in the pregnant ewe A. Andaluz *, O. Trasserras, F. Garcı´a
*
Departament de Medicina I Cirurgia Animals, Facultat de Veterina`ria, edifici V, Universitat Auto`noma de, Barcelona, 08193 Bellaterra, Spain
Abstract The objective of this study was to determine the effects of propofol (PRF) on maternal and fetal cardiopulmonary function during the last trimester of pregnancy. Six pregnant 2–3 year-old Ripollesa sheep, each weighing 78 ± 8 kg were used in the study and prepared by placing catheters in the maternal jugular vein and carotid artery. A catheter was also placed in the fetal femoral artery. Twenty-four hours later the sheep were anaesthetized with PRF (6 mg/kg intravenous (IV) followed by a continuous infusion at a rate of 0.4 mg/kg/min for 60 min) and cardiopulmonary data collected. Further data were collected for 105 min following termination of the infusion. The maternal mean arterial pressure (MAP) and diastolic arterial pressure (DAP) were significantly decreased (P < 0.05) during the first 15 min of the infusion period, while the maternal pH was also significantly decreased. Maternal PaCO2 and PaO2 were significantly increased throughout the total infusion period. It was further observed that the fetal pH decreased significantly, throughout the infusion period, whereas the fetal MAP, DAP and PaCO2 were significantly increased during the first 15 min of the infusion, after which time all parameters returned to control values. No differences in either maternal or fetal parameters were observed between control and recovery times. Ó 2004 Elsevier Ltd. All rights reserved. Keywords: Propofol; Infusion; Sheep; Cardiovascular effects; Fetus
1. Introduction Propofol (PRF) is an injectable anaesthetic agent that is widely used both for the induction and maintenance of general anaesthesia. In human anaesthesia, it has gained popularity because it produces a smooth induction and a rapid recovery, owing to its pharmacokinetic characteristics (Langley and Heel, 1988). It is a small lipophilic molecule which is rapidly metabolised, chiefly in the liver. Because of these characteristics, PRF has become a widely used anaesthetic agent in obstetrical anaesthesia (Valtonen et al., 1989). However, the effects of PRF on the fetus are unclear. In women undergoing caesarean section, PRF readily crosses the placenta and *
Corresponding authors. Tel./fax: +34 935811512. E-mail addresses: [email protected] (A. Andaluz), [email protected] (F. Garcı´a). 1090-0233/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tvjl.2004.02.006
neonatal depression may occur, although the significance of this depression is unknown (Bacon and Razis, 1994; Jauniaux et al., 1998). The most important effects of PRF are on the cardiovascular and respiratory systems. After an intravenous (IV) bolus administration, hypotension and a reduction in cardiac output may occur but heart rate usually remains unaffected. Apnoea can also occur with respiratory depression caused by a decrease in tidal volume and respiratory rate (Taylor et al., 1986; Thurmon et al., 1996; Grim et al., 2001). Pain on injection is common in humans but appears to be rare in small animals (Paddleford, 1999). Adverse neurological effects, such as convulsions and involuntary movements, have been described after PRF administration in humans (Cochran et al., 1996) and studies have indicated transitory signs of excitement in 8.1–11% of dogs and cats (Davies, 1991; Duke, 1995).
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Several studies have been performed to evaluate the pharmacokinetics and cardiovascular effects of PRF in sheep (Runciman et al., 1990; Correia et al., 1996; Lin et al., 1997). Moreover, pregnant ewes have been used as models for studies of placental transfer and fetal exposure to different anaesthetics such as lidocaine (Guay et al., 1992), remifentanil (Kan et al., 1998), halothane and isoflurane (Palahniuk and Shnider, 1974) and ketamine (Levinson et al., 1973). Alon et al. (1993) studied the effects of PRF in pregnant ewes and their fetuses during PRF infusion. They used a combination of PRF and a succinylcholine dose for the induction and nitrous oxide (N2O) during the experimental study. No adverse effects on maternal and fetal variables were found, with the exception of transient maternal bradycardia after succinylcholine administration. The authors attributed all adverse effects reported to succinylcholine use at induction, not to PRF. The objective of our study was to determine the effects of PRF on fetal and cardiopulmonary function during the last trimester of pregnancy in sheep.
2. Material and methods 2.1. Animals Six pregnant Ripollesa ewes, between days 105 and 135 of gestation were used. Their mean weight was 78.8 ± 8.09 kg and the ewes were between 2 and 3 years of age.
catheters were advanced and then sutured in place using silk. The incision was closed using reabsorbable sutures. The left jugular catheter was used for fluid and drug administration. The left carotid artery was used for blood sampling and recording of maternal blood pressure and heart rate. Through a hysterotomy incision, the fetal hindlimb was exposed and the femoral artery catheterised using a 16 G polypropylene catheter (Cavafix, B. Braun) for blood sampling and recording of fetal blood pressure and heart rate. The hind limb was replaced and 0.9% NaCl warmed solution was injected to replace the estimated amount of amniotic fluid lost during the surgical preparations. The placenta and the uterus were closed with an inverting pattern. The fetal catheter exited through the left side of the motherÕs flank and was protected using small plastic bags sutured to the abdominal wall. The ewesÕ temperature, heart rate, respiratory rate, end-tidal carbon dioxide, arterial blood pressure, pulse and electro cardiogram were monitored throughout surgery using a Datex Ohmeda Cardiocap II monitor. Cardiovascular variables of the fetuses were recorded once the fetal catheter had been placed in position. When the ewes had regained their reflexes, they were returned to their box for a minimum of 24 h. During this period, the dam and fetus venous and arterial catheters were flushed with heparinised saline (0.9% saline with 5 U heparin/mL) every 8 h to avoid clotting. The animals were checked every 3 h for signs of pain. Every 12 h, the animals received 0.01 mg/kg subcutaneously buprenorphine and the antibiotic cefalexine, 20 mg/kg IV, every 12 h.
2.2. Surgical procedure 2.3. Animal treatments The surgical procedure followed that reported by Capece et al. (2001) with some modification. Before anaesthesia, food was withheld from all the animals for 12 h but water was freely available until just before induction. The ewes were premedicated with 0.2 mg/kg IV midazolam (Dormicum, Roche Laboratories) and 0.01 mg/kg IV buprenorphine (Buprex, Schering-Plough Laboratories) using a catheter positioned in the right jugular vein. Fifteen minutes after tranquillisation, the animals were allowed to breathe spontaneously while inhaling 5% isofluorane in 100% oxygen, delivered by mask until anaesthesia was induced. The trachea was intubated with a 10 mm endotracheal tube, and anaesthesia maintained with isofluorane (vaporizer setting 2%) in 100% oxygen, at a flow rate of 25 mL/kg/min, though a semi-closed circular system. Throughout anaesthesia, 10 mL/kg/h of warmed Lactated RingerÕs solution was administered through the right jugular catheter. In each animal, a catheter was placed in the left jugular vein and a second in the left carotid artery. The
Following a stability period of 60 min, each ewe was positioned in right lateral recumbency. Maternal and fetal heart rate, arterial blood pressure and maternal pulse-oximetry and respiratory rate were recorded at 0, 5, 10, 15, 30, 45 and 60 min Arterial blood gases were determined at 30 min using an IRMA Blood Analysis System Series 2000 (Diametrics, Medical Inc.). At the end of the stabilizing period, a dose of 6 mg PRF/kg IV over 90 s was given, followed by an IV infusion of 0.4 mg PRF/kg/min for 1 h administered via the left jugular vein. The infusions were performed using a Medfusion 2010 Syringe Pump. PRF-Lipuro 1% supplied by Braun Medical (Spain). During the study period, the ewesÕ tracheas were intubated and 100% oxygen was administered at a flow rate of 25 mL/kg/h via the endotracheal tube. The cardiorespiratory parameters of the ewes and the fetuses were recorded at 5, 10, 15, 30, 45 and 60 min of the PRF infusion. Arterial blood gases, for both, ewes and fetuses, were determined at 15 and 45 min after starting
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the PRF infusion. Cardiopulmonary parameters were recorded 5, 10, 15, 30, 45, 60, 75, 90 and 105 min after the termination of the infusion. Arterial blood gases were collected at 15 and 60 min. The tracheas were extubated when the swallowing reflex returned (5.7 ± 1.2 min after the cessation of the PRF infusion). Throughout the experimental procedure, maintenance fluid therapy was administered using warmed Lactated RingerÕs solution at 10 mL/kg/h IV. At the end of the study all animals were euthanased using an IV dose of sodium pentobarbital.
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the effects of PRF reported in other studies (Robertson et al., 1992; Correia et al., 1996). All procedures were approved by the Ethical Commission of Animal and Human Experimentation (Spanish Government, Authorization Number DARP 2074) under the auspices of the Ethical Commission of the Autonomous University of Barcelona.
3. Results 3.1. Maternal cardiovascular variables
2.4. Statistical analysis Statistical Analysis was performed using SAS v8.0 software and validation of all parameters was undertaken to localise missing or incorrect values. The variable response was analysed using a mixed model for repeated measurements. The variable ‘‘time’’ was chosen as a fixed effect, in addition to the other variables specified in the model. When possible, an unstructured correlation matrix was used. In other cases an autoregressive structure was assumed. Cardiac variables, in both the mothers and fetuses were grouped in different periods; while all parameters registered during the control period were grouped in the same period. For the analysis, the infusions of PRF at 5, 10 and 15 min were grouped in period I1, and for those at 30, 45 and 60 min in the period I2. The parameters recorded during the recovery were grouped in two periods, period R1 at 5, 10 and 15 min and period R2 at 30, 45, 60, 75 and 90 min of recovery. These estimations were applied based on the duration of
During I1, maternal MAP and DAP decreased significantly (P < 0.05) in relation to the control values whereas in I2 these variables returned to control values. Maternal MAP and DAP remained at control values throughout the rest of the study and recovery period (Table 1). The maternal heart rate remained close to control values throughout the study (Table 1). 3.2. Maternal acid–base status, oxygenation, O2 saturation There were significant differences between controls at 15 and 45 min of the infusion for pH, pCO2 and pO2. There was a significant decrease in maternal mean pH, and a significant increase in maternal mean PaCO2 and PaO2 during the infusion period (Table 2) but during recovery all these parameters returned to control values. In the infusion period, the maternal mean HCO3 increased significantly at 45 min. There were significant
Table 1 Maternal cardiovascular and respiratory variables (mean values ± SD) Control
HR (beats/min) SAP (mmHg) DAP (mmHh) MAP (mmHg)
Infusion
146 ± 6 142 ± 3 101 ± 4 115 ± 3
Recovery
I1
I2
R1
R2
120 ± 12 107 ± 14 63 ± 5* 78 ± 5*
139 ± 11 117 ± 8 79 ± 9 93 ± 9
149 ± 6 138 ± 2 94 ± 5 115.1 ± 3
133 ± 4 138 ± 5 97 ± 7 113 ± 7
HR = heart rate, SAP = systolic arterial pressure, DAP = diastolic arterial pressure, MAP = mean arterial pressure. * Significant changes. Table 2 Maternal acid–base variables (mean values ± SD) Control
Infusion
Recovery
I1 pH PaCO2 (mmHg) PaO2 (mmHg) BEecf HCO3 (mEq/L) *
Significant changes.
7.44 ± 0.03 31.5 ± 7.3 93.5 ± 12.7 2.8 ± 1.0 21.4 ± 1.1
I2 *
7.23 ± 0.04 56.5 ± 8.0* 219.8 ± 12.7* 3.0 ± 1.2 23.9 ± 1.1
R1 *
7.19 ± 0.04 75.6 ± 8.8* 232.4 ± 13.9* 1.4 ± 1.2 26.7 ± 1.2*
7.52 ± 0.08 39.0 ± 16.5 94.4 ± 20.9 0.9 ± 2.0 21.4 ± 1.8
R2 7.46 ± 0.04 32.2 ± 8.8 96.0 ± 12.7 0.06 ± 1.2 23.6 ± 1.2
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Table 3 Fetal cardiovascular and respiratory variables (mean values ± SD)
HR (beats/min) SAP (mmHg) DAP (mmHh) MAP (mmHg)
Control
Infusion
Recovery
I1
I2
R1
R2
180 ± 9 75 ± 2 50 ± 3 61 ± 2
251 ± 2* 98 ± 8 62 ± 3* 77 ± 4*
222 ± 11 77 ± 3 53 ± 2 63 ± 2
225 ± 10 77 ± 3 55 ± 3 64 ± 2
215 ± 11 73 ± 3 53 ± 2 60 ± 2
HR = heart rate, SAP = systolic arterial pressure, DAP = diastolic arterial pressure, MAP = mean arterial pressure. * Significant changes. Table 4 Fetal acid–base variables (mean values ± SD) Control
pH PaCO2 (mmHg) PaO2 (mmHg) BEecf HCO3 (mEq/L) *
7.39 ± 0.04 47.1 ± 8.3 23.5 ± 4.6 3.2 ± 2.3 28.3 ± 2.0
Infusion
Recovery
I1
I2
R1
R2
7.18 ± 0.04* 70.7 ± 8.3* 49.6 ± 4.4 2.2 ± 2.3 26.1 ± 2.0
7.13 ± 0.04* 83.7 ± 9.0* 29.9 ± 7.0 2.2 ± 2.4 26.9 ± 2.1
7.42 ± 0.06 38.4 ± 16.3 20.2 ± 0.3 3.1 ± 3.2 27.6 ± 3.02
7.34 ± 0.04 49.2 ± 9.0 22.3 ± 8.0 1.1 ± 2.4 27.1 ± 2.1
Significant changes.
differences in maternal mean base excess between the recovery period and the infusion period although there were no significant differences when compared to the control values (Table 2). Maternal respiratory rate, pulse-oximetry and blood electrolyte concentration remained stable throughout the study. 3.3. Fetal cardiovascular variables Fetal MAP, DAP and heart rate increased significantly during I1 but remained close to the control values during I2. In the recovery period all cardiovascular parameters were normal (Table 3). 3.4. Fetal acid–base variables There was a significant decrease in pH and PaCO2 values compared to the control period at 15 and 45 min of infusion (Table 4). All other variables remained unchanged.
4. Discussion The anaesthetic and surgical techniques used were those described by Capece et al. (2002) with some minor modifications. Short-acting anaesthetic agents with a rapid metabolism were chosen, including midazolam and isoflurane, so that the anaesthetic requirements for the surgical procedures would have minimal effects on the fetus and the eweÕs recovery would be relatively safe and rapid (Thurmon et al., 1996; Paddleford, 1999).
We used the femoral artery instead of the carotid artery because it permitted less exposure of the fetus. Laparotomy was performed at a paramedial site to preserve the integrity of the mammary vessels. The PRF dosages used for the induction and maintenance of the anaesthesia and the times chosen for recording all the variables, were similar to those described in previous studies of non-pregnant ewes by Lin et al. (1997) and by Correia et al. (1996) and were considered adequate for the performance of the experimental procedures in our ewes. 4.1. Maternal findings The induction and maintenance of anaesthesia with PRF are associated with cardiovascular and respiratory depression. This depression is higher during induction, particularly, if PRF is administered rapidly (Grounds et al., 1985; Branson and Gross, 1994; Short and Bufalari, 1999). In the present study, it was observed that the maternal heart rate decreased during the infusion from 146.1 ± 6.8 beats/min to 120.8 ± 12.1 beats/min, however, these changes were not significant. The decrease in maternal MAP observed in our study did not differ from results previously obtained in both animal and human patients (Grounds et al., 1985; Short and Bufalari, 1999) undergoing PRF anaesthesia. Grounds et al. (1985) described a reduction in the arterial blood pressure of between 20% to 40% of preinduction values following IV administration in humans. Similar results have been obtained in human females undergoing caesarean section (Moore et al., 1989). Alon et al. (1993) studied the effects of PRF on maternal and fetal cardiovascular variables in pregnant
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ewes, using succinylcholine for the intubation of the animals and nitrous oxide (N2O) during the study period. In the study performed by Alon et al. (1993) a severe bradycardia and a slight decrease in the arterial blood pressure was observed and attributed to the administration of succinylcholine for intubation in the presence of PRF. The cardiovascular changes in animals given succinylcholine remain unclear. Succinylcholine may cause vagal or sympathomimetic effects depending on whether muscarinic or sympathetic receptors are activated (Klein, 1987). Cardiovascular changes in animals given succinylcholine are variable. Arterial blood pressure frequently increases, and both bradycardia and tachycardia have been observed following succinylcholine injection (Hildebrand, 1992; Thurmon et al., 1996). Furthermore, paralysis of the larynx is not necessary for successful intubation in sheep and its use is currently unacceptable because of the high risk of aspiration of regurgitated rumen contents if the intubation is not performed rapidly (Hildebrand, 1992; Carroll and Hartsfield, 1996). In the study performed by Alon et al. (1993), the cardiovascular effects of PRF would be masked by the use of succinylcholine. Nitrous oxide is infrequently used for ruminant anaesthesia since it accumulates in gas filled compartments and may promote tympany and hypoxaemia, especially during lateral or dorsal recumbency. The accumulation of gas in the sheepÕs rumen may increase arterial and pulmonary blood pressure. Lunn et al. (1977) studied the effects of N2O in bovines, observing that its use in concentrations >30% in unanaesthetized calves, resulted in a significant increases in cardiac output and in the mean aortic, pulmonary and right atrial pressures. Our results differed from those reported by Runciman et al. (1990) undertaken on non-pregnant ewes; who reported a significant increase in heart rate and MAP during PRF anaesthesia in sheep. Nevertheless, several studies, have reported the hypotensive effects of PRF after its administration (Correia et al., 1996). In the present study, the maternal acid–base status varied significantly from values obtained in the control period. It was observed that the maternal pH decreased significantly during the infusion time as a result of the increase in PaCO2. Respiratory depression has been widely described in both humans and animals undergoing PRF anaesthesia (Taylor et al., 1986; Thurmon et al., 1996). During the study period, the respiratory rate did not change significantly from the control period. However, three of the six ewes were apnoeic after the IV administration, a condition which lasted for 1.4 ± 1.1 min This transient period of apnoea following IV. PRF has previously been reported in sheep (Correia et al., 1996), dogs and cats (Smith et al., 1993; Thurmon et al., 1996) and in humans (Taylor et al., 1986).
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During the study period, the tracheas of all the animals were intubated and they received 100% oxygen, so that the PaO2 increased significantly during the infusion period until the recovery time when the tracheas were extubated and the administration of 100% oxygen ceased. The extubation time in our study (5.7 ± 1.2 min) was longer than that described by Correia et al. (1996) in non-pregnant ewes. However, our PRF dose was slightly higher and there was no-surgical stimulus, which may explain the prolongation of the extubation time. The cardiovascular and acid–base changes observed during PRF anaesthesia in pregnant ewes in our study, are similar to those described by Palahniuk and Shnider (1974) during halothane and isoflurane anaesthesia. However, the acid–base changes observed in our study were slight higher than those described by Palahniuk and Shnider (1974) for inhalational anaesthetics. 4.2. Fetal findings During the study period, fetal cardiovascular and acid–base status showed a significant variation from the control period values. The fetal arterial heart rate and arterial blood pressure, increased significantly during the infusion period I1 possibly reflecting a fetal response to maternal stress associated with the induction of anaesthesia and/or fetal distress caused by a reduction in the uterine blood flow. Although in the present study, the uterine blood flow was not monitored, the increase in fetal heart rate and arterial blood pressure as a result of fetal distress, was as described for other anaesthetic agents such as ketamine (Fisher and Paton, 1974). Alon et al. (1993) did not observe any change in the uterine blood flow during PRF anaesthesia in pregnant sheep but the use of N2O and succinylcholine may have interfered with the results obtained in their study. N2O diffuses rapidly across the placenta and may produce hypoxaemia in the fetus and newborn (Blechner et al., 1969). The PaO2 values recorded in AlonÕs study were, however, similar to those we recorded. Polvi et al. (1996), in a study performed in pregnant women at full term, showed that maternal and fetal central vascular resistance were decreased by 30% N2O inhalation. Since uterine blood flow is inversely proportional to uterine vascular resistance (Thurmon et al., 1996), the combination of different anaesthetics in the study performed by Alon et al. (1993) may have masked the real effects produced by PRF alone. In our study PRF only was used so there could be no interaction with other anaesthetic agents. The acidosis and the increase in fetal PaCO2 observed could be secondary to a rise in maternal PaCO2. This effect on the fetus may reflect a decrease in the uteroplacental perfusion and in uterine blood flow. The fetal acidosis found in our study was similar to that reported after an IV administration of several anaesthetic agents
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to a pregnant ewe (Palahniuk and Shnider, 1974; Levinson et al., 1973). These workers described a significant fetal acidosis during moderate and deep levels of anaesthesia (1.5 and 2.0 of the Minimum Alveolar Concentration (MAC) value respectively), using halothane and isoflurane; whereas Levinson et al. (1973) described a sight rise in fetal PaCO2 during ketamine anaesthesia. During the recovery period all of the fetal variables returned to control values. This rapid recovery from PRF anaesthesia has been described during caesarean section in human patients (Valtonen et al., 1989; Sanchez-Alcaraz et al., 1998). In these studies the blood gas analyses of neonates were within the normal range and the neonatal viability (assessed by Apgar Score), were well preserved. However, other authors have described evidence of neonatal depression due to PRF administration to the mother (Celleno et al., 1989; Gin et al., 1991). We conclude that PRF has no adverse effects on the pregnant ewe other than those described following its use in non-pregnant animals and humans or in pregnant ewes undergoing inhalational anaesthesia. However the effects of PRF on fetuses may be important in other circumstances, such as in prolonged infusion periods in the hypoxaemic fetus; in the fetus with cardiac disease or during a caesarean section.
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