Anesth Analg 2007;104:799-806
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000259013.59084.bd
PEDIATRIC ANESTHESIA
The Mechanisms of Pain-Induced Pulmonary Vasoconstriction: An Experimental Study in Fetal Lambs
Veronique Houfflin Debarge, MD, PhD*
,
Bérengère Sicot, MD*,
Sophie Jaillard, MD, PhD,
Iva Gueorgiva, MD
,
Anne Delelis, MD*,
P. Deruelle, MD, PhD*,
Ann Sophie Ducloy, MD||, and
Laurent Storme, MD
From the *Department of Obstetrics, Centre Hospitalier Régional Universitaire, Lille, France; JE 2490 and Departement Hospitalo-Universitaire de Recherche Experimentale, Faculté de Médecine de Lille, Université de Lille II, Lille, France; and Departments of Neonatology and ||Anesthesiology, Centre Hospitalier Régional Universitaire, Lille, France.
Address correspondence to Véronique Houfflin Debarge, MD, Clinique d'Obstétrique, Hôpital Jeanne de Flandre, Centre Hospitalier Régional et Universitaire, 59037 Lille Cedex, France. Address e-mail to v-houfflin-debarge{at}chru-lille.fr.
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Abstract
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BACKGROUND: Nociceptive stimulation induces pulmonary vasoconstriction in fetuses and newborns. The mechanism of this response is not fully understood. As the systemic hemodynamic response to pain is mainly mediated by sympathetic stimulation, we hypothesized that pain-induced pulmonary vasoconstriction results from the activation of catecholaminergic receptors. To test this hypothesis, we studied the pulmonary vascular response to nociceptive stimuli in fetal lambs before and after 
-adrenoceptor blockade.
METHODS: Surgery was performed in fetal lambs. Catheters were placed into the ascending aorta, superior vena cava, and main pulmonary artery. An ultrasonic flow transducer was placed around the left pulmonary artery, and subcutaneous catheters were placed in the limb. The hemodynamic responses to (1) subcutaneous injection of formalin (which is used as nociceptive stimulus in experimental studies), (2) prazosin (specific 1-adrenoceptor antagonist), and (3) formalin during prazosin infusion were evaluated. Plasma cortisol and catecholamine concentrations were measured.
RESULTS: Pulmonary vascular resistance (PVR) increased by 50% (P < 0.01) after the formalin test. PVR did not change after the formalin test during prazosin infusion or during prazosin infusion alone. Catecholamine and cortisol levels did not change during any of the protocols.
DISCUSSION: Our results indicate that the fetal pulmonary vasoconstrictive response to pain involves 1-adrenoceptors activation. As plasma catecholamine concentrations did not change after the formalin test, we speculate that the pulmonary vascular response to nociceptive stimuli could be triggered by a local release of catecholamine induced by sympathetic stimulation.
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Introduction
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Cardiovascular and endocrine responses to pain have largely been documented in both preterm and full-term newborn infants but also in the human fetus (1–5). Stressful events can also cause acute deterioration of respiratory function. A decrease in arterial oxygen saturation has been reported during circumcision or stressful intensive care procedures in term infants with respiratory failure (5,6). Although the mechanism of stress-induced hypoxemic response remains uncertain, several pieces of evidence support the hypothesis that pain has a potent impact on the pulmonary circulation (7,8). We (9) previously demonstrated that nociceptive stimuli induce potent pulmonary vasoconstriction in the ovine fetus. Furthermore, analgesia improves the outcome in infants with pulmonary hypertension and abolishes pulmonary vasoconstriction (8–10). All these data strongly suggest that stressors may impair the perinatal pulmonary circulation. However, the mechanisms of stress-induced pulmonary vasoconstriction are unknown.
Pain enhances sympathetic tone, resulting in an increase in cardiac rate and systemic blood pressure. Sympathetic nerve stimulation can cause direct pulmonary vasoconstriction related to local norepinephrine production (11). -Adrenoceptors are involved in the sympathetically mediated vasoconstriction of human vessels (12). Therefore, we hypothesized that pain may induce pulmonary vasoconstriction in the perinatal period through local release of catecholamines induced by sympathetic stimulation. To test this hypothesis, we studied the pulmonary vascular response to a nociceptive stimulus in chronically prepared, late-gestation fetal lambs before and after -adrenoceptor blockade.
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METHODS
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Animal Preparation
All animal procedures and protocols used in this study were reviewed and approved by the French Ministère de l'Agriculture, de la Pêche et de l'Alimentation before the studies were conducted. Mixed-breed (Columbia-Rambouillet) pregnant ewes at 128 days gestation (term = 147 days) were fasted for 24 h prior to surgery. Ewes were sedated with IV pentobarbital sodium (total dose: 2–4 g) and anesthetized with 1% bupivacaine hydrochloride (4 mg) by lumbar puncture. The sedation of the ewes was maintained by intermittent injection of pentobarbital and the ewes breathed spontaneously throughout the surgery. Under sterile conditions, the fetal lamb's left forelimb was delivered through a uterine incision. A skin incision was made under the left forelimb after local infiltration with lidocaine (2 mL, 1% solution). Polyvinyl catheters (gauge 20) were advanced into the ascending aorta and the superior vena cava after insertion in the axillary artery and vein. A left thoracotomy exposed the heart and great vessels. A catheter (gauge 20) was inserted into the main pulmonary artery by direct puncture through purse-string suture. An ultrasonic flow transducer, size 6 (Transonic Systems, Ithaca, NY), was placed around the left pulmonary artery to measure bloodflow. Three other catheters (gauge 22) were placed subcutaneously into the left hindpaw for formalin injection. The utero-placental circulation was kept intact and the fetus was gently replaced into the uterus. An additional catheter was placed in the amniotic cavity to measure pressure. Ampicillin (500 mg) was added to the amniotic cavity prior to closure of the hysterotomy. The flow transducer and catheters were exteriorized through a subcutaneous tunnel to an external flank pouch. Food and water were provided ad libitum after surgery. Vascular catheters were maintained by daily infusions of 2 mL of heparinized saline (10 U/mL). Catheter positions were checked at autopsy. Studies were performed after a minimum recovery time of 96 h. Estimated weight of the fetal lambs was 3000 g.
Physiologic Measurements
The flow transducer was connected to an internally calibrated flowmeter (T201, Transonic Systems, Ithaca, NY) for continuous measurements of left pulmonary artery bloodflow. The output filter of the flowmeter was set at 30 Hz. The absolute value of flow was determined from the mean of phasic bloodflow signals (at least 30 cardiac cycles), with zero bloodflow defined as the measured flow value immediately before the beginning of systole. The main pulmonary artery, aortic, and amniotic catheters were connected to a blood pressure transducer (Merlin monitor, Hewlett-Packard, Palo Alto). Pressures were referenced to the amniotic cavity pressure. Heart rate was determined from the phasic pulmonary bloodflow (Qp) signal. Pulmonary vascular resistance (PVR) in the left lung was calculated as the difference between mean pulmonary artery (PAP) and left atrial pressures divided by mean left Qp. Based from our past studies, in which left atrial pressure was found constantly close to 2 cm H2O, a value of 2 cm H2O was used as an estimate of left atrial pressure (13,14).
Blood samples from the aorta were used for blood gas analysis and oxygen saturation measurements (OSM 3 hemoximeter and ABL 520, Radiometer, Copenhagen, Denmark), and for plasma cortisol and catecholamine (norepinephrine, epinephrine and dopamine) concentration measurements. A volume of sterile 0.9% saline equal to blood samples was infused to prevent hypovolemic stress. Samples were immediately centrifuged and stored at –80°C until further analysis. The plasma cortisol concentration was measured by chemiluminescence (Cortisol Chemiluminescence Assay, Nichols Advantage®, Nichols Institute Diagnostics, San Juan Capistrano, CA). The intra- and interassay coefficients of variation were 9% and 12%, respectively. Plasma catecholamine levels were measured by high pressure liquid chromatography (Alumina from Chromsystems, Germany, HPLC: Coulochem II, ESA, Chelmsford, USA). The inter- and intra-assay coefficients of variation were 6% and <5%, respectively.
Drug Preparation
Formaldehyde and 0.9% saline were used to prepare the formalin solution. Two milliliter of 1% formalin was injected subcutaneously. Prazosin (Sigma-Aldrich, Germany) was dissolved in sterile water to a concentration of 0.1 mg/mL (3 mg in 30 mL H2O).
Experimental Design
Three different experimental protocols were included in this study: (1) pulmonary hemodynamic response to formalin test; (2) pulmonary hemodynamic response to prazosin-specific 1-adrenoceptor antagonist; and (3) pulmonary hemodynamic response to formalin injection during prazosin infusion. All protocols were applied in a random order.
A minimum recovery period of 24 h was required between each protocol. The data of our previous study showed that consecutive intradermal (ID) formalin (up to 3 injections) separated by 24 h does not induce tolerance, provided that the injection sites are different (9). To ensure that complete recovery was achieved before starting a protocol, we verified that the measured hemodynamic variables and arterial blood gases returned to baseline values.
Protocol 1: Effects of the Formalin Test on Pulmonary Circulation
To investigate the effects of a nociceptive stimulus on the fetal pulmonary circulation, we studied the hemodynamic response to the formalin test. Mean PAP, mean aortic pressure (AoP), amniotic pressure, left Qp, and fetal heart rate (FHR) were recorded at 5-min intervals throughout the study period. PVR in the left lung was calculated. After 30 min of stable baseline measurements, 2 mL of 1% formalin was injected into one of the subcutaneous catheters. The duration of each experiment was at least 140 min. Fetal blood gases, pH, cortisol, and catecholamine levels were measured before and 30 min after the formalin test.
Protocol 2: Effects of an 1-Adrenoceptor Antagonist on Pulmonary Circulation
To investigate the effects of an 1-adrenoceptor antagonist on fetal pulmonary circulation, we studied the hemodynamic response to prazosin. Hemodynamic measurements were performed as in Protocol 1. After 30 min of stable baseline measurements, prazosin was infused at a rate of 6 mL/h (10 µg/min) for 90 min. Preliminary tests showed that lower doses or bolus alone did not provide sustained 1-adrenoceptor blockade. Fetal blood gases, pH, plasma cortisol, and catecholamine levels were measured before and 30 min after the beginning of prazosin infusion.
Protocol 3: Effects of 1-Adrenoceptor Blockade on the Pulmonary Vascular Response to Formalin Test
To investigate the role of the 1-adrenoceptors on the pulmonary hemodynamic response to the formalin test, the same hemodynamic measurements as in Protocol 1 were conducted during prazosin infusion (6 mL/h = 10 µg/min during 90 min). After 30 min of stable baseline measurements, prazosin was infused at a rate of 6 mL/h (10 µg/min) for 90 min. Two milliliter of 1% formalin was injected into one of the subcutaneous catheters, 20 min after the beginning of prazosin infusion. Fetal blood gases, pH, plasma cortisol, and catecholamine levels were measured before and 30 min after formalin injection.
Data Analysis
The results are presented as mean ± sem. The data were analyzed using repeated-measures and factorial analysis of variance. Intergroup differences were analyzed with the Fisher's, Scheffe's, and Bonferroni/ Dunn's least significant test (Stat View for PC, Abacus Concepts, Berkeley, CA). Mann–Whitney tests (independent values) were also performed on the quantitative data to test for statistical differences between groups. A P < 0.05 was considered statistically significant. In each experiment, n represents the number of studied fetuses.
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RESULTS
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Eight pregnant ewes were operated on at 128 days of gestation (term 147 days). Baseline values (means PAP, Qp, PVR, FHR, AoP, blood gas, pH, plasma cortisol, and catecholamine levels) were similar in the three protocols.
Protocol 1: Effects of the Formalin Test on Pulmonary Circulation (n = 8)
Mean PAP increased by 17% (from 46 ± 2 to 54 ± 2 mm Hg; P < 0.0001) after the formalin test (Fig. 1). Mean Qp decreased by 15% (from 72 ± 5 to 63 ± 6 mL/min; P < 0.05) and mean PVR increased by 50% (from 0.62 ± 0.04 to 0.95 ± 0.18 mm Hg/mL/min; P < 0.01) after the formalin test (Fig. 1). However, the pulmonary vascular response was biphasic. Both mean Qp and PVR returned briefly to baseline, 30 min after the formalin test (Fig. 1). Mean AoP increased by 15% (from 45 ± 1 to 52 ± 6 mm Hg; P < 0.0001) (Fig. 2). Changes were parallel to mean PAP. FHR after the formalin test increased by 20% (from 155 ± 9 to 182 ± 9; P < 0.001) (Fig. 2). The formalin test did not alter fetal blood gases, pH, or plasma catecholamine levels (Table 1). Despite a slight increase, the plasma cortisol concentration did not change after the formalin test (from 2.39 ± 0.4 to 3.17 ± 0.6 µg/dL) (Table 1).
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Figure 1. Pulmonary hemodynamic response to formalin test (n = 8). Formalin increased mean pulmonary artery pressure (PAP) (P < 0.0001), and mean pulmonary vascular resistance (PVR) (P < 0.01). Left pulmonary artery bloodflow (Qp) decreased (P < 0.05) after the formalin test. F, formalin injection. Values are expressed as means ± sem.
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Figure 2. Cardiovascular response to formalin test (n = 8). Fetal heart rate and aortic pressure (AoP) increased after formalin test (respectively, P < 0.001 and P < 0.0001). F, formalin injection. Values are expressed as means ± sem.
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Table 1. Fetal Blood Gases from the Aorta (mm Hg), pH, Cortisol, and Catecholamine Levels Before and After Formalin, Prazosin, and Prazosin + Formalin
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Protocol 2: Effects of an 1-Adrenoceptor Antagonist on Pulmonary Circulation (n = 8)
Mean PAP, Qp, PVR, AoP, and FHR did not change during prazosin infusion (Figs. 3 and 4). Blood gases, pH, plasma catecholamine, or cortisol concentrations did not change during the study period (Table 1).
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Figure 3. Pulmonary hemodynamic response to prazosin (n = 8). Mean pulmonary artery pressure (PAP), mean left pulmonary artery bloodflow (Qp), and mean pulmonary vascular resistance (PVR) did not change during prazosin infusion. Values are expressed as means ± sem.
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Figure 4. Cardiovascular response to prazosin (n = 8). Mean aortic pressure (AoP) and fetal heart rate did not change during prazosin infusion. Values are expressed as means ± sem.
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Protocol 3: Effects of 1-Adrenoceptor Blockade on the Pulmonary Vascular Response to Formalin Test (n = 8)
Mean PAP increased by 8% (from 47 ± 8 to 51 ± 7 mm Hg; P < 0.05), whereas Qp and PVR did not change (Fig. 5).
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Figure 5. Pulmonary hemodynamic response to formalin during prazosin infusion (n = 7). Mean left pulmonary artery bloodflow (Qp) and mean pulmonary vascular resistance (PVR) did not change during prazosin infusion. Mean pulmonary artery pressure (PAP) increased by 8% (P < 0.05). F, formalin injection. Values are expressed as means ± sem.
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Mean AoP, FHR, blood gas, pH, and plasma catecholamine levels did not change after the formalin test in the prazosin-treated fetuses (Fig. 6, Table 1).
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Figure 6. Cardiovascular response to formalin during prazosin infusion (n = 7). Mean aortic pressure (AoP) and fetal heart rate did not change after formalin infusion in prazosin-treated fetal lambs. F, formalin injection. Values are expressed as means ± sem.
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Despite a slight increase, the plasma cortisol concentration did not change after the formalin test (from 2.63 ± 0.4 to 3.62 ± 0.5 µg/dL) (Table 1).
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DISCUSSION
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In this in vivo experimental study, we tested the hypothesis that nociceptive stimuli modulate pulmonary vascular tone during perinatal life through an activation of catecholaminergic receptors. To test this hypothesis, the pulmonary vascular response to subcutaneous formalin injection was studied in chronically prepared, late-gestation fetal lambs, with and without an 1-adrenoceptor antagonist. We found that nociceptive stimulation increased the PVR. -1-Adrenoceptor blockade abolished this pulmonary vasoconstrictive response, whereas 1-adrenoceptor blockade alone did not alter basal pulmonary vascular tone. The formalin test did not change plasma catecholamine concentrations. These results support the hypothesis that the increase in PVR mediated by nociceptive stimuli involves 1-adrenoceptors activation.
Our study provides new information regarding the hemodynamic effects of fetal nociceptive stimuli. The systemic effects of formalin-induced pain have been studied (15–17). Nociceptive stimuli increase heart rate and AoP through an increase of sympathetic nervous system output (16). Growing evidence indicates that stressful events also alter pulmonary circulation. Stressful intensive care procedures increase PAP and cause hypoxemia in infants with respiratory failure or congenital heart defect (5,7). Opioid analgesia reduces this hypoxemic response to stress and improves the outcome in infants with pulmonary hypertension (5,10). We (9) previously reported that nociceptive stimuli increase basal pulmonary vascular tone in fetal lambs. Although this pulmonary vasoconstrictive response is abolished by opioid analgesia (9), the mechanisms by which nociceptive stimuli may induce pulmonary vasoconstriction remained unclear.
As the systemic hemodynamic response to pain is mediated by the sympathetic nervous system, we speculated that the lungs' circulatory effects of nociceptive stimuli were related to activation of catecholaminergic receptors. We used the formalin test, commonly used in animal models to study the effects of nociceptive stimuli (17), to assess this hypothesis. The injection produces tissue injuries and induces mild pain. Subcutaneous formalin injection causes highly reproducible pain-mediated hemodynamic responses, including increase in AoP and heart rate for about 1 h (15–17). In adult animals, the behavioral and cardiovascular response to formalin injection is biphasic. The first phase is observed immediately after injection and lasts about 10 min. The second phase appears 20–30 min after the injection and is longer and more intense than the first (15,17,18). The early phase is caused by direct nociceptor stimulation and C-fiber activation, whereas the second phase is mostly dependant on an inflammatory reaction in the peripheral tissue (17). The biphasic cardiovascular response is not observed in newborn rats and occurs substantially later when the autonomic nervous system is matured (15). In our study, the cardiovascular responses to the formalin test, heart rate, Aop, PAP, and PVR were biphasic, suggesting that maturation of the regulatory mechanisms might be achieved earlier in fetal lambs.
In accordance with our previous study, we found that subcutaneous formalin injection increases FHR, increases both AoP and PAP, and increases pulmonary vascular tone. Because the ductus arteriosus is widely opened in the fetus, gradient pressure between the pulmonary artery and aorta is constant and low (about +2 mm Hg). Thus, a change in AoP is mirrored by PAP. It is likely that the increase in PAP after ID formalin injection resulted from an increase in AoP. Previous studies clearly showed that the physiological response to an increase in PAP in the fetus is pulmonary vasodilation due to the mechanical increase in shear stress (19,20). Therefore, the formalin-mediated passive increase in PAP should have increased Qp and decreased PVR. However, we found that ID formalin injection induced a decrease in Qp and an increase of PVR. Our present data show that 1-adrenoceptor antagonists prevent an ID formalin-mediated increase in pulmonary vascular tone. This result indicates that the pulmonary vasoconstrictive response to the formalin test results from activation of 1-adrenoceptors.
Activation of 1-adrenoceptors is mediated by catecholamines. Catecholamines may be released directly at the level of the pulmonary vascular smooth muscle cells through activation of sympathetic nerves (21). High sympathetic nerve activity was found in the perinatal lung (22). Pulmonary vessels are richly innervated with sympathetic fibers (23). Norepinephrine is the main sympathetic neurotransmitter (22,24). In fetal lambs, stimulation of the sympathetic nerves results in pulmonary vasoconstriction (25), which is more pronounced in fetal lambs than in adults (25,26). Thus, there is evidence that the pulmonary vascular response to the formalin test could be triggered by local release of catecholamines induced by sympathetic stimulation. Usually, an increase in the sympathetic nerve firing rate induces a proportional overflow of catecholamines from organs into the circulation (22,24). Surprisingly, no change in circulating catecholamine levels was found after the formalin test. This result is in accordance with our previous study showing that the formalin test does not alter the plasma catecholamine concentration in fetal lambs (9). It is not clear why blood catecholamine levels do not change after the formalin test, but low Qp in the fetus may be involved. Indeed, the sympathetic release of catecholamines depends on regional bloodflow (24). Therefore, the increase in nerve firing underlying sympathetically mediated pulmonary vasoconstriction could remain undetected if catecholamine washout decreased in proportion to Qp (24). Alternatively, we cannot exclude the possibility that the pulmonary vascular response to formalin may be caused by the release of other mediators, such as serotonin, endothelin, and thromboxane, through remote 1-adrenoceptors activation. As blood samples for catecholamine plasma concentration measurements were performed 30 min after ID formalin injection, we may have missed a brief and early increase of plasma catecholamine concentration. Although this possibility cannot be excluded, and increase in plasma catecholamine concentration is unlikely, as previous studies have shown that the circulating catecholamines mediate pulmonary vasodilation during the perinatal period (14,27,28). In particular, norepinephrine infusion was found to induce a notable decrease in PVR in the fetal lamb (14,27).
In the present study, the nociceptive stimuli-induced increase in pulmonary vascular tone was abolished by prazosin which, although usually considered a specific 1-adrenoceptor antagonist, may have other nonspecific effects. Since we used only a single 1-adrenoceptor antagonist, we cannot exclude that an additional receptor may be involved, at least in part, in the pain-mediated pulmonary vascular response.
In our study, we excluded other possible mechanisms of formalin-induced pulmonary vasoconstriction. Hypoxia, for example, can cause an increase in pulmonary vascular tone. However, fetal blood gases did not change after the formalin test. The increase in PAP may have resulted from a decrease in ductus arteriosus diameter, but this hypothesis is unlikely, as the pressure gradient between the pulmonary artery and aorta remained constant after formalin injection, indicating that ductal flow and resistance did not change.
Our experiments were performed in a fetal animal model. Whether the results can be extrapolated to newborns is uncertain. However, fetal lambs have been used extensively to study perinatal pulmonary circulation (9,13,14,29–31), and chronically prepared, late-gestation fetal lambs provide reproducible and reliable measurements of basal pulmonary vascular tone and reactivity to birth-related stimuli. Fetal pulmonary circulation is characterized by high ductus arteriosus and low Qp associated with right-to-left shunting through the ductus arteriosus and the foramen ovale. Persistent pulmonary hypertension of the newborn (PPHN) results from failure of the pulmonary circulation to dilate at birth. This syndrome is characterized by a sustained increase of PVR, causing extrapulmonary right-to-left shunting of blood across the ductus arteriosus and foramen ovale and severe hypoxemia. Thus, some of the main features of fetal pulmonary circulation are observed in PPHN. Furthermore, numerous studies reported that fetal hormonal and hemodynamic responses to painful stimulus are similar to those recorded in newborns (1–3,32–34).
In conclusion, we found that nociceptive stimuli in utero increase PAP and PVR through activation of 1-adrenoceptors. Our study supports the hypothesis that, during perinatal life, pain may increase sympathetic tone resulting in catecholamine-induced pulmonary vasoconstriction.
This study is of clinical importance as it provides further evidence that the fetus is able to respond to nociceptive stimuli. In addition to a vasoconstrictor effect, stimulation of 1-adrenoceptors increases DNA and protein synthesis in vascular smooth muscle cells (35), and excessive activation of 1-adrenoceptors has been involved in the pathophysiology of pulmonary hypertension (35). We speculate that fetal pain may have a potential impact on pulmonary circulation and lung development. Furthermore, our study provides new insights on the mechanisms by which a stressful event may worsen hypoxemia in newborn infants with PPHN (5). Nociceptive stimulation, through 1-adrenoceptor activation, may increase pulmonary vascular tone, leading to increased right-to-left shunting through the ductus arteriosus and the foramen ovale and to severe hypoxemia. In the past, 1-adrenoceptor antagonists, such as tolazoline, have been used for the management of PPHN. Indeed, the beneficial effects of tolazoline on oxygenation for PPHN have been reported (36,37). However, the systemic effects of tolazoline (hypotension) and the availability of selective pulmonary vasodilator drugs, such as inhaled nitric oxide, explain why 1-adrenoceptor blockers are no longer used for PPHN. In the same way, opioid analgesia has been reported to reduce the hypoxemic response to stress (5,38) and to improve the outcome in infants with pulmonary hypertension (10). Our study further supports the need for analgesia in newborn infants with PPHN to prevent stressful event-mediated pulmonary hypertension.
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ACKNOWLEDGMENTS
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The authors gratefully acknowledge Dr. B. Soudan and Dr. N. Rouaix for technical support.
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Footnotes
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Accepted for publication December 22, 2006.
Supported by Délégation à la Recherche du CHRU de Lille; Fondation de France; Fondation de l'Avenir; Faculté de Médecine, Université de Lille II.
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Abstract
Introduction
