PHYSIOLOGY AND REPRODUCTION

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1 PHYSIOLOGY AND REPRODUCTION Pulmonary Wedge Pressures Confirm Pulmonary Hypertension in Broilers Is Initiated by an Excessive Pulmonary Arterial (Precapillary) Resistance M. E. Chapman 1 and R. F. Wideman, Jr. Department of Poultry Science, University of Arkansas, Fayetteville, Arkansas ABSTRACT High retrograde pressure through the pulmonary population, but wedge pressures did not differ between venous system caused by failure of the left ventri- cle or left atrio-ventricular valve may result in the elevated the resistant, base, and unselected lines. Right:total ventricular weight ratios (RV:TV) and the percentage saturation of hemoglobin with oxygen in arterial blood ranged pulmonary arterial pressure and right ventricular hypertrophy associated with pulmonary hypertension syndrome (PHS; ascites) in broiler chickens. In the present Wedge pressure, however, remained similar when pre- in value from 0.18 to 0.44 and 65 to 96%, respectively. study, unanaesthetized male broilers from an ascites-resistant line, the base population from which the resistant ascitic broilers with high RV:TV values and low oximetry values were compared with clinically healthy broilers. In line was derived, and a separate unselected line were all birds, whether healthy or showing pre-ascitic characteristics, the wedge pressure was slightly higher than the used to determine whether changes in wedge pressure (thought to be similar to left atrial pressure) are predictive right atrial pressure but substantially lower than pulmonary arterial pressure. These observations provide defin- of differences in the pulmonary arterial pressure of clinically healthy and pre-ascitic broilers. Venous, right atrial, right ventricular, pulmonary arterial, and wedge pressures were obtained by inserting a catheter into a wing consequence of excessive pulmonary arterial or arteriole itive proof that pulmonary hypertension is initiated as a vein and progressively advancing the catheter into a pulmonary branch artery until the catheter tip became measuring the pulmonary arterial wedge pressure, and resistance. Pulmonary venous pressure is estimated by wedged in and occluded the flow through a terminal artery. Mean right ventricular and pulmonary arterial pressures were lower in the resistant line than in the base high wedge pressures would be evident if pulmonary hypertension was caused by the elevated downstream resistances associated with left-sided heart failure. (Key words: pulmonary hypertension, broiler, heart, blood pressure, catheter) 2001 Poultry Science 80: INTRODUCTION Pulmonary hypertension syndrome (PHS, ascites) in broilers is associated with right ventricular hypertrophy and an elevated blood pressure within the pulmonary circulation (Cueva et al., 1974). Pulmonary hypertension initiates the sequential development of hypoxemia, rightsided congestive heart failure, central venous congestion, cirrhosis of the liver, and accumulation of ascitic fluid into the abdominal cavity. Apparently, PHS-susceptible broilers have an inherent potential to outgrow their cardio-pulmonary capacity (Wideman and Bottje, 1993). According to this hypothesis, the pulmonary circulation cannot accept the required cardiac output at flow rates and pressures that are sufficiently low to avoid triggering pulmonary hypertension and systemic hypoxemia. Where the pulmonary vasculature is anatomically inadequate to accept the required cardiac output, and the cardiac output cannot be accommodated through compensatory mechanisms known to reduce the pulmonary vascular resistance in mammals, such as flow-dependant pulmonary vasodilation and the recruitment of previously un- or under-perfused vascular channels, right ventricular work and pulmonary arterial pressure must increase. The high rate of blood flow through the pulmonary vasculature prevents red blood cells from residing at the gas exchange surfaces long enough to achieve full saturation of the hemoglobin with oxygen, and therefore hypoxemia ensues (Wideman and Bottje, 1993; Wideman, 2000). An alternative hypothesis has been suggested in which left ventricular myocardial or valvular failure would cause back pressure through the pulmonary venous system, resulting in the elevated pulmonary arterial Received for publication May 15, Accepted for publication November 20, To whom correspondence should be addressed: mchapman@comp. uark.edu. Abbreviation Key: PHS = pulmonary hypertension syndrome; RV:TV = right:total ventricular weight ratio. 468

2 PULMONARY WEDGE PRESSURES IN PULMONARY HYPERTENSION 469 pressure and right ventricular hypertrophy (Olkowski et al., 1998). Pulmonary venous pressure is generally assumed to be close to the pulmonary arterial wedge pressure (Bhattacharya et al., 1982). The wedge pressure can be obtained by inserting a catheter into a pulmonary branch artery until the catheter tip occludes the flow through a terminal artery or arteriole so there is a continuous column of motionless blood from the catheter tip and throughout the vein draining the occluded region. The wedge pressure at the catheter tip, therefore, is similar to the pressure at the downstream end of the draining vein. Because the pressure drop through the larger pulmonary veins is small, wedge pressure is thought to be similar to left atrial pressure. Measurements in anesthetized cats have shown that pulmonary capillary pressure is about midway between that of the arterial and venous systems and that much of the pressure drop in the pulmonary circulation occurs within the capillaries (Bhattacharya et al., 1982). At very high pulmonary blood flow rates, capillary pressure in the lung of the dog was closer to arterial than venous pressures (Younes et al., 1987). It was concluded, therefore, that capillary pressure is at least equal to the average of arterial and venous pressures. Thus, an increase in left atrial and pulmonary venous pressures would cause an increase in pulmonary arterial wedge pressure and theoretically could raise pulmonary artery pressure with the potential to cause ascites in susceptible chickens. One study showed that capillary transmural pressure was increased when the venous pressure was raised in isolated rat lungs (Parker et al., 1997). If leftsided heart failure causes pulmonary arterial hypertension in pre-ascitic broilers, then the increase in the pulmonary arterial pressure should be associated with a similar increment in pulmonary arterial wedge pressure. However, if pulmonary arterial hypertension is caused by inadequate pulmonary vascular capacity or pulmonary arteriole constriction (excessive precapillary resistance), then pre-ascitic increases in pulmonary arterial pressure should only be associated with modest corresponding increases in wedge pressures. Previously, broiler breeders were selected for their ability to survive unilateral pulmonary arterial occlusion, and therefore they possessed a cardio-pulmonary capacity capable of accommodating the challenge of high cardiac output and an elevated pulmonary vascular resistance (Wideman and French, 1999, 2000). These birds were used to produce ascites-resistant generations that, when compared to the base population, showed a reduced incidence of ascites when grown as rapidly as possible while exposed to low temperatures. In the present study, unanesthetized progeny from the base population, the ascites 2 Hubbard ISA, Walpole, NH Hubbard ISA, Hot Springs, AR Vet/Ox 4403 pulse oximeter using the universal C-sensor, Sensor Devices, Inc., Waukesha, WI Konigsberg Instruments, Inc., Pasadena, CA resistant line, and a separate unselected line were used to determine whether changes in the wedge pressure are predictive of differences in the pulmonary arterial pressure of clinically healthy and pre-ascitic broilers. Broilers can reliably be predicted to have entered the pre-ascitic stages of the pathophysiological progression leading to terminal ascites when the right:total ventricular weight ratios (RV:TV) are 0.28 and when progressive undersaturation (<80%) of the arterial hemoglobin with oxygen (hypoxemia) ensues (Roush et al., 1996, 1997, Kirby et al., 1997, Wideman et al., 1997, 1998). MATERIALS AND METHODS Male chicks from the base and Generation 2 resistant lines (Wideman and French, 1999, 2000) were hatched on January 7, 2000, at the Hubbard ISA Research hatchery. 2 In addition, male chicks from a separate unselected line were hatched on January 19, The chicks were wingbanded and shipped on the day of hatch (Day 1) to the poultry environmental research laboratory at the University of Arkansas. They were placed on fresh wood shavings in environmental chambers (8 m 2 floor space) and were brooded at 33 C from Days 1 to 5, 29 C from Days 6 to 10, and 27 C from Days 11 to 17. Thereafter, the base population and resistant lines were challenged with subthermoneutral temperatures (14 to 15 C). The unselected line was maintained at 21 C until the experiment was terminated. The photoperiod was 24 h light from Days 1 to 5, and 23 h light/1 h darkness thereafter. Water was provided ad libitum via bell type waterers. A cornsoybean meal starter ration (22.7% CP, 3,059 kcal ME/ kg, 1.5% arginine, and 1.43% lysine) was provided ad libitum and had been formulated to meet or exceed the minimum NRC (1984) standards for all ingredients. The diet was provided as crumbles during Weeks 1 and 2 and as pellets thereafter. Broilers from the base line (n = 11), unselected line (n = 13), and the resistant line (n = 15) were used regardless of their evident status (clinically healthy, pre-ascitic, ascitic). Prior to obtaining blood pressure recordings at 6 to 7 wk of age, the percentage saturation of hemoglobin with oxygen was measured using a universal C sensor attached to a pulse oximeter. 4 Oxygen saturation can be used as an index of hypoxemia, and low oximetry readings are highly characteristic of pre-ascitic broilers that subsequently will succumb to ascites (Julian and Mirsalimi, 1992; Wideman and Kirby, 1995a,b; Wideman et al., 1998c). Unanaesthetized birds were placed on a heated surgical board (30 C) and restrained in dorsal recumbancy. All blood pressure readings were made with the transducer at the level of the thoracic inlet. The feathers between the elbow and shoulder joint were plucked. An incision was made over the basilica vein after 2% lydocaine HCl had been administered intracutaneously as a local anesthetic. A Silastic 5 catheter (0.012 in i.d., in o.d.) filled with 0.8% sodium chloride containing 200 IU heparin/ml was inserted into the basilica vein. The catheter was attached

3 470 CHAPMAN AND WIDEMAN by respiratory motion due the noncompliance of the avian lung. After a satisfactory recording was obtained the birds were euthanized by cervical dislocation, and the heart was removed, dissected, and weighed for the calculation of the right/total ventricular weight (RV:TV) ratio as an accurate index of pulmonary hypertension (Burton et al., 1968; Cueva et al., 1974; Sillau et al., 1980; Huchzermeyer et al., 1988; Peacock et al.,1989). Ascites was diagnosed only when ascitic fluid accumulation was evident, or when a plasma clot adhered to the surface of the liver. Individual body weights were collected on Day 14 and again at the time of necropsy. The data were analyzed using a t-test, ANOVA, or ANOVA on ranks using the Student-Newman-Keuls method for the separation of treatment means (Jandel Scientific, 1994). RESULTS FIGURE 1. Typical blood pressure recordings taken from a clinically healthy broiler (a) and a cyanotic broiler (b). The clinically healthy broiler had a right:total ventricular weight ratio (RV:TV) of 0.21 and 88% saturation of hemoglobin with oxygen. The cyanotic broiler had an RV:TV ratio of 0.34 and 68% saturation of hemoglobin with oxygen. PAP = pulmonary arterial pressure. to a BLPR blood pressure transducer interfaced through a Transbridge preamplifier 6 to a Biopac MP 100 data acquisition system using AcqKnowledge 7 software. Pressure recordings were begun, and the catheter was advanced through the right atrium and ventricle into a pulmonary artery while monitoring the characteristic pulse pressures to identify the location (Owen et al., 1995). The catheter was then slowly advanced until its tip became wedged in the pulmonary arterial vasculature. A sudden drop in the pulmonary artery pressure indicated that wedge pressure was being recorded. The catheter then was gradually withdrawn to again record pulmonary arterial, right ventricular, right atrial, and venous pressures. Withdrawing the catheter slowly from its wedged position into the pulmonary artery confirmed that wedge pressure had been recorded. Prior to recording, the system was calibrated for accuracy against a mercury manometer. Pulse pressures were not observed as wedge pressure was being recorded, rather, the rhythmic changes observed in wedge pressure (Figure 1) are caused 6 World Precision Instruments, Sarasota, FL Biopac Systems, Inc., Goleta, CA There were no differences among the lines between Day 14 or final body weights (Table 1). A typical blood pressure recording from a clinically healthy broiler, with high percentage saturation of hemoglobin with oxygen (88%) and a low RV:TV ratio (0.21), showed a mean pulmonary artery pressure of approximately 20 mm Hg (Figure 1a). The blood pressure recording of a pre-ascitic broiler, with low percentage saturation of hemoglobin with oxygen (68%), and a high RV:TV ratio (0.34), showed a mean pulmonary artery pressure 45 mm Hg (Figure 1b). In both cases, the average wedge pressure was quantitatively similar to right atrial pressure instead of pulmonary arterial pressure. Obtaining recordings from ascitic broilers proved to be virtually impossible, consequently ascitic data are not included in Table 1 or the figures that follow. The distended right ventricle and incompetent right atrio-ventricular valve of ascitic broilers prevented advancement and retention of the catheter in the pulmonary artery. The catheter tended to coil within the right ventricle without entering the pulmonary artery or was repeatedly ejected into the right atrium along with blood regurgitated from the right ventricle through the incompetent monocuspid right atrio-ventricular valve. Venous pressure recordings at the level of the wing vein were attempted in 12 ascitic broilers and succeeded in only one. In this solitary ascitic broiler, pressures averaged 16.2 mm Hg, 14.6 mm Hg, 24.3 mm Hg, 33.1 mm Hg, and 18.2 mm Hg for venous, right atrial, right ventricular, pulmonary arterial, and wedge pressures, respectively. Values summarized by line are shown in Figure 2. Right atrial and venous pressures did not differ between the resistant, base, and unselected lines. Also, there were no differences in wedge pressures between the resistant, base, and unselected lines. In contrast, pulmonary arterial pressure of the base population was higher than that of the unselected and resistant lines. Pulmonary arterial pressures of unselected lines and resistant lines however, did not differ. The mean right ventricular pressure was also higher in the base population than in the unselected and resistant lines. Within each line, pulmonary arterial

4 PULMONARY WEDGE PRESSURES IN PULMONARY HYPERTENSION 471 TABLE 1. Day 14 and final BW, the percentage saturation of hemoglobin with oxygen, weights of the right ventricle (RV) and left ventricle plus septum (LV+S), and right:total ventricular weight ratios (RV:TV) in broilers from the ascites resistant line, the base population, and an unselected line Day 14 BW Final BW Oximetry RV LV+S RV:TV Number of mean ± SE mean ± SE mean ± SE mean ± SE mean ± SE mean ± SE Line observations (g) (g) (%) (g) (g) (g) Unselected line ,849 ± ± ± ± ± 0.01 Base population ± 10 2,598 ± ± ± ± ± 0.02 Resistant line ± 7 2,897 ± ± ± ± ± 0.01 pressure was considerably higher than mean wedge pressure, whereas wedge pressure was only modestly higher than venous and right atrial pressures (Figure 2). The RV:TV values for individual broilers, regardless of line, ranged from 0.18 to Data were sorted independent of line into two groups, with birds exhibiting an RV:TV value of 0.28 and above composing one group (n = 14), and those with an RV:TV value of less than 0.28 (n = 25) composing the other (Figure 3). Birds with high RV:TV values had higher right ventricular and pulmonary arterial blood pressures. Wedge pressure, however, was not different between the high and low RV:TV groups and was considerably lower than pulmonary arterial pressure. Wedge pressures of both the high and low RV:TV groups were only modestly higher than venous and right atrial pressures (Figure 3). Oximetry measurements ranged from 65 to 96% saturation of hemoglobin with oxygen for individual broilers regardless of line. In order to ascertain effects of hypoxemia on wedge pressure, individual data were sorted by oxygen saturation of hemoglobin. Birds with an oximetry reading of 85% oxygen saturation (n = 23) showed lower venous, right atrial, right ventricular and pulmonary arterial pressures when compared to birds with an oxygen saturation of <85% (n = 16) (Figure 4). Broilers with <85% saturation of hemoglobin with oxygen had a higher wedge pressure than broilers with high oxygen saturation, although the mean wedge pressures of both groups remained substantially lower than the respective pulmonary arterial pressures (Figure 4). DISCUSSION Wedge pressures comprise an average value across pulmonary venous and left atrial hydrostatic pressures. Wedge pressures were obtained from unanesthetized male broilers having RV:TV ratios ranging from 0.18 to 0.44 and corresponding pulmonary arterial pressures ranging from 13 mm Hg to 47 mm Hg, respectively. In all birds, whether healthy or showing pre-ascitic characteristics such as cyanosis (low blood oxygen levels) and high RV:TV ratios, wedge pressure was similar to the FIGURE 2. Mean blood pressures of the resistant, base and unselected lines, recorded as a catheter was advanced through the wing vein (VP) and then into to the right atrium (RAP), right ventricle (RVP), pulmonary artery (PAP), until wedge pressure (WP) was found. Blood pressures were also recorded as the catheter was withdrawn (PAP2, RVP2, RAP2, VP2). There was no difference in wedge pressure between the resistant, base, and unselected lines. The wedge pressure was modestly higher than venous and right atrial pressures but was considerably lower in all lines than the pulmonary arterial pressure. Letters a and b represent differences (P 0.05) between the broiler lines at a single location. Letters v to z represent differences (P 0.05) within a single line between the different locations. FIGURE 3. Comparison of mean venous (VP, VP2), right atrial (RAP, RAP2), right ventricular (RVP, RVP2), pulmonary arterial (PAP, PAP2), and wedge pressures (WP) between broilers exhibiting a right:total ventricular weight ratio (RV:TV) of 0.28 and above and those with an RV:TV value of less than Mean blood pressures were recorded as a catheter was advanced through the wing vein (VP) and then into to the right atrium (RAP), right ventricle (RVP), pulmonary artery (PAP), until wedge pressure (WP) was found. Blood pressures were also recorded as the catheter was withdrawn (PAP2, RVP2, RAP2, VP2). Letters a and b represent differences (P 0.05) between the two groups at a single location. Letters v to z represent differences (P 0.05) within a group between the different locations.

5 472 CHAPMAN AND WIDEMAN pulmonary artery pressure measured in this ascitic broiler. Moreover, accurately defined pre-ascitic broilers with pulmonary arterial pressures of over 40 mm Hg showed similar wedge pressures when compared to clinically healthy broilers. Care should be taken when gathering data from fully ascitic broilers in order to determine those factors that cause the onset of PHS, as left-sided heart failure may occur as a result of prolonged hypoxemia and cardiac deterioration in the final stages of ascites. However, wedge pressure measurements from preascitic broilers and a solitary ascitic broiler do not suggest that left ventricular or mitral valve insufficiency contribute to the initiation of pulmonary hypertension. ACKNOWLEDGMENTS FIGURE 4. Comparison of venous (VP, VP2), right atrial (RAP, RAP2), right ventricular (RVP, RVP2), pulmonary arterial (PAP, PAP2), and wedge pressures (WP) between broilers exhibiting 85% and above saturation of hemoglobin with oxygen, and those with less than 85% oxygen saturation. Mean blood pressures were recorded as a catheter was advanced through the wing vein (VP) and then into the right atrium (RAP), right ventricle (RVP), pulmonary artery (PAP), until wedge pressure (WP) was found. Blood pressures were also recorded as the catheter was withdrawn (PAP2, RVP2, RAP2, VP2). Letters a and b represent differences (P 0.05) between the two groups at a single location. Letters v to z represent differences (P 0.05) within a group between the different locations. right atrial pressure and was much lower than pulmonary arterial pressure. These observations provide definitive proof that pulmonary hypertension is initiated as a consequence of elevated pulmonary arterial or arteriole (upstream) resistance, because low wedge pressures cannot exist when pulmonary hypertension is caused by the elevated downstream resistances associated with left ventricular or mitral valve insufficiency (Dawson and Lineham, 1997). Broilers from the resistant line that survived prolonged cold stress showed lower pulmonary arterial pressures than survivors from the base population. Wedge pressures between genetic lines however, were very similar and consistently lower than pulmonary arterial pressure. This result provides further evidence that pulmonary arterial hypertension, caused by a mismatch between cardiac output and pulmonary vascular capacity, initiates sequential events leading to ascites under conditions of fast growth and cool temperature challenge (Wideman and French, 1999, 2000). The wedge pressure of one ascitic bird was recorded, but obtaining recordings from 12 additional ascitic individuals proved to be impossible. The distended right ventricle and regurgitating right atrio-ventricular valves in these ascitic birds prevented advancement of a catheter into the pulmonary artery. The ascitic bird had a pulmonary arterial pressure of 33 mm Hg, a right atrial pressure of 14.6 mm Hg, and a wedge pressure of 18.2 mm Hg, which was considerably higher than wedge pressures recorded in any other broilers. However, the higher wedge pressure cannot account for the greatly elevated This research was supported by a US-Israel Binational Agricultural Research and Development grant (BARD US ), and by a grant from Hubbard ISA, Walpole, NH REFERENCES Bhattacharya, J., S. Nanjo, and N. C. Staub, Micropuncture measurement of lung microvacular pressure during 5-HT infusion. J. Appl. Physiol. 52: Burton, R. R., E. L. Besch, and A. H. 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