AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 7, NUMBER 2 April 1990
HEMODYNAMIC CHANGES IN A TERM NEWBORN PIGLET MODEL OF PATENT DUCTUS ARTERIOSUS Thomas A. Malone, M.D., Barbara S. Stonestreet, M.D., Moses Goddard, M.D., and William Oh, M.D.
Patent ductus arteriosus (PDA) is a common form of congenital heart disease in fullterm infants. To investigate the morbidities associated with a left to right PDA shunt, we produced a PDA in six full-term newborn piglets (less than 36 hours old) by bathing the ductus arteriosus with prostaglandin E (PGE) and infiltrating it with formalin. In five agematched piglets, the ductus arteriosus was ligated to serve as controls. Microsphere determinations of left ventricular output (LVO) and regional blood flow (Q) were made on three consecutive days. We produced left to right shunts of 36 to 47% (mean) in the experimental piglets. The experimental piglets had a 22 to 36% increase in LVO with a one- to twofold reduction in percentage of LVO to the kidneys and carcass (p < 0.05). Although percentage of LVO to the gastrointestinal tract was reduced (p < 0.05), no reduction of absolute Q to the gastrointestinal tract was observed. Brain and heart Q were similar in both groups. We conclude that significant hemodynamic changes result from left to right shunting in the full-term newborn piglet with PDA. These hemodynamic changes, such as reduction in renal blood flow, are relevant information that will help explain the morbidities observed in infants with a hemodynamically significant PDA with a left to right shunt.
Isolated patent ductus arteriosus (PDA) is a common congenital heart abnormality in full-term infants.1-2 Functional closure of the ductus arteriosus (DA) occurs in the first 2 days of life and patency of the ductus beyond this period is usually permanent.3 Congenital infections, chronic hypoxia, and a congenital deficiency of ductal smooth muscle4 have all been associated with a PDA in full-term newborns. Premature infants have a higher incidence of PDA than full-term newborns. A number of investigators have reported the hemodynamic changes that result from left to right ductal shunting in premature lambs5-6 and infants.7"9 However, the hemodynamic consequences of left to right shunting in the full-term newborn with reference to redistribution of cardiac output have not been described. Understanding the hemodynamic changes to various organs in the full-term newborn with a left to right
shunt across a PDA is useful in the clinical management of these infants. The purpose of the current study was to establish a newborn piglet model of PDA and to investigate the hemodynamic changes that result from left to right ductal shunting in the first 4 days of life. The study was done at this age to maintain ductal patency experimentally and to simulate conditions of a PDA in newborns in the first few days of life. MATERIALS AND METHODS
Surgical Procedure
Eleven newborn piglets, less than 36 hours of age, were intubated and ventilated on a rodent respirator (Harvard model 681, Millis, MA). Under ni-
Department of Pediatrics, Women & Infants' Hospital of Rhode Island and Brown University Program in Medicine, Providence, Rhode Island Supported in part by the National Research Training Grant IT 32-HD07232, National Institute of Child Health and Human Development, Bethesda, Maryland Reprint requests: Dr. Oh, Department of Pediatrics, Women and Infants' Hospital, 101 Dudley Street, Providence, RI 02905
184
Copyright © 1990 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
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ABSTRACT
NEWBORN PIGLET MODEL OF PDA/Malone et al.
Study Protocol
Determinations of left ventricular output, regional bloodflow,arterial blood gases, and hematocrit were made at postoperative hours: 17 to 21 (day 1), 42 to 46 (day 2), and 65 to 70 (day 3) using the methodology described by Clyman et al.5 The study protocol was approved by the institution's Animal Research Committee. Tissue Preparation and Data Analysis
At autopsy, catheter placement and patency of the DA were confirmed. The organ's regional blood flow was calculated by methods previously described by Rudolph et al 1 1 1 2 and Nowicki et al. 13 Analysis of variance for repeated measures was used within each group on the three study days to
determine statistical significance. If significance was present, Dunnett's multiple range t test was used to confirm the significance at p < 0.05.14 Student's unpaired t test was used for between-group comparisons and statistical significance was determined with the Bonferroni adjustment.14 All data were expressed as mean ± standard deviation. RESULTS
The animal weights were similar in both groups and were 1270±311in the experimental group and 1410 ± 193 in the control group, respectively. As shown in Table 1, heart rate, hematocrit, arterial blood gases, and body temperature did not differ between the groups on the 3 study days and were within the expected range for newborn piglets.15 The experimental group had a higher stroke volume and respiratory rate on day 3 and a lower mean arterial blood pressure on day 1 when compared with the control piglets. Table 2 summarizes the percentage of left to right shunting observed in the six experimental piglets. No right to left shunting was observed in any of the piglets. Bronchial blood flow measured as percentage of left ventricular output to the lungs in the control piglets was 1.0 ± 0.4% on day 1,1.4 ± 0.6% on day 2, and 3.0 ± 1.9% on day 3 (expressed as mean ± standard deviation). The figure illustrates the changes in left ventricular output in the two groups. In the experimental piglets, left ventricular output increased significantly by day 3 compared with day 1. On day 3, there was a significant difference in left ventricular output between the control and the experimental piglets. This increase in left ventricular output in the experimental piglets resulted from an increase in stroke volume and not heart rate (Table 1).
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trous oxide (70%) and local lidocaine (1%) anesthesia, catheters were placed into the left ventricle via the left carotid artery, the inferior vena cava via the right femoral vein, the midthoracic aorta via the left femoral artery, and the right femoral artery. The experimental group (PDA) had an additional catheter placed into the right axillary artery. Following peripheral catheter placement, an open thoractomy was performed under general halothane (1.5%) anesthesia at the level of the third or fourth intercostal space. The DA was identified, bathed with prostaglandin Ej (1 ml), and then was infiltrated beneath the adventitia with a formalin and methylene blue solution, as first described by Rudolph et al 10 and Clyman et al.5 In the control group of 5, the DA was litigated with a surgical hemoclip (no. 523160 Edward Week and Co., Research Triangle Park, NC).
Table 1. Physiologic Parameters Day 1
Parameter
Heart rate (beats/min) Stroke volume (ml-kg"1) Mean arterial blood pressure (mmHg) Respiratory rate (breaths/min) Hematocrit (%) Arterial pH Arterial partial oxygen pressure (mmHg) Arterial partial carbon dioxide pressure (mmHg) Temperature (°C)
Exp* Con* Exp Con Exp Con Exp Con Exp Con Exp Con Exp Con Exp Con Exp Con
*Con: control, n = 5; Exp: = experimental, n = 6. Mean ± SD. Number is given in parentheses. *p < 0.02 versus control group.
190 198 2.08 1.84 52 68 49 47 27.7 28.0 7.47 7.46 78 78 39 38 37.9 38.2
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
25 16 0.45 0.30 5* 10 20 (4) 8 (4) 5.2 1.6 0.05 0.05 13 11 5 4 1.4 0.5
Day 2 183 197 2.56 1.96 55 69 60 47 26.7 29.2 7.45 7.46 69 74 43 38 37.5 37.4
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
21 54 0.61 0.37 6 11 14 (4) 10 5.0 1.3 0.03 0.03 8 4 4 7 0.4 0.4
Day 3 159 157 3.24 1.69 58 68 58 39 26.3 30.2 7.47 7.45 74 81 42 40 37.2 37.7
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
39 (5)f 27 0.63* (5) 0.26 8 (5) 11 8* (5) 5 4.0 (5) 2.2 0.02 (5) 0.04 11 (5) 4 8 (5) 5 0.7 (5) 0.6
+
185
AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 7, NUMBER 2
April 1990
Piglet 1 2 3 4 5 6 Mean ± SD
Day 1
Day 2
Day 3
64 39 28 19 61 5 36 ± 23
67 52 43 19 64 8 42 ± 24
70 ND* 56 27 70 11 47 ± 27
*ND: not determined.
Table 3 summarized the regional blood flow measurements of the various organs in both groups. Renal bloodflowwas significantly lower in the experimental group when compared with the control group on study days 2 and 3. Carcass bloodflowwas significantly lower in the experimental group when compared with the control group on study days 1 and 2. Carcass bloodflowon day 3 did not differ between the two groups. Blood flow to the small bowel, heart, and brain did not show any significant differences between the groups. Table 4 summarizes the organ blood flow determinations expressed as percentage of left ventricular output. In the experimental group, there is a significant decrease in the percentage of left ventricular output to the kidneys (days 2 and 3), the carcass (all 3 days), and the small bowel (days 2 and 3) when compared with the control piglets. Brain and heart bloodflow,expressed as percentage of left ventricular output, show no differences between the groups.
Table 3.
Day 1 Day 2 Day 3
Exp* Con* Exp Con Exp Con
192 272 166 284 163 227
± ± ± ± ± ±
Regional Organ Blood Flow (ml-min-MOO gm~1) Carcass
Kidney 70 84 37+* 73 28+* 41
A left to right shunt of 5 to 70% was produced in our experimental piglets. The large variability in the shunts produced is probably a result of several factors, including age of the piglet at the time of the surgery, effectiveness of the formalin infiltration in maintaining ductal patency, and fluctuations in pulmonary vascular resistance. Younger piglets may have had greater ductal patency resulting in larger left to right shunts,16 and some piglets could have responded to left to right shunting with changes in pulmonary vascular resistance resulting in smaller left to right shunts. The experimental piglets demonstrated a marked increase in left ventricular output during the 3 study days as contrasted with a decrease in left ventricular output in the control piglets (Fig. 1). The decrease in left ventricular output in the control piglets on day 3 was probably secondary to recovery from thoracotomy, which has been documented in newborn lambs,17 and possibly related to the surge of catecholamine that occurs at birth and subsides by day 2 to 3 of life.18 The increase in cardiac output in the experimental group is due to an increase in stroke volume and not heart rate (Table 1). This increase in stroke volume and cardiac output represents the major compensatory response to left to right shunting through a PDA in newborn piglets and corresponds to a similar response described in premature lambs5 and infants9 with a PDA. Absolute blood flow was decreased to the kidneys and carcass in the experimental piglets compared with the control piglets. This is consistent with
15.3 27.0 16.6 27.6 16.9 17.8
± ± ± ± ± ±
5.1 + 5.5 3.9+ 4.3 6.1 3.1*
Small Bowel 100 138 89 131 98 100
± ± ± ± ± ±
32 43 26 35 37 12
Heart 182 255 203 209 169 103
± ± ± ± ± ±
49 102 95 97 69 32
Brain 69 79 83 97 88 87
± ± ± ± ± ±
22 20 11 13 33 14
*Con : control; Exp: experimental. Mean ± SD. P < 0.02 versus control. * P < 0.05 versus day 1.
+
Table 4. Kidney Day 1 Day 2 Day 3
186
Exp* Con* Exp Con Exp Con
4.4 5.8 3.4 5.8 2.9 6.7
± ± ± ± ± ±
2.0 1.6 1.6+ 1.0 1.4+ 1.3
Regional Blood Flow: Percentage of Left Ventricular Output Carcass 31.4 59.4 30.9 59.4 28.6 53.6
*Con: control; Exp: experimental. Mean ± SD. +p < 0.02 versus control.
± ± ± ± ± ±
11.0+ 6.7 15.7+ 7.7 15.0+ 5.2
Small Bowel 9.2 14.1 7.1 13.7 6.7 13.7
± ± ± ± ± ±
3.8 4.8 3.5+ 3.7 3.0+ 3.1
Heart 4.6 6.0 4.2 4.8 3.0 3.4
± ± ± ± ± ±
1.7 1.1 1.5 1.3 0.8 0.4
Brain 4.2 4.5 4.4 5.3 4.2 6.9
± ± ± ± ± ±
1.9 1.2 1.7 0.6 3.1 1.1
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DISCUSSION
Table 2. Percent Left to Right Shunt in Experimental Piglets
NEWBORN PIGLET MODEL OF PDA/Malone et al. LEFT VENTRICULAR OUTPUT ml • (min • kg) 800 700 -
• EXPERIMENTAL • CONTROL M ± SD * p < 0.02 vs Control + p < 0.05 vs Day 1
600 • 500 • 400 • 300 • 200 -
brain. It appears that in the presence of a hemodynamically significantly left to right ductal shunt, the piglets compensated with an increase in cardiac output and changes in local autoregulation of blood flow, resulting in a reduction in the percentage of cardiac output to the low priority organs: the kidney, the carcass, and the small bowel. It is of interest that the percentage of distribution of cardiac output to the brain and heart was unaltered. It is apparent that increases in cardiac output were sufficient to maintain blood flow to these two organs. However, autoregulation is a complex interaction of metabolic, hormonal, and vascular components and future studies specifically studying these modalities are needed before any conclusions can be drawn.
100 •
Figure 1. subjects.
Changes in left ventricular outputs in study
previous studies in premature lambs, which have demonstrated that blood flow to the kidneys and carcass are decreased with left to right ductal shunts. 56 However, the reductions in blood flow to the carcass and the kidney in newborn piglets are seen over the wide range of left to right shunts produced, whereas in the premature lamb model, carcass flow was decreased only with shunts of greater than 40%.5 Previous work in premature lambs demonstrated that left to right ductal shunts resulted in a significant reduction in blood flow to the gastrointestinal tract. 56 In our study, no reduction in absolute small bowel blood flow was observed. This may in part be due to the large interanimal variability of the small bowel blood flow and the magnitude of the left to right shunts; however, a distinct possibility is that the left to right ductal shunts in the full-term newborn piglet do not affect gastrointestinal blood flow as much as in the premature lamb. The values of absolute blood flow to the brain and heart do not differ significantly between the two groups. The possible protection of these two high priority organs from reductions in blood flow with the magnitude of left to right shunts produced in our model is consistent with studies demonstrating the maintenance of heart and brain blood flow in other abnormal physiologic states.19"21 Similarly, in premature lambs, brain bloodflowis decreased only when left to right PDA shunts are larger than 60% and heart blood flow is not compromised regardless of shunt size. When the organ blood flow was expressed as percentage of cardiac output, the experimental piglets demonstrated a redistribution of cardiac output with a decrease in percentage of organ bloodflowto the kidneys, carcass, and small bowel, but no change in the distribution of cardiac output to the heart and
1. Anthony CL, Arnon RG, Fitch CW, eds: Patent ductus arteriosus. In Pediatric Cardiology. New York: Medical Examination Publishing, 1979, p 227 2. Nadas AS, Fyler DC, eds: Communications between systemic and pulmonary circuits with predominantly left to right shunts. In Pediatric Cardiology. Philadelphia: WB Saunders, 1972, p 405 3. Gersony WM: Patent ductus arteriosus. Pediatr Clin North Am 33:546, 1986 4. GiHenberger-de-Groot AC: Persistent ductus arteriosus: Most probably a primary congenital malformation. Br Heart J 6:610, 1977 5. Clyman RI, Mauray F, Heymann MA, Roman CS: Cardiovascular effects of a patent ductus arteriosus in preterm lambs with respiratory distress. J Pediatr 111:579-587, 1987 6. Baylen BG, Ogata H, Ikegami M, Jacobs H, Jobe A, Emmanouilides GC: Left ventricular performance and regional blood flows before and after ductus arteriosus occlusion in premature lambs treated with surfactant. Circulation 67:837-843, 1983 7. Merritt TA, Harris JP, Roghmaounn K, et al: Early closure of the patent ductus arteriosus in very low birth weight infants: A controlled trial. J Pediatr 99:281-286, 1981 8. Martin CG, Snider RA, Katz SM, Peabody JL, Brady JP: Abnormal cerebral blood flow patterns in preterm infants with a large patent ductus arteriosus. J Pediatr 101: 487-493, 1982 9. Alverson DC, Eldridge MW, Johnson JD, et al: Effect of patent ductus arteriosus on left ventricular output in preterm infants. J Pediatr 102:754-757, 1983 10. Rudolph AM, Heymann MA, Fishman N, Lakier JB: Formalin infiltration of the ductus arteriosus. A method for palliation of infants with selected congenital cardiac lesions. N Engl J Med 292:1263-1268, 1975 11. Rudolph AM, Heymann MA: Circulation of the fetus in utero: Methods for studying distribution of blood flow, cardiac output, and organ bloodflow.Circ Res 21:163184, 1967 12. Heymann MA, Payne BD, Hoffman JIE, Rudolph AM: Blood flow measurements with radionuclide-labelled particles. Prog Cardiovasc Dis 20:55-79, 1977 13. Nowicki PT, Stonestreet BS, Hansen NB, Yao AC, Oh W: Gastrointestinal blood flow and oxygen consumption in the awake newborn piglets: Effects of feeding. Am J Physiol 245:G697-702, 1983 14. Wallenstein S, Zucker CL, Fleiss JL: Some statistical methods useful in circulation research. Circ Res 47:1-9, 1980 15. DeRoth L, Downie HG: Basic cardiovascular parameters in the underweight neonatal swine. Biol Neonate 34:155160, 1978 187
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REFERENCES
AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 7, NUMBER 2 April 1990 mental cold stress. Am J Physiol 251:G308-313, 1986 20. Volpe JJ: Neonatal intraventricular hemorrhage. N Engl J Med 304:886-891, 1981 21. Lang CH, Bagby GJ, Ferguson JL, Spitzer JJ: Cardiac output and redistribution of organ blood flow in hypermetabolic sepsis. Am J Physiol 246:R331-337, 1984
The authors thank Armando Signore, Carolyn Mueller, and Ray Boynton for their excellent technical assistance, and Lea M. Gold for preparation of the manuscript.
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16. Rowe RD, Sinclaire JD, Kerr AR, Gage PW: Duct flow and mitral regurgitation during changes of oxygenation in newborn swine. J Appl Physiol 19:1157-1163, 1964 17. Sidi D, Kuipers JRG, Heymann MA, Rudolph AM: Recovery of Cardiovascular function in newborn lambs after thoracotomy. Pediatr Res 16:705-710, 1982 18. Eliot RJ, Lam R, Leake RD, Hobel CJ, Fischer DA: Plasma catecholamine concentrations in infants at birth and during the first 48 hours of life. J Pediatr 96:311-315, 1980 19. Mayfield SR, Stonestreet BS, Brubakk AM, Shaul P, Oh W: Regional blood flow in newborn piglets during environ-
188
HEMODYNAMIC CHANGES IN A TERM NEWBORN PIGLET MODEL OF PATENT DUCTUS ARTERIOSUS Thomas A. Malone, M.D., Barbara S. Stonestreet, M.D., Moses Goddard, M.D., and William Oh, M.D.
Patent ductus arteriosus (PDA) is a common form of congenital heart disease in fullterm infants. To investigate the morbidities associated with a left to right PDA shunt, we produced a PDA in six full-term newborn piglets (less than 36 hours old) by bathing the ductus arteriosus with prostaglandin E (PGE) and infiltrating it with formalin. In five agematched piglets, the ductus arteriosus was ligated to serve as controls. Microsphere determinations of left ventricular output (LVO) and regional blood flow (Q) were made on three consecutive days. We produced left to right shunts of 36 to 47% (mean) in the experimental piglets. The experimental piglets had a 22 to 36% increase in LVO with a one- to twofold reduction in percentage of LVO to the kidneys and carcass (p < 0.05). Although percentage of LVO to the gastrointestinal tract was reduced (p < 0.05), no reduction of absolute Q to the gastrointestinal tract was observed. Brain and heart Q were similar in both groups. We conclude that significant hemodynamic changes result from left to right shunting in the full-term newborn piglet with PDA. These hemodynamic changes, such as reduction in renal blood flow, are relevant information that will help explain the morbidities observed in infants with a hemodynamically significant PDA with a left to right shunt.
Isolated patent ductus arteriosus (PDA) is a common congenital heart abnormality in full-term infants.1-2 Functional closure of the ductus arteriosus (DA) occurs in the first 2 days of life and patency of the ductus beyond this period is usually permanent.3 Congenital infections, chronic hypoxia, and a congenital deficiency of ductal smooth muscle4 have all been associated with a PDA in full-term newborns. Premature infants have a higher incidence of PDA than full-term newborns. A number of investigators have reported the hemodynamic changes that result from left to right ductal shunting in premature lambs5-6 and infants.7"9 However, the hemodynamic consequences of left to right shunting in the full-term newborn with reference to redistribution of cardiac output have not been described. Understanding the hemodynamic changes to various organs in the full-term newborn with a left to right
shunt across a PDA is useful in the clinical management of these infants. The purpose of the current study was to establish a newborn piglet model of PDA and to investigate the hemodynamic changes that result from left to right ductal shunting in the first 4 days of life. The study was done at this age to maintain ductal patency experimentally and to simulate conditions of a PDA in newborns in the first few days of life. MATERIALS AND METHODS
Surgical Procedure
Eleven newborn piglets, less than 36 hours of age, were intubated and ventilated on a rodent respirator (Harvard model 681, Millis, MA). Under ni-
Department of Pediatrics, Women & Infants' Hospital of Rhode Island and Brown University Program in Medicine, Providence, Rhode Island Supported in part by the National Research Training Grant IT 32-HD07232, National Institute of Child Health and Human Development, Bethesda, Maryland Reprint requests: Dr. Oh, Department of Pediatrics, Women and Infants' Hospital, 101 Dudley Street, Providence, RI 02905
184
Copyright © 1990 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
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ABSTRACT
NEWBORN PIGLET MODEL OF PDA/Malone et al.
Study Protocol
Determinations of left ventricular output, regional bloodflow,arterial blood gases, and hematocrit were made at postoperative hours: 17 to 21 (day 1), 42 to 46 (day 2), and 65 to 70 (day 3) using the methodology described by Clyman et al.5 The study protocol was approved by the institution's Animal Research Committee. Tissue Preparation and Data Analysis
At autopsy, catheter placement and patency of the DA were confirmed. The organ's regional blood flow was calculated by methods previously described by Rudolph et al 1 1 1 2 and Nowicki et al. 13 Analysis of variance for repeated measures was used within each group on the three study days to
determine statistical significance. If significance was present, Dunnett's multiple range t test was used to confirm the significance at p < 0.05.14 Student's unpaired t test was used for between-group comparisons and statistical significance was determined with the Bonferroni adjustment.14 All data were expressed as mean ± standard deviation. RESULTS
The animal weights were similar in both groups and were 1270±311in the experimental group and 1410 ± 193 in the control group, respectively. As shown in Table 1, heart rate, hematocrit, arterial blood gases, and body temperature did not differ between the groups on the 3 study days and were within the expected range for newborn piglets.15 The experimental group had a higher stroke volume and respiratory rate on day 3 and a lower mean arterial blood pressure on day 1 when compared with the control piglets. Table 2 summarizes the percentage of left to right shunting observed in the six experimental piglets. No right to left shunting was observed in any of the piglets. Bronchial blood flow measured as percentage of left ventricular output to the lungs in the control piglets was 1.0 ± 0.4% on day 1,1.4 ± 0.6% on day 2, and 3.0 ± 1.9% on day 3 (expressed as mean ± standard deviation). The figure illustrates the changes in left ventricular output in the two groups. In the experimental piglets, left ventricular output increased significantly by day 3 compared with day 1. On day 3, there was a significant difference in left ventricular output between the control and the experimental piglets. This increase in left ventricular output in the experimental piglets resulted from an increase in stroke volume and not heart rate (Table 1).
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trous oxide (70%) and local lidocaine (1%) anesthesia, catheters were placed into the left ventricle via the left carotid artery, the inferior vena cava via the right femoral vein, the midthoracic aorta via the left femoral artery, and the right femoral artery. The experimental group (PDA) had an additional catheter placed into the right axillary artery. Following peripheral catheter placement, an open thoractomy was performed under general halothane (1.5%) anesthesia at the level of the third or fourth intercostal space. The DA was identified, bathed with prostaglandin Ej (1 ml), and then was infiltrated beneath the adventitia with a formalin and methylene blue solution, as first described by Rudolph et al 10 and Clyman et al.5 In the control group of 5, the DA was litigated with a surgical hemoclip (no. 523160 Edward Week and Co., Research Triangle Park, NC).
Table 1. Physiologic Parameters Day 1
Parameter
Heart rate (beats/min) Stroke volume (ml-kg"1) Mean arterial blood pressure (mmHg) Respiratory rate (breaths/min) Hematocrit (%) Arterial pH Arterial partial oxygen pressure (mmHg) Arterial partial carbon dioxide pressure (mmHg) Temperature (°C)
Exp* Con* Exp Con Exp Con Exp Con Exp Con Exp Con Exp Con Exp Con Exp Con
*Con: control, n = 5; Exp: = experimental, n = 6. Mean ± SD. Number is given in parentheses. *p < 0.02 versus control group.
190 198 2.08 1.84 52 68 49 47 27.7 28.0 7.47 7.46 78 78 39 38 37.9 38.2
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
25 16 0.45 0.30 5* 10 20 (4) 8 (4) 5.2 1.6 0.05 0.05 13 11 5 4 1.4 0.5
Day 2 183 197 2.56 1.96 55 69 60 47 26.7 29.2 7.45 7.46 69 74 43 38 37.5 37.4
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
21 54 0.61 0.37 6 11 14 (4) 10 5.0 1.3 0.03 0.03 8 4 4 7 0.4 0.4
Day 3 159 157 3.24 1.69 58 68 58 39 26.3 30.2 7.47 7.45 74 81 42 40 37.2 37.7
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
39 (5)f 27 0.63* (5) 0.26 8 (5) 11 8* (5) 5 4.0 (5) 2.2 0.02 (5) 0.04 11 (5) 4 8 (5) 5 0.7 (5) 0.6
+
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AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 7, NUMBER 2
April 1990
Piglet 1 2 3 4 5 6 Mean ± SD
Day 1
Day 2
Day 3
64 39 28 19 61 5 36 ± 23
67 52 43 19 64 8 42 ± 24
70 ND* 56 27 70 11 47 ± 27
*ND: not determined.
Table 3 summarized the regional blood flow measurements of the various organs in both groups. Renal bloodflowwas significantly lower in the experimental group when compared with the control group on study days 2 and 3. Carcass bloodflowwas significantly lower in the experimental group when compared with the control group on study days 1 and 2. Carcass bloodflowon day 3 did not differ between the two groups. Blood flow to the small bowel, heart, and brain did not show any significant differences between the groups. Table 4 summarizes the organ blood flow determinations expressed as percentage of left ventricular output. In the experimental group, there is a significant decrease in the percentage of left ventricular output to the kidneys (days 2 and 3), the carcass (all 3 days), and the small bowel (days 2 and 3) when compared with the control piglets. Brain and heart bloodflow,expressed as percentage of left ventricular output, show no differences between the groups.
Table 3.
Day 1 Day 2 Day 3
Exp* Con* Exp Con Exp Con
192 272 166 284 163 227
± ± ± ± ± ±
Regional Organ Blood Flow (ml-min-MOO gm~1) Carcass
Kidney 70 84 37+* 73 28+* 41
A left to right shunt of 5 to 70% was produced in our experimental piglets. The large variability in the shunts produced is probably a result of several factors, including age of the piglet at the time of the surgery, effectiveness of the formalin infiltration in maintaining ductal patency, and fluctuations in pulmonary vascular resistance. Younger piglets may have had greater ductal patency resulting in larger left to right shunts,16 and some piglets could have responded to left to right shunting with changes in pulmonary vascular resistance resulting in smaller left to right shunts. The experimental piglets demonstrated a marked increase in left ventricular output during the 3 study days as contrasted with a decrease in left ventricular output in the control piglets (Fig. 1). The decrease in left ventricular output in the control piglets on day 3 was probably secondary to recovery from thoracotomy, which has been documented in newborn lambs,17 and possibly related to the surge of catecholamine that occurs at birth and subsides by day 2 to 3 of life.18 The increase in cardiac output in the experimental group is due to an increase in stroke volume and not heart rate (Table 1). This increase in stroke volume and cardiac output represents the major compensatory response to left to right shunting through a PDA in newborn piglets and corresponds to a similar response described in premature lambs5 and infants9 with a PDA. Absolute blood flow was decreased to the kidneys and carcass in the experimental piglets compared with the control piglets. This is consistent with
15.3 27.0 16.6 27.6 16.9 17.8
± ± ± ± ± ±
5.1 + 5.5 3.9+ 4.3 6.1 3.1*
Small Bowel 100 138 89 131 98 100
± ± ± ± ± ±
32 43 26 35 37 12
Heart 182 255 203 209 169 103
± ± ± ± ± ±
49 102 95 97 69 32
Brain 69 79 83 97 88 87
± ± ± ± ± ±
22 20 11 13 33 14
*Con : control; Exp: experimental. Mean ± SD. P < 0.02 versus control. * P < 0.05 versus day 1.
+
Table 4. Kidney Day 1 Day 2 Day 3
186
Exp* Con* Exp Con Exp Con
4.4 5.8 3.4 5.8 2.9 6.7
± ± ± ± ± ±
2.0 1.6 1.6+ 1.0 1.4+ 1.3
Regional Blood Flow: Percentage of Left Ventricular Output Carcass 31.4 59.4 30.9 59.4 28.6 53.6
*Con: control; Exp: experimental. Mean ± SD. +p < 0.02 versus control.
± ± ± ± ± ±
11.0+ 6.7 15.7+ 7.7 15.0+ 5.2
Small Bowel 9.2 14.1 7.1 13.7 6.7 13.7
± ± ± ± ± ±
3.8 4.8 3.5+ 3.7 3.0+ 3.1
Heart 4.6 6.0 4.2 4.8 3.0 3.4
± ± ± ± ± ±
1.7 1.1 1.5 1.3 0.8 0.4
Brain 4.2 4.5 4.4 5.3 4.2 6.9
± ± ± ± ± ±
1.9 1.2 1.7 0.6 3.1 1.1
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DISCUSSION
Table 2. Percent Left to Right Shunt in Experimental Piglets
NEWBORN PIGLET MODEL OF PDA/Malone et al. LEFT VENTRICULAR OUTPUT ml • (min • kg) 800 700 -
• EXPERIMENTAL • CONTROL M ± SD * p < 0.02 vs Control + p < 0.05 vs Day 1
600 • 500 • 400 • 300 • 200 -
brain. It appears that in the presence of a hemodynamically significantly left to right ductal shunt, the piglets compensated with an increase in cardiac output and changes in local autoregulation of blood flow, resulting in a reduction in the percentage of cardiac output to the low priority organs: the kidney, the carcass, and the small bowel. It is of interest that the percentage of distribution of cardiac output to the brain and heart was unaltered. It is apparent that increases in cardiac output were sufficient to maintain blood flow to these two organs. However, autoregulation is a complex interaction of metabolic, hormonal, and vascular components and future studies specifically studying these modalities are needed before any conclusions can be drawn.
100 •
Figure 1. subjects.
Changes in left ventricular outputs in study
previous studies in premature lambs, which have demonstrated that blood flow to the kidneys and carcass are decreased with left to right ductal shunts. 56 However, the reductions in blood flow to the carcass and the kidney in newborn piglets are seen over the wide range of left to right shunts produced, whereas in the premature lamb model, carcass flow was decreased only with shunts of greater than 40%.5 Previous work in premature lambs demonstrated that left to right ductal shunts resulted in a significant reduction in blood flow to the gastrointestinal tract. 56 In our study, no reduction in absolute small bowel blood flow was observed. This may in part be due to the large interanimal variability of the small bowel blood flow and the magnitude of the left to right shunts; however, a distinct possibility is that the left to right ductal shunts in the full-term newborn piglet do not affect gastrointestinal blood flow as much as in the premature lamb. The values of absolute blood flow to the brain and heart do not differ significantly between the two groups. The possible protection of these two high priority organs from reductions in blood flow with the magnitude of left to right shunts produced in our model is consistent with studies demonstrating the maintenance of heart and brain blood flow in other abnormal physiologic states.19"21 Similarly, in premature lambs, brain bloodflowis decreased only when left to right PDA shunts are larger than 60% and heart blood flow is not compromised regardless of shunt size. When the organ blood flow was expressed as percentage of cardiac output, the experimental piglets demonstrated a redistribution of cardiac output with a decrease in percentage of organ bloodflowto the kidneys, carcass, and small bowel, but no change in the distribution of cardiac output to the heart and
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REFERENCES
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The authors thank Armando Signore, Carolyn Mueller, and Ray Boynton for their excellent technical assistance, and Lea M. Gold for preparation of the manuscript.
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