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Prostaglandin D2 reverses induced pulmonary hypertension in the newborn lamb
458
March 1982 The Journal o f P E D I A T R I C S
Prostaglandin D: reverses induced pulmonary hypertension in the newborn lamb We investigated the effects o f PGD2 in six near-term newborn lambs with induced pulmonary hypertension (mean pulmonary arterial pressure equal to mean systemic arterial pressure). In each lamb PGD2 decreased mean pulmonary arterial pressure, increased pulmonary blood fow, and thereJbre decreased pulmonary vascular resistance without changing mean systemic arterial pressure. A bolus dose o f 20 I~g PGD2 decreased pulmonary arterial pressure by 30%, increased pulmonary blood flow by 45 %, and decreased pulmonary vascular resistance by 54 % ; systemic arterial pressure increased by 4%. At all doses, pulmonary vascular resistance fell further than systemic vascular resistance, the ratio o f percent change in pulmonary vascular resistance to percent change in systemic vascular resistance was approximately 2: 1. Similar changes occurred with continuous infusions o f PGD2. These effects suggest a role for PGD2 in the normal regulation of pulmonary vascular resistance and blood flow at birth. In addition, because PGD2 in these circumstances increases pulmonary blood flow and reduces pulmonary arterial pressure, it may merit further trials in nonhuman primates; it may be an appropriate agent for treating newborn infants with persistent pulmonary hypertension.
Scott J. Soifer, M.D., Frederick C. Morin llI, M.D., and Michael A. Heymann, M.D.,* S a n F r a n c i s c o , C a l i f .
THE SYNDROME of persistent pulmonary hypertension of the newborn infant with cyanosis, tachypnea, and an anatomically normal heart 17 accounts for approximately 1% of all admissions to newborn intensive care units.5 Pulmonary blood flow remains low because pulmonary vascular resistance remains abnormally high after birth. The clinical course is variable, and therapy has been mainly supportive and nonspecific; it has included hyperventilation and infusion of a vasodilating agent such as tolazoline1,47 and prostacyclin? These agents are generalized vasodilators and usually produce systemic hypotension that often requires administration of large volumes of fluid
From the Cardiovascular Research Institute and the Departments of Pediatrics and Obstetrics, Gynecology, and Reproductive Sciences, University o f California, San Francisco. Supported by grants from the United States Public Health Service, HL 24056, HL 23681, HL 07192, and HL 07185. *Reprint address: 1403-HSE, University of California, San Francisco, CA 94143.
Vol. 100, No. 3, pp. 458-463
or colloid, or infusion of systemic vasoconstrictors such as dopamine, to maintain adequate systemic perfusion. Despite these measures the mortality of this syndrome remains in excess of 40%. 5,6 Abbreviations used PGDz: prostaglandin DE PGIz: prostacyclin In an effort to identify a more specific vasodilating agent for treatment of this syndrome prostacyclin and other prostaglandins have been evaluated in fetal and neonatal animals.9~4 These agents reduce pulmonary vascular resistance, but simultaneously reduce systemic vascular resistance equally and therefore have no advantage over tolazoline. Cassin et al ~5 recently showed that in perfused fetal goat lungs prostaglandin D 2 produces a fall in pulmonary arterial pressure with no apparent effect on the systemic circulation. We studied in more detail, in six intact animals, the effects of PGD2 on the pulmonary and systemic circulations.
0022-3476/82/030458+06500.60/0 9 1982 The C. V. Mosby Co.
Volume 100 Number 3
Prostaglandin D2 and pulmonary hypertension
459
Table. Measured variables during normal oxygenation, hypoxia, and hypoxia after 20 ~g of PGD2 based on five lambs, all values are means _ standard error
Hypoxia
Arterial Po2 (torr) Arterial Pco2 (torr) Arterial pH Mean pulmonary arterial pressure (mm Hg) Mean systemic arterial pressure (mm Hg) Pulmonary blood flow (ml/kg/min) Pulmonary vascular resistance (ram Hg/ml/kg/min)
Room air
Before
After 20 ~g PGDe
75 _+ 3 33 -+ 3 7.40 _+ 0.04
22 +_ 4 30 + 2 7.38 +_ 0.2
24 _+ 5 32 • 1 7.40 _+ 0.01
50 +_ 3
64 _+ 5
47 +_ 3
72 _+ 2
66 +_ 2
67 _+ 2
160 _+ 19
137 _+ 17
208 _+ 28
0.30 _+ 0.04
0.42 _+ 0.07
0.24 _+ 0.04
METHODS Six mixed-breed pregnant ewes at 144 to 148 days' gestation underwent hysterotomy; polyvinyl catheters were inserted into a fetal hind limb artery and vein and the jugular vein, as described) 6 In order to prevent fetal respiratory movement during surgery, pancuronium bromide (0.5 mg) was given intravenously. A tracheostomy was performed and a fluid-filled, large bore polyvinyl catheter was inserted for later ventilation. After thoracotomy, a precalibrated electromagnetic flow transducer was placed around the main pulmonary trunk, and polyvinyl catheters were placed in the pulmonary trunk proximal and distal to the flow transducer and in the left atrium. 16 The ductus arteriosus was ligated, a chest tube was inserted, and the chest was closed. The umbilical cord was ligated, the lamb was placed on a heating pad under a radiant warmer, and mechanical ventilation was begun with a Harvard animal ventilator at a rate of 30 to 40/minute with a tidal volume of about 10 ml/kg estimated weight. Each lamb was ventilated with room air. After 15 minutes, the inspired oxygen concentration was decreased by the addition of nitrogen until mean pulmonary arterial blood pressure rose to approximate mean systemic arterial blood pressure. In five lambs, 0.1 to 100 #g doses of PGD2, selected randomly, were given into the distal pulmonary arterial catheter; 30 seconds were used for each injection. In three lambs, PGD2 was infused into the distal pulmonary arterial catheter at doses of 0.5 to 20 #g/minute for periods of 7.5 to 15 minutes. In two animals, the infusions were also into the inferior vena cava and descending aorta. Control infusions of an identical volume of vehicle without drug were given at the beginning of each experiment. After each drug administration, flows and pressures were allowed to return to baseline before the next dose was
given. The absence of intracardiac shunting during hypoxia and during infusions of PGD2 was demonstrated by the indocyanine green dye dilution technique. Each animal was weighed at the end of the study. There is a large endogenous production of prostaglandins associated with surgery and delivery/v Because this might interfere with the assessment of the administered prostaglandin, 5 mg of lyophilized indomethacin (Lyoindocin) was given intravenously during and at the end of surgery to suppress endogenous production. The indomethacin and PGD2 were prepared immediately prior to each experiment. One milligram of desiccated PGD2 was removed from storage in a refrigerator at -20~ and dissolved in 0.06 ml of absolute alcohol; this solution was diluted with sterile water to make 1 ml aliquots with various concentrations of PGDE (0.1 to 100 #g/ml) and then stored on ice in a darkened container. Pulmonary arterial, systemic arterial, right atrial, and left atrial pressures and pulmonary arterial blood flow were recorded continuously. 16 Phasic airway pressure was measured by a Statham DM131PC airway pressure transducer. Systemic arterial blood PO2, Pco2, and pH, oxygen saturation, and hemoglobin concentration were measured intermittently. To determine the effects of PGD2 during hypoxia, baseline values were measured immediately prior to each PGD2 administration. Response values for each bolus injection were taken at the point of lowest mean pulmonary arterial pressure, and for each infusion when a new steady state was reachedl Pulmonary vascular resistance was calculated from mean pulmonary arterial and left atrial pressures and pulmonary blood flow per kilogram body weight. Because there was no intracardiac shunting, cardiac output was equal to pulmonary blood flow and systemic vascular resistance could be calculated from
460
Soifer, Morin, and Heymann
The Journal of Pediatrics March 1982
Righl Atriol 20[.= Pressure (turn Hg) 0
Left Ahial 2~ Pressure (mm Hg) 0 L_
i
II
-
i
I
II
I00 Pulmonary Arterial Pressure (ram Hg)
O
Meon 100V Pulmonory Aderiol Pressure (mm Hg) OL
Hear! Rote
300 u
(beots/rain} 180LMean Pulmonary 1300[Arteriol Blood J _ . _ . J Flow (ml/min) O6 tim/)7 ~ P6Oe 5 zzg/kg
Fig. 1. The effects of a bolus injection of 5 /~g/kg of PGD= into the pulmonary artery. mean systemic arterial and right atrial pressures and pulmonary blood flow per kilogram body weight. The results from all bolus injections were pooled and a linear regression analysis of the percent change from baseline of the vascular pressures, flows, and resistances on the log~0 of the dose of PGD2/kg body weight was performed? The slopes of the regressions for pulmonary and systemic vascular resistance on the dose of PGDz were compared by paired t testJ 8 The infusion data were analyzed identically. RESULTS In each lamb, with induction of hypoxia after indomethacin administration, mean pulmonary arterial pressure increased to approximate the slightly decreased systemic arterial pressure 19 (Table). Pulmonary blood flow decreased, and calculated pulmonary vascular resistance increased. During hypoxia Pao2 fell into the 15 to 25 torr range whereas Paco2 and pH remained normal, When given by bolus injection, PGD2 decreased pulmonary arterial pressure and increased pulmonary blood flow and heart rate in each lamb (Fig. 1). Systemic arterial and left atrial pressures increased slightly in most instances. The maximum effect occurred approximately 45 seconds after injection. There were no significant changes in arterial blood gas values, pH, or phasic airway pressure. The pooled data from all lambs (Table and Fig. 2) show that, at a total dose of 20 ~g, beyond which there w[is increase in effect, there was a 27% decrease in mean pulmonary arterial pressure, a 52% increase in pulmonary
blood flow, a 2% increase in mean systemic arterial pressure, and a 43% fall in calculated pulmonary vascular resistance, Regression analysis of the pooled data reveal the fall in mean pulmonary arterial pressure and the increase in pulmonary blood flow to be dose related (P < 0.001 and P < 0.002, respectively), but the change in mean systemic arterial pressure was not significant. Calculated pulmonary vascular resistance fell in a dose-related manner (Fig. 3). Systemic vascular resistance also decreased, but to a lesser degree, and was associated with the increase in cardiac output without a significant change in systemic arterial pressure. The ratio of the percent change of pulmonary vascular resistance to the percent change in systemic vascular resistance was approximately 2: 1 at each dose. The slope (Fig. 4) of the regression of the percent change in pulmonary vascular resistance vs dose of PGD2 was significantly steeper than that of the percent change in systemic vascular resistance (P < 0.001), indicating a significantly greater, dose-related effect on calculated pulmonary vascular resistance. Continuous infusion of PGD2 had similar hemodynamic effects (Fig. 5). There was a significant dose-related decrease in mean pulmonary arterial pressure (P < 0.01) and calculated pulmonary vascular resistance (P < 0.01), and a significant dose-related increase in pulmonary blood flow (P < 0.01), without change in systemic arterial pressure (Fig. 6). These effects lasted for the duration (up to 15 minutes) of the infusion and were similar in magnitude to those seen with bolus injection. Similar responses were also seen with infusions into either the inferior vena cava or the descending aorta. DISCUSSION We found that PGD2 lowered pulmonary arterial pressure without significantly changing systemic arterial pressure in near-term newborn lambs in which pulmonary hypertension had been induced by ventilation with a low inspired 02 concentration and administration of indomethacin. No other pharmacologic agent has been shown to have this greater specificity for the pulmonary circulation. Prostaglandins 12, Eb and E2, tolazoline, and acetylcholine all decrease pulmonary arterial pressure and increase pulmonary blood flow in fetal and newborn animals with pulmonary hypertension; they also decrease systemic arterial pressure significantly. Pulmonary blood flow and cardiac output were markedly increased by PGD2. This increase was associated with the increase in heart rate and probably was enhanced by the decrease in afterload of the right ventricle secondary to the decrease in pulmonary arterial pressure. Because pulmonary arterial pressure decreased and systemic arterial pressure remained unchanged with the increase in
Volume 1O0 Number 3
Prostaglandin De and pulmonary hypertension
4 61
PULMONARY BLOOD FLOW
(..9
=.,--
oN_
L)
Z
MEAN SYSTEMIC ARTERIAL PRESSURE
-40~--
MEAN PULMONARY ARTERIAL PRESSURE
/ 'i 0.1
I I
I IO
I IOO
PROSTAGLANDIN D2 (2LLg)
Fig. 2. The effects of increasing doses of PGDz given by bolus injection into the pulmonary artery of five lambs. Values are means _+SE.
VASCULAR
PULMONARY V A S C U L A R RESISTANCE
RESISTANCE
O
--2r
w -4c[-
--40
o o-",~~"
sy.,=9.5,
~/.z r~ 0
W IX
--6C
--60'
o'OI
[
I
I
I
[
OII
I
IO
0.01
0, I
PROSTAGLANOIN DR ( # g / k g )
Fig. 3. Regression analysis of percentage changes in pulmonary vascular resistance vs the log~0of the dose of PGD2. Thirty-eight bolus injections were given into the pulmonary artery in five lambs. The 95% confidence limits are shown. cardiac output, pulmonary vascular resistance decreased more than systemic vascular resistance at each dose of PGD2. We speculate tha;t the decrease in pulmonary vascular resistance occurred because PGD2 directly dilated the small pulmonary arteries. At the 20 #g dose, PGD2 returned pulmonary vascular resistance, as well as pulmonary arterial pressure and pulmonary blood flow, to approximately those values recorded during ventilation with room air. The PGD2 eliminated the induced increase in pulmonary vasomotor tone. In pump-perfused fetal goat lungs, Cassin et a115 have shown that PGD2 decreases pulmonary arterial pressure without changing systemic arterial pressure. In lambs 2 to 4 weeks old, with hypoxic pulmonary hypertension, Lock et
•
[ I
IO
PROSTAGLANDIN D2 (.,~.g/kg)
Fig. 4. Regression analyses of percentage changes in systemic and pulmonary vascular resistances vs the log~0 of the dose of PGD2. Thirty-seven injections were given into the pulmonary artery of five lambs; P < 0.001 for the regression of systemic vascular resistance and P < 0.00l for the regression of pulmonary vascular resistance. The slope of the regression for pulmonary vascular resistance is significantly steeper than the slope for systemic vascular resistance (P < 0.001).
aP 4 have shown that PGD2 increases pulmonary vascular resistance. In a preliminary study we have found that PGD2 produces mild pulmonary vasoconstriction in the lamb at one week of age. In adult dogs, Wasserman et aF ~ have shown that PGDz increases pulmonary arterial pressure and causes bronchoconstriction. 2~ The PGD2 did not alter Pac% or phasic airway pressure in our lambs and bronchoconstriction apparently did not occur. Because the difference in the responses of the systemic and pulmonary circulations in the newborn animals and the changes in the
462
Soifer, Matin, and Heymann
The Journal of Pediatrics March 1982
PULMONARY
Right Atrial 20[r- IIII Pressure (mmHg) 0 L
I I
'e,, Atria,
40
Pressure (mm Hg) I00[ Systemic Arterial Pressure (mm Hg}
_ III
I
I
III
IIIIIII
0L IOC Pulmonary Arterial Pressure (mm Hg) C Mean IO0[Pulmonary Arterial J ~ . _ Pressure (rnm Hg) OL Heart Rate (beats/rain)
BLOOD FLOW
IIII I II
u~ (.9 I
0
z uJ n~ o. - 2 0
--40
240 r 120L
Mean Pulmonary 800 F Arterial 81ood Flow (rnl/rain) 01-
20
z
MEAN PULMONARY I IIII
f
PGD2
1.0
I
I
I
I
I IIII
ARTERIAL
I0.0
PRESSURE I
PROSTAGLANDIN 02 ()-tg/min)
25 ).,glkg/m~n
l I Ifmn
Fig. 6. Effects of increasing doses of PGD~ given by infusion into the pulmonary artery. Values are means _+SE.
Fig. 5. The effects of an infusion of 2.5 #g/kg/minute PGD~ into the pulmonary artery.
pulmonary vascular effect with advancing age suggest a role for PGD2 in the normal regulation of pulmonary blood flow and pulmonary vascular resistance in the immediate postnatal period, further studies seem indicated. The effects of PGD2 on the pulmonary circulation in the immediate newborn period may be important in the clinical management of newborn infants in whom a normal pulmonary circulation is not established immediately after birth (persistent pulmonary hypertension, meconium aspiration, pneumonia, and sepsis) in part due to pulmonary vasospasmJ 7,'8 If, in these infants, PGD2 had effects similar to those in our lambs, pulmonary vascular resistance would fall and pulmonary and systemic blood flows would increase, resulting in improved systemic oxygen delivery. In addition, because pulmonary arterial pressure falls and systemic arterial pressure is unaltered, rightto-left shunting through the ductus arteriosus would diminish or even disappear. This too would result in improved systemic oxygen delivery. Thus, PGD2 warrants further experimental evaluation as a potential agent for treating newborn infants with significant pulmonary hypertension. The PGD2 was kindly supplied by Dr. John Pike of the Upjohn Company. Ly0indocin was kindly supplied by Dr. Marten Rosenberg of Merck, Sharpe, and Dohme. We gratefully acknowledge the assistance of Ms. Christine Roman, Ms. Susan Axelrod, and Mr. Les Williams. REFERENCES 1. Goetzman BW, Sunshine P, Johnson JD, Wennberg RP, Hackel A, Merten DF, Bartoletti AL, and Silverman NH:
2.
3.
4.
5. 6.
7.
8.
9.
I0.
I I.
12.
13.
Neonatal hypoxia and pulmonary vasospasm: Response to tolazoline, J PEDI~TR 89:617, 1976. Levin DL, Heymann MA, Kitterman JA, Gregory GA, Phibbs RH, and Rudolph AM: Persistent pulmonary hypertension of the newborn infant, J PEDIATR89:626, 1976. Peckham G J, and Fox WW: Physiologic factors affecting pulmonary artery pressure in infants with persistent pulmonary hypertension, J PEDIATR93:1005, 1978. Stevenson DK, Kasting DS, Darnall RA, Aviagno RL, Johnson JD, Malachowski N, Beets CL, and Sunshine P: Hypoxemia associated with neonatal pulmonary disease: The use and limitations of tolazoline, J PEDIATR95:595, 1979. Goetzman BW, and Riemenschneider TA: Persistence of the fetal circulation, Pediatr Rcs 2:37, 1980. Stevens DC, Schreiner RL, Bull M J, Bryson CO, Lemons JA, Gresham EL, Grosfeld JL, Weber TR: An analysis of totazoline therapy in the critically ill neonate, J PEDIATR 15:964, 1980. Drummond WH, Gregory GA, Heymann MA, and Phibbs RH: The independent effects of hyperventilation, tolazoline, and dopamine on infants with persistent pulmonary hypertension, J PEDIATR98:603, 1981. Lock JE, alley PM, Coceani F, Swyer PR, and Rowe RD: Use of prostacyclin in persistent fetal circulation, Lancet 1:1343, 1979. Tyler T, Leffler C, Wallis R, and Cassin S: Effects of prostaglandins of the E-series on pulmonary and systemic circulations of newborn goats during normoxia and hypoxia, Prostaglandins 10:963, 1975. Leffler WC, and Hessler JR: Pulmonary and systemic vascular effects of exogenous prostaglandin I2 in fetal lambs, Eur J Pharmacol 54:37, 1979. Green R, Rajas J, and Sundell H: Pulmonary vascular response to prostacyclin in fetal lambs, Prostaglandins 18:927, 1979. Cassin S: Rote of prostaglandins and thromboxanes in the control of the pulmonary circulation in the fetus and newborn, Sere Perinatol 4:101, 1980. Tripp ME, Drummond WH, Heymann MA, and Rudolph
Volume 1O0 Number 3
14.
15.
16.
17.
AM: Hemodynamic effects of pulmonary arterial infusion of vasodilators in newborn lambs, Pediatr Res 14:1311, 1980. Lock JE, Olley PM, and Coceani F: Direct pulmonary vascular responses to prostaglandins in the newborn lamb, Am J Physiol 238:H631, 1980. Cassin S, Tod M, Philips J, Frisinger J, Jordan J, and Gibbs C: Effects of prostaglandin D2 On perinatal circulation, Am J Physiol 240:H755, 1981. Rudolph AM, and Heymann MA: Methods for studying the circulation of the fetus in utero, in Nathanielsz PW, editor, Animal models in fetal medicine (l), vol 2, Amsterdam, 1980, Elsevier North Holland Biomedical Press, p 1. Clyman R1, Mauray F, Roman C, Rudolph AM, and Hey-
Prostaglandin D2 and pulmonary hypertension
463
mann MA: Circulating prostaglandin E2 concentrations and patent ductus arteriosus in fetal and neonatal lambs, J PEDIATR 97:455, 1980. 18. Snedecor GW, and Cochran WG: Statistical methods, ed 7, Ames, 1980, The Iowa State University Press, pp 149, 387. 19. Leffler CW, Tyler TL, and Cassin S: Effect of indomethacin on pulmonary vascular response to ventilation of fetal goats, Am J Physiol 234:H346, 1978. 20. Wasserman MA, DuCharme DW, Griffin RL, Pegraaf GL, and Robinson FG: Bronchopulmonary and cardiovascular effects of prostaglandin Dz in the dog, Prostaglandins 13:255, 1977.
March 1982 The Journal o f P E D I A T R I C S
Prostaglandin D: reverses induced pulmonary hypertension in the newborn lamb We investigated the effects o f PGD2 in six near-term newborn lambs with induced pulmonary hypertension (mean pulmonary arterial pressure equal to mean systemic arterial pressure). In each lamb PGD2 decreased mean pulmonary arterial pressure, increased pulmonary blood fow, and thereJbre decreased pulmonary vascular resistance without changing mean systemic arterial pressure. A bolus dose o f 20 I~g PGD2 decreased pulmonary arterial pressure by 30%, increased pulmonary blood flow by 45 %, and decreased pulmonary vascular resistance by 54 % ; systemic arterial pressure increased by 4%. At all doses, pulmonary vascular resistance fell further than systemic vascular resistance, the ratio o f percent change in pulmonary vascular resistance to percent change in systemic vascular resistance was approximately 2: 1. Similar changes occurred with continuous infusions o f PGD2. These effects suggest a role for PGD2 in the normal regulation of pulmonary vascular resistance and blood flow at birth. In addition, because PGD2 in these circumstances increases pulmonary blood flow and reduces pulmonary arterial pressure, it may merit further trials in nonhuman primates; it may be an appropriate agent for treating newborn infants with persistent pulmonary hypertension.
Scott J. Soifer, M.D., Frederick C. Morin llI, M.D., and Michael A. Heymann, M.D.,* S a n F r a n c i s c o , C a l i f .
THE SYNDROME of persistent pulmonary hypertension of the newborn infant with cyanosis, tachypnea, and an anatomically normal heart 17 accounts for approximately 1% of all admissions to newborn intensive care units.5 Pulmonary blood flow remains low because pulmonary vascular resistance remains abnormally high after birth. The clinical course is variable, and therapy has been mainly supportive and nonspecific; it has included hyperventilation and infusion of a vasodilating agent such as tolazoline1,47 and prostacyclin? These agents are generalized vasodilators and usually produce systemic hypotension that often requires administration of large volumes of fluid
From the Cardiovascular Research Institute and the Departments of Pediatrics and Obstetrics, Gynecology, and Reproductive Sciences, University o f California, San Francisco. Supported by grants from the United States Public Health Service, HL 24056, HL 23681, HL 07192, and HL 07185. *Reprint address: 1403-HSE, University of California, San Francisco, CA 94143.
Vol. 100, No. 3, pp. 458-463
or colloid, or infusion of systemic vasoconstrictors such as dopamine, to maintain adequate systemic perfusion. Despite these measures the mortality of this syndrome remains in excess of 40%. 5,6 Abbreviations used PGDz: prostaglandin DE PGIz: prostacyclin In an effort to identify a more specific vasodilating agent for treatment of this syndrome prostacyclin and other prostaglandins have been evaluated in fetal and neonatal animals.9~4 These agents reduce pulmonary vascular resistance, but simultaneously reduce systemic vascular resistance equally and therefore have no advantage over tolazoline. Cassin et al ~5 recently showed that in perfused fetal goat lungs prostaglandin D 2 produces a fall in pulmonary arterial pressure with no apparent effect on the systemic circulation. We studied in more detail, in six intact animals, the effects of PGD2 on the pulmonary and systemic circulations.
0022-3476/82/030458+06500.60/0 9 1982 The C. V. Mosby Co.
Volume 100 Number 3
Prostaglandin D2 and pulmonary hypertension
459
Table. Measured variables during normal oxygenation, hypoxia, and hypoxia after 20 ~g of PGD2 based on five lambs, all values are means _ standard error
Hypoxia
Arterial Po2 (torr) Arterial Pco2 (torr) Arterial pH Mean pulmonary arterial pressure (mm Hg) Mean systemic arterial pressure (mm Hg) Pulmonary blood flow (ml/kg/min) Pulmonary vascular resistance (ram Hg/ml/kg/min)
Room air
Before
After 20 ~g PGDe
75 _+ 3 33 -+ 3 7.40 _+ 0.04
22 +_ 4 30 + 2 7.38 +_ 0.2
24 _+ 5 32 • 1 7.40 _+ 0.01
50 +_ 3
64 _+ 5
47 +_ 3
72 _+ 2
66 +_ 2
67 _+ 2
160 _+ 19
137 _+ 17
208 _+ 28
0.30 _+ 0.04
0.42 _+ 0.07
0.24 _+ 0.04
METHODS Six mixed-breed pregnant ewes at 144 to 148 days' gestation underwent hysterotomy; polyvinyl catheters were inserted into a fetal hind limb artery and vein and the jugular vein, as described) 6 In order to prevent fetal respiratory movement during surgery, pancuronium bromide (0.5 mg) was given intravenously. A tracheostomy was performed and a fluid-filled, large bore polyvinyl catheter was inserted for later ventilation. After thoracotomy, a precalibrated electromagnetic flow transducer was placed around the main pulmonary trunk, and polyvinyl catheters were placed in the pulmonary trunk proximal and distal to the flow transducer and in the left atrium. 16 The ductus arteriosus was ligated, a chest tube was inserted, and the chest was closed. The umbilical cord was ligated, the lamb was placed on a heating pad under a radiant warmer, and mechanical ventilation was begun with a Harvard animal ventilator at a rate of 30 to 40/minute with a tidal volume of about 10 ml/kg estimated weight. Each lamb was ventilated with room air. After 15 minutes, the inspired oxygen concentration was decreased by the addition of nitrogen until mean pulmonary arterial blood pressure rose to approximate mean systemic arterial blood pressure. In five lambs, 0.1 to 100 #g doses of PGD2, selected randomly, were given into the distal pulmonary arterial catheter; 30 seconds were used for each injection. In three lambs, PGD2 was infused into the distal pulmonary arterial catheter at doses of 0.5 to 20 #g/minute for periods of 7.5 to 15 minutes. In two animals, the infusions were also into the inferior vena cava and descending aorta. Control infusions of an identical volume of vehicle without drug were given at the beginning of each experiment. After each drug administration, flows and pressures were allowed to return to baseline before the next dose was
given. The absence of intracardiac shunting during hypoxia and during infusions of PGD2 was demonstrated by the indocyanine green dye dilution technique. Each animal was weighed at the end of the study. There is a large endogenous production of prostaglandins associated with surgery and delivery/v Because this might interfere with the assessment of the administered prostaglandin, 5 mg of lyophilized indomethacin (Lyoindocin) was given intravenously during and at the end of surgery to suppress endogenous production. The indomethacin and PGD2 were prepared immediately prior to each experiment. One milligram of desiccated PGD2 was removed from storage in a refrigerator at -20~ and dissolved in 0.06 ml of absolute alcohol; this solution was diluted with sterile water to make 1 ml aliquots with various concentrations of PGDE (0.1 to 100 #g/ml) and then stored on ice in a darkened container. Pulmonary arterial, systemic arterial, right atrial, and left atrial pressures and pulmonary arterial blood flow were recorded continuously. 16 Phasic airway pressure was measured by a Statham DM131PC airway pressure transducer. Systemic arterial blood PO2, Pco2, and pH, oxygen saturation, and hemoglobin concentration were measured intermittently. To determine the effects of PGD2 during hypoxia, baseline values were measured immediately prior to each PGD2 administration. Response values for each bolus injection were taken at the point of lowest mean pulmonary arterial pressure, and for each infusion when a new steady state was reachedl Pulmonary vascular resistance was calculated from mean pulmonary arterial and left atrial pressures and pulmonary blood flow per kilogram body weight. Because there was no intracardiac shunting, cardiac output was equal to pulmonary blood flow and systemic vascular resistance could be calculated from
460
Soifer, Morin, and Heymann
The Journal of Pediatrics March 1982
Righl Atriol 20[.= Pressure (turn Hg) 0
Left Ahial 2~ Pressure (mm Hg) 0 L_
i
II
-
i
I
II
I00 Pulmonary Arterial Pressure (ram Hg)
O
Meon 100V Pulmonory Aderiol Pressure (mm Hg) OL
Hear! Rote
300 u
(beots/rain} 180LMean Pulmonary 1300[Arteriol Blood J _ . _ . J Flow (ml/min) O6 tim/)7 ~ P6Oe 5 zzg/kg
Fig. 1. The effects of a bolus injection of 5 /~g/kg of PGD= into the pulmonary artery. mean systemic arterial and right atrial pressures and pulmonary blood flow per kilogram body weight. The results from all bolus injections were pooled and a linear regression analysis of the percent change from baseline of the vascular pressures, flows, and resistances on the log~0 of the dose of PGD2/kg body weight was performed? The slopes of the regressions for pulmonary and systemic vascular resistance on the dose of PGDz were compared by paired t testJ 8 The infusion data were analyzed identically. RESULTS In each lamb, with induction of hypoxia after indomethacin administration, mean pulmonary arterial pressure increased to approximate the slightly decreased systemic arterial pressure 19 (Table). Pulmonary blood flow decreased, and calculated pulmonary vascular resistance increased. During hypoxia Pao2 fell into the 15 to 25 torr range whereas Paco2 and pH remained normal, When given by bolus injection, PGD2 decreased pulmonary arterial pressure and increased pulmonary blood flow and heart rate in each lamb (Fig. 1). Systemic arterial and left atrial pressures increased slightly in most instances. The maximum effect occurred approximately 45 seconds after injection. There were no significant changes in arterial blood gas values, pH, or phasic airway pressure. The pooled data from all lambs (Table and Fig. 2) show that, at a total dose of 20 ~g, beyond which there w[is increase in effect, there was a 27% decrease in mean pulmonary arterial pressure, a 52% increase in pulmonary
blood flow, a 2% increase in mean systemic arterial pressure, and a 43% fall in calculated pulmonary vascular resistance, Regression analysis of the pooled data reveal the fall in mean pulmonary arterial pressure and the increase in pulmonary blood flow to be dose related (P < 0.001 and P < 0.002, respectively), but the change in mean systemic arterial pressure was not significant. Calculated pulmonary vascular resistance fell in a dose-related manner (Fig. 3). Systemic vascular resistance also decreased, but to a lesser degree, and was associated with the increase in cardiac output without a significant change in systemic arterial pressure. The ratio of the percent change of pulmonary vascular resistance to the percent change in systemic vascular resistance was approximately 2: 1 at each dose. The slope (Fig. 4) of the regression of the percent change in pulmonary vascular resistance vs dose of PGD2 was significantly steeper than that of the percent change in systemic vascular resistance (P < 0.001), indicating a significantly greater, dose-related effect on calculated pulmonary vascular resistance. Continuous infusion of PGD2 had similar hemodynamic effects (Fig. 5). There was a significant dose-related decrease in mean pulmonary arterial pressure (P < 0.01) and calculated pulmonary vascular resistance (P < 0.01), and a significant dose-related increase in pulmonary blood flow (P < 0.01), without change in systemic arterial pressure (Fig. 6). These effects lasted for the duration (up to 15 minutes) of the infusion and were similar in magnitude to those seen with bolus injection. Similar responses were also seen with infusions into either the inferior vena cava or the descending aorta. DISCUSSION We found that PGD2 lowered pulmonary arterial pressure without significantly changing systemic arterial pressure in near-term newborn lambs in which pulmonary hypertension had been induced by ventilation with a low inspired 02 concentration and administration of indomethacin. No other pharmacologic agent has been shown to have this greater specificity for the pulmonary circulation. Prostaglandins 12, Eb and E2, tolazoline, and acetylcholine all decrease pulmonary arterial pressure and increase pulmonary blood flow in fetal and newborn animals with pulmonary hypertension; they also decrease systemic arterial pressure significantly. Pulmonary blood flow and cardiac output were markedly increased by PGD2. This increase was associated with the increase in heart rate and probably was enhanced by the decrease in afterload of the right ventricle secondary to the decrease in pulmonary arterial pressure. Because pulmonary arterial pressure decreased and systemic arterial pressure remained unchanged with the increase in
Volume 1O0 Number 3
Prostaglandin De and pulmonary hypertension
4 61
PULMONARY BLOOD FLOW
(..9
=.,--
oN_
L)
Z
MEAN SYSTEMIC ARTERIAL PRESSURE
-40~--
MEAN PULMONARY ARTERIAL PRESSURE
/ 'i 0.1
I I
I IO
I IOO
PROSTAGLANDIN D2 (2LLg)
Fig. 2. The effects of increasing doses of PGDz given by bolus injection into the pulmonary artery of five lambs. Values are means _+SE.
VASCULAR
PULMONARY V A S C U L A R RESISTANCE
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Fig. 3. Regression analysis of percentage changes in pulmonary vascular resistance vs the log~0of the dose of PGD2. Thirty-eight bolus injections were given into the pulmonary artery in five lambs. The 95% confidence limits are shown. cardiac output, pulmonary vascular resistance decreased more than systemic vascular resistance at each dose of PGD2. We speculate tha;t the decrease in pulmonary vascular resistance occurred because PGD2 directly dilated the small pulmonary arteries. At the 20 #g dose, PGD2 returned pulmonary vascular resistance, as well as pulmonary arterial pressure and pulmonary blood flow, to approximately those values recorded during ventilation with room air. The PGD2 eliminated the induced increase in pulmonary vasomotor tone. In pump-perfused fetal goat lungs, Cassin et a115 have shown that PGD2 decreases pulmonary arterial pressure without changing systemic arterial pressure. In lambs 2 to 4 weeks old, with hypoxic pulmonary hypertension, Lock et
•
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IO
PROSTAGLANDIN D2 (.,~.g/kg)
Fig. 4. Regression analyses of percentage changes in systemic and pulmonary vascular resistances vs the log~0 of the dose of PGD2. Thirty-seven injections were given into the pulmonary artery of five lambs; P < 0.001 for the regression of systemic vascular resistance and P < 0.00l for the regression of pulmonary vascular resistance. The slope of the regression for pulmonary vascular resistance is significantly steeper than the slope for systemic vascular resistance (P < 0.001).
aP 4 have shown that PGD2 increases pulmonary vascular resistance. In a preliminary study we have found that PGD2 produces mild pulmonary vasoconstriction in the lamb at one week of age. In adult dogs, Wasserman et aF ~ have shown that PGDz increases pulmonary arterial pressure and causes bronchoconstriction. 2~ The PGD2 did not alter Pac% or phasic airway pressure in our lambs and bronchoconstriction apparently did not occur. Because the difference in the responses of the systemic and pulmonary circulations in the newborn animals and the changes in the
462
Soifer, Matin, and Heymann
The Journal of Pediatrics March 1982
PULMONARY
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Fig. 6. Effects of increasing doses of PGD~ given by infusion into the pulmonary artery. Values are means _+SE.
Fig. 5. The effects of an infusion of 2.5 #g/kg/minute PGD~ into the pulmonary artery.
pulmonary vascular effect with advancing age suggest a role for PGD2 in the normal regulation of pulmonary blood flow and pulmonary vascular resistance in the immediate postnatal period, further studies seem indicated. The effects of PGD2 on the pulmonary circulation in the immediate newborn period may be important in the clinical management of newborn infants in whom a normal pulmonary circulation is not established immediately after birth (persistent pulmonary hypertension, meconium aspiration, pneumonia, and sepsis) in part due to pulmonary vasospasmJ 7,'8 If, in these infants, PGD2 had effects similar to those in our lambs, pulmonary vascular resistance would fall and pulmonary and systemic blood flows would increase, resulting in improved systemic oxygen delivery. In addition, because pulmonary arterial pressure falls and systemic arterial pressure is unaltered, rightto-left shunting through the ductus arteriosus would diminish or even disappear. This too would result in improved systemic oxygen delivery. Thus, PGD2 warrants further experimental evaluation as a potential agent for treating newborn infants with significant pulmonary hypertension. The PGD2 was kindly supplied by Dr. John Pike of the Upjohn Company. Ly0indocin was kindly supplied by Dr. Marten Rosenberg of Merck, Sharpe, and Dohme. We gratefully acknowledge the assistance of Ms. Christine Roman, Ms. Susan Axelrod, and Mr. Les Williams. REFERENCES 1. Goetzman BW, Sunshine P, Johnson JD, Wennberg RP, Hackel A, Merten DF, Bartoletti AL, and Silverman NH:
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AM: Hemodynamic effects of pulmonary arterial infusion of vasodilators in newborn lambs, Pediatr Res 14:1311, 1980. Lock JE, Olley PM, and Coceani F: Direct pulmonary vascular responses to prostaglandins in the newborn lamb, Am J Physiol 238:H631, 1980. Cassin S, Tod M, Philips J, Frisinger J, Jordan J, and Gibbs C: Effects of prostaglandin D2 On perinatal circulation, Am J Physiol 240:H755, 1981. Rudolph AM, and Heymann MA: Methods for studying the circulation of the fetus in utero, in Nathanielsz PW, editor, Animal models in fetal medicine (l), vol 2, Amsterdam, 1980, Elsevier North Holland Biomedical Press, p 1. Clyman R1, Mauray F, Roman C, Rudolph AM, and Hey-
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mann MA: Circulating prostaglandin E2 concentrations and patent ductus arteriosus in fetal and neonatal lambs, J PEDIATR 97:455, 1980. 18. Snedecor GW, and Cochran WG: Statistical methods, ed 7, Ames, 1980, The Iowa State University Press, pp 149, 387. 19. Leffler CW, Tyler TL, and Cassin S: Effect of indomethacin on pulmonary vascular response to ventilation of fetal goats, Am J Physiol 234:H346, 1978. 20. Wasserman MA, DuCharme DW, Griffin RL, Pegraaf GL, and Robinson FG: Bronchopulmonary and cardiovascular effects of prostaglandin Dz in the dog, Prostaglandins 13:255, 1977.