Adv. Cardiol., vol. 26, pp. 65-75 (Karger, Basel 1979)
Pharmacologic Treatment of Patent Ductus arteriosus WILLIAM F. FRIEDMAN
Department of Pediatric Cardiology, University Hospital, San Diego, Calif.
Significant left-to-right shunting across the patent ductus arteriosus (PDA) commonly complicates the clinical course of prematurely born infants. The ductal shunt has been implicated especially in the deterioration of pulmonary function in infants with respiratory distress syndrome in whom congestive failure is often unresponsive to digitalis and diuretics. The ductus arteriosus is a widely patent vessel connecting the pulmonary trunk and descending aorta in fetal life. In the fetus, most of the output of the right ventricle bypasses the unexpanded fetal lungs via the ductus arteriosus and enters the descending aorta where it travels to the placenta, the fetal organ of oxygenation. Until recently, it was assumed that the ductus arteriosus was a passively open channel during fetal life, and that it constricted postnatally by, as yet, undefined molecular mechanisms in response to the abrupt rise in arterial p02 that accompanies the first breath of life. Suggestive evidence now exists that even in utero the size of the ductus arteriosus lumen may be influenced importantly by prostaglandins. The effect of prostaglandins on the smooth muscle tone of the fetal ductus arteriosus can be seen in figure l. In the chronically instrumented fetal lamb, the administration of indomethacin, an inhibitor of prostaglandin synthesis, causes constriction of the fetal ductus arteriosus (fig. 1), whereas prostaglandin EJ infusion reverses this effect (fig. 2). The ductus arteriosus remains a unique structure after birth since its patency may, on the one hand, result in cardiac decompensation and, on the other hand, may provide the only life-sustaining conduit to preserve systemic or
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Introduction
66
FRIEDMAN
FETAL LAMB 124 doys gestation 4 days Post-op. MPA (mmHgl
:~ ~1IIs~.~.~~ ii~~~ ~~~m
Desc. Ao. (mmHg) PDA Dimensions (mm)
ITP
(mmHg) PDA Dimensions (mml
8.03 • •__ 7.23 ~~~ 6.4
Indocin 0.2 mgl kg i.v. (10min)
pulmonary arterial blood flow in the presence of associated cardiac malformations. Appreciable left-to-right shunting across the PDA frequently complicates the clinical course of prematurely born infants. The ductal shunt has been implicated especially in the deterioration of pulmonary function in infants with respiratory distress syndrome in whom severe congestive heart failure is often unresponsive to digitalis and diuretics. Recently, clinical trials at the University of California, San Diego, and at the University of California, San Francisco, have shown that the ductus arteriosus in pre-term infants with cardiopulmonary deterioration and hyaline membrane disease can be constricted and closed by the administration of inhibitors of prostaglandin synthesis [1, 2, 4]. In this report, we intend to present an update on our experience [3].
Downloaded by: University of Cambridge 131.111.164.128 - 3/20/2019 11:48:37 AM
Fig. 1. Representative experiment in which indomethacin produced profound constriction of the fetal ductus arteriosus. PDA dimensions are measured directly with sonomicrometer crystals while pressures are recorded simultaneously from the fetal ascending aorta, main pulmonary artery (MPA), and descending aorta (Desc. Ao.) The constriction is best appreciated in the lower panel. A rise in main pulmonary arterial pressure was associated with ductal constriction. ITP = Intra-tracheal pressure.
Drug Closure of PDA
67
FETAL LAMB
MPA (mmHQ) Desc. Ao. (mmHg) PDA Dimensions (mm)
ITP
(mmHg) PDA Dimensions (mm)
3° 15
°3mmmmmE~mm~~2$rnili~~
~~~~~~~~~~~~~~HHlli
8'7.23°311 _ _ _ t' 6.4
PGE, (0.1 fJg/kg/min
Reversal of Indocin Constriction of PDA
Fig. 2. Representative experiment in which an infusion of PGE1 restored PDA dimensions to normal after constriction had been achieved with indomethacin (0.1 mg/kg i.v.). Little change was observed in MPA pressure during PDA dilatation and aortic pressure rose slightly. Abbreviations as in figure 1.
In our initial clinical experience with sick pre-term infants who received indomethacin to constrict and close the PDA, a large dose (2.5-5 mg/kg) of the drug was delivered orally or per rectum [2]. Within 12-24 h of drug administration, permanent disappearance occurred of all of the clinical symptoms and physical, radiographic, and cardiac ultrasound signs attributable to substantial left-to-right shunting through a PDA. However, several infants transiently exhibited renal dysfunction with a rise in blood urea nitrogen and serum creatinine concentrations and a reduction in urine volume. In the initial clinical trial in San Francisco, salicylates, as well as a smaller dose of indomethacin, were utilized [4]. Salicylates were not found to be particularly effective, and the smaller doses of indomethacin were not associated with transient renal dysfunction.
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Initial Experience
FRIEDMAN
68
Prostaglandins are virtually ubiquitous in animal tissues and appear to be formed from polyunsaturated fatty acids, and released in most human organs in response to many varied stimuli. It seems likely that these lipids act throughout the body as local mediators or modulators of physiological functions. Many of the prostaglandins have marked effects on pulmonary and systemic blood vessels. It should be stated at the outset that pharmacological closure of the ductus arteriosus in pre-term infants must still be considered experimental. In the experience to be discussed, indomethacin was employed in an attempt to constrict and close the ductus arteriosus in pre-term infants who would have otherwise undergone surgical ligation of their PDA. Indomethacin was chosen because of its known potency as an inhibitor of prostaglandin synthetase and its widespread use for diverse medical indications in the adult population. However, it should be recognized clearly that a large family of drugs exist that have been shown to interfere with the synthesis of prostaglandins. Studies have not yet been performed to identify a single agent with an especially selective action upon ductus arteriosus smooth muscle and little or no action upon other organ systems.
Since our initial experience with the 6 infants described above, indomethacin has been employed in 35 premature infants. It is our current practice clinically to employ an experimental intravenous preparation of sodium indomethacin which ensures delivery of the desired dose. It should be recognized that an oral suspension or a solution of uniform composition of indomethacin does not exist commercially and that potential problems in dosimetry and absorption have not been evaluated critically when the drug is delivered through a nasogastric tube to the preterm infant. During an II-month period, from November, 1976, in collaboration with Drs. ALLEN MERRITI, BERNARD FELDMAN, and LOUIS GLUCK, we have administered indomethacin to 35 preterm infants who would have otherwise undergone surgical ligation of their PDA. During this time period, 24 preterm infants underwent ductal ligation because contraindications were present to indomethacin administration. In all of these infants, the ductal shunt was responsible for deterioration of pulmonary function, or severe congestive heart failure was unresponsive to digitalis and diuretics. In 4 infants, severe episodes of apnea and bradycardia provided the indication for closure of the ductus.
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Recent Clinical Experience
69
Drug Closure of PDA Table 1. PDA population
Birth wt, g
Onset clin. sings, days
Onset of llled. therapy days
1st dose indolllethacin
Indomethacin treated infants RDS 29 30.1 (2.1) Others' 6 28.2 (1.7)
1361 ± 363 951 ± 187
3.8 ± 1.9 7.6 ± 5.4
4.4 ± 1.5 8.2 ± 2.8
8.7 ± 4.5 13.0 ± 5.7
Ligated infants RDS 17 Others' 7
1326 ± 286 1436 ± 487
4.2 ± 2.1 7.2 ± 2.5
5.6 ± 2.3 8.7 ± 1.4
7.9 ± 2.9 15.0 ± 4.2
CJestage weeks
~ulllber
30.2 (2.2) 31.0 (2.9)
, Apnea and bradycardia, 4; Mikity-Wilson with ventilatory failure, 2. Apnea and bradycardia, 5; illllllature lung disease, 1.
2
10
•
INDOMETHACIN
o LIGATION
8 6 4
I!!z w
2
~
501). 750
751- 1,001- 1,251- 1,501- 1,7511,000 1,250 1,500 1,750 2jl00
IL
o rr: w
BIRTHWEIGHT, 9
'~!~~. . -. . J.L.- ~~~IJ ~~~ 2
2
2
!
2
.oL...L......l...D •
25
26
27
28
29
30
31
32
33
34
35
GESTATIONAL AGE, weeks
Table I and figures 3 and 4 provide a clinical profile of the 42 infants, all but 6 of whom suffered from respiratory distress syndrome. The route of administration and the number of doses of indomethacin (0.2 mg/kg) employed in our study population are illustrated in table II. The majority of infants required more than one dose of indomethacin by any route. In 31 of the 35 indomethacin infants, the PDA constricted promptly and signs and symptoms were alleviated. One of the 4 infants who received indomethacin
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Fig. 3. Birth weight and gestational age of the pre-teflll infants in WhOlll phaflllacological or surgical intervention was elllployed.
70
FRIEDMAN Table II. Indomethacin administration
Route i. v.
p.o. Single Rx course Dose 1 Dose 2 Dose 3
10 3 2
4 5 0
15
9 (Total = 24)
Double Rx course First course Dose 1 Dose 2 Dose 3
Second course Dose 1 Dose 2 Dose 3
4 1 1
3 2 0
6
5
4 1 0
3 3 0
5
6 (Total = 11)
Number
Indomethacin- Treated RDS 261 51 Others
Surgical Ligation RDS Others
1
17 6
Hours F10 2 >0.3
Total Hours IMV
HoursIMV postfirst dose indomethacin
117.5 ± 65.8 80.3 ± 38.8 p- c
F~rDD
u.!::!
200
0
CONTROL
50
0
«:;: 0
u;
~
_ z -0
25
Cl:c.
>- ., ~...,
LPC 2 mM
0
CJ
C
>>-
LPC
DO
CONTROL
LPC 2
mM
Fig. 3. Effects of LPC on action potentials.
msec
2.2 min
msec
msec
msec
msec
200
msec
400
-100 L..L..._ _' - - _ - ' -_ _- - ' - - _ - - - ' o 200 400 msec
msec
i, _ _ _ _ 67min
o
...."
msec msec msec
msec
msec
",
-100~---'--__:_~--'-'-'--==
o
200
msec
400
Fig. 4. Serial changes in action potentials recorded from canine Purkinje fibers in vitro after exposure to lysophosphatidyl choline (LPC, 2mM) bound to albumin and fatty acid for 2.2 min (upper right panel), the time at which the response was maximal. The lower two panels depict the reversibility evident when subsequent perfusion was maintained with buffer, albumin, and fatty acid but no LPC. As can be seen, recovery was progressive during an interval of 67 min.
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msec
SOBEL/CORR
82
1 to 1.5 mg/ml, LPC completely inhibited both spontaneous and electrically stimulated depolarization (data not shown). When perfusion was maintained without LPC, these parmeters recovered slowly to 89, 46, 86, and 92% of control (values before exposure of the cells to LPC) within 70 min. However, during this recovery period, automaticity was markedly exaggerated, with rates exceeding values durin& the control interval by an average 137%. Illustrative examples of effects of LPC on action potentials are shown in figure 4. Thus LPC exerts profound electrophysiological effects, compatible with potentiation of reentry rhythms, and leads to marked augmentation of automaticity during recovery as well.
These observations indicate that changes in cardiac phospholipid content occur rapidly after the onset of ischemia, with increases in lysophosphoglycerides and a decline in PC and PE evident within 5 min. It appears likely that the accumulated lysophospholipids are derived from partial catabolism of membrane constituents, based on the inverse relationship observed and results from preliminary experiments in which phospholipids were prelabeled with 14C-palmitate prior to the onset of ischemia [14]. In myocardium not subjected to low flow, the overall concentrations of lysophosphoglycerides are less than those required to exert striking electrophysiological effects on isolated canine Purkinje fibers in vitro. However, higher concentrations may contribute to the genesis of malignant dysrhythmias associated with ischemia in vivo judging from their profound effects on dV / dt, resting potential, action potential duration, and automaticity. Accumulation of lysophosphoglycerides might account for several recent observations including correlations between the extent and persistence of malignant ventricular dysrhythmia and enzymatically estimated infarct size in patients [13], and precipitation of dysrhythmia by perfusion of normal myocardium with blood from ischemic zones attributable to as yet uncharacterized components, besides potassium or catecholamines [2]. Since several of the effects elicited by LPC have been identified as factors predisposing to reentry (decreased peak dV/dt, reduction of action potential duration, and diminution of resting potential), and since early malignant dysrhythmia induced by ischemia appears to be due to reentrant mechanisms, accumulation of these compounds may contribute. On the other hand, the striking augmentation of automaticity during the recovery phase, when Purkinje fibers were perfused first with LPC and then with solutions containing no LPC
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Discussion
83
with spontaneous rates of depolarization exceeding control rates by more than 100%, suggests that effects of lower concentrations of lysophospholipids or responses of cells to transitory exposure may potentiate malignant dysrhythmias due to increased automaticity, such as those occurring later after the onset of ischemia. Sudden cardiac death generally occurs in association with extensive underlyng coronary artery disease. Patients resuscitated from primary ventricular fibrillation without overt, transmural myocardial infarction exhibit the highest risk of subsequent sudden death of any subset yet identified. These observations are compatible with the speculation that noxious metabolites, accumulating in proportion to the mass of jeopardized myocardium and the intensity of ischemia, may give rise to the malignant ventricular dysrhythmias seen. The striking disparity between cardiac electrical stability in anoxic hearts perfused with anaerobic solutions (in which slowing of rate is followed ultimately by asystole, generally without ventricular tachyarrhythmia or fibrillation), and the chaotic ventricular dysrhythmias including fibrillation associated with ischemia, is compatible with this speculation. If lysophosphoglycerides represent a class of metabolites capable of mediating these events, it is not surprising that accumulation does not occur in hypoxic, but not ischemic hearts. Thus, lysophosphoglycerides do not accumulate in hearts subjected to low perfusion even though hypoxia results as long as bulk perfusion is maintained at levels prevailing in vivo, where oxygenation is facilitated by perfusion with blood (table I). The present results do not shed light on the cellular or subcellular locus of lysophospholipids accumulating in ischemic hearts. However, these substances may be deleterious even if they are derived from nonmyocardial constituents. Phospholipids or erythrocytes within the vasculature of ischemic zones could be one precursor pool, but this is clearly not an obligatory source based on the results with hearts perfused with blood-free media. Judging from recently recognized relationships between depletion of highenergy phosphates, lysophospholipids, and hemolysis in erythrocytes [3], there may be a connection between depletion of specific pools of A TP in ischemic myocardial cells and activation of phospholipases. It is not yet clear whether the accumulated lysophosphoglycerides observed can become incorporated in membranes of viable cells surrounding severely ischemic zones. However, since lysophospholipids exert detergent-like effects in several systems, including erythrocytes, bacteria, and skeletal muscle cells in culture, they are potentially capable of producing sarcolemmal damage in ischemic myocardium. Assessment of this possibility with pulse-labeling
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The Lysolipid Hypothesis
SOBEL/CORR
84
experiments is complex because of difficulties in isolating, purifying, and characterizing myocardial sarcolemma under conditions minimizing: (1) transfer of lipid constituents between organelles and between different classes of lipids; (2) reacylation, and (3) further catabolism of the lysophospholipids themselves. However, elucidation of the extent to which lysophospholipids elicit injury and clarification of factors affecting activation and inhibition of myocardial phospholipases, lysophospholipid acylases, and acyl transferases should be helpful in defining the possible role of accumulation of lysophospholipids in the genesis of malignant arrhythmias and dissemination of injury induced by ischemia.
2
BARTLETI, G. R: Phosphorus assay in column chromatography. J. biol. Chern. 234: 466--468 (1959).
2
DOWNAR, E.; JANSE, M. J., and DURRER, D.: The effect of ischemic blood on transmembrane potentials of normal porcine ventricular mycardium. Circulation 55: 455-462 (1977).
3
GAZITT, Y.; ORAD, I., and LoITER, A.: Changes in phospholipid susceptibility toward phospholipases induced by ATP depletion in avian and amphibian erythrocyte membranes. Biochim. biophys. Acta 382: 65-72 (1975).
4
HARNARAYAN, c.; BENNETI, M. A.; PENTECOST, B. L., and BREWER, D. B.: Quantitative study of infarcted myocardium in cardiogenic shock. Br. Heart J. 32: 728-732 (1970). HARRIS, A. S.; BISTENI, A.; RUSSELL, R A.; BRIGHAM, J. c., and FIRESTONE, J. E.: Excitatory factors in ventricular tachycardia resulting from myocardial ischemia. Potassium a major excitant. Science 119: 200-203 (1954).
5
6
HERDSON, P. B.; SOMMERS, H. M., and JENNINGS, R B.: A comparative study of the fine structure of normal and ischemic dog myocardium with special reference to early changes following temporary occlusion of a coronary artery. Am. J. Path. 46: 367-386 (1965).
7
HOFFSTEIN, S.; GENNARO, D. E.; Fox, A. C.; HIRSCH, J.; STREULI, F., and WEISSMANN, G.: Colloidal lanthanum as a marker for impaired plasma membrane permeability in ischemic dog myocardium. Am. J. Path. 79: 207-218 (1975).
8
INOUE, K. and KrrAGAWA, T.: Effect of exogenous lysolecithin on liposomal membranes. Its relation to membrane fluidity. Biochim. biophys. Acta 363: 361-372 (1974).
9
KrEKSHUS, J. K. and SOBEL, B. E.: Depressed myocardial creatine phosphokinase activity following experimental myocardial infraction in rabbit. Circulation Res. 27: 403-414 (1970).
10
NEEDLEMAN, P.; MARSHALL, G. R, and SOBEL, B. E.: Hormone interactions in the isolated rabbit heart. Synthesis and coronary vasomotor effects of prostaglandins, angiotensin, and bradykinin. Circulation Res. 37: 802-808 (1975).
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References
The LysoJipid Hypothesis
12
13
14
15
16
17
18 19
PAGE, D. L.; CAULFIELD, J. B.; KASTOR, J. A.; DESANCTIS, R. W., and SANDERS, C. A.: Myocardial changes associated with cardiogenic shock. New Engl. J. Med. 285: 133-137 (1971). RAy, T. K.; CRONAN,J.E.,jr.;MAVlS,R.D., andVAGELOS,P. R: The specific acylation of glycerol 3-phosphate to monoacylglycerol 3-phosphate in Escherichia coli. J. bioI. Chern. 245: 6442--6446 (1970). ROBERTS, R; HUSAIN, A.; AMBOS, H. D.; OLIVER, G. C.; COX, J., jr., and SOBEL, B. E.: Relation between infarct size and ventricular arrhythmia. Br. Heart J. 37: 1169-1175 (1975). ROBISON, A. K.; HANSEN, V. A., and SOBEL, B. E.: Accumulation of lysophosphatides, potential mediators of irreversible injury in ischemic myocardium (abstr.). Circulation 56: suppl. III, p. 168 (1977). SHELL, W. E.; LAVELLE, J. F.; COVELL, J. W., and SOBEL, B. E.: Early estimation of myocardial damage in conscious dogs and patients with evolving acute myocardial infarction. J. din. Invest. 52: 2579-2590 (1973). SILBERT, D. F.; ULBRIGHT, T. M., and HONEGGER, J. L.: Utilization of exogenous fatty acids for complex lipid biosynthesis and its effect on de novo fatty acid fonnation in Escherichia coli K-12. Biochemistry, N. Y.12: 164-171 (1973). SOBEL, B. E.; CORR, P. B.; ROBISON, A. K.; GOLDSTEIN, R A.; WITKOWSKI, F. X., and KLEIN, M. S.: Accumulation of lysophosphoglycerides with arrhythmogenic properties in ischemic myocardium. J. din. Invest. 62 (in press, 1978). BOSCH, H. VAN DEN: Phosphoglyceride metabolism. Annu. Rev. Biochem. 43: 243-277 (1974). WILKINSON, P. J. and CATER, D. B.: An electron-microscope study of the effects of lysolecithin on BP8 ascites-tumour cells and phagocytes of mice, compared with the effects of a specific antitumour serum plus complement. J. Path. 97: 219-230 (1969).
B. E. SOBEL, MD, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO 63110 (USA)
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11
85
Pharmacologic Treatment of Patent Ductus arteriosus WILLIAM F. FRIEDMAN
Department of Pediatric Cardiology, University Hospital, San Diego, Calif.
Significant left-to-right shunting across the patent ductus arteriosus (PDA) commonly complicates the clinical course of prematurely born infants. The ductal shunt has been implicated especially in the deterioration of pulmonary function in infants with respiratory distress syndrome in whom congestive failure is often unresponsive to digitalis and diuretics. The ductus arteriosus is a widely patent vessel connecting the pulmonary trunk and descending aorta in fetal life. In the fetus, most of the output of the right ventricle bypasses the unexpanded fetal lungs via the ductus arteriosus and enters the descending aorta where it travels to the placenta, the fetal organ of oxygenation. Until recently, it was assumed that the ductus arteriosus was a passively open channel during fetal life, and that it constricted postnatally by, as yet, undefined molecular mechanisms in response to the abrupt rise in arterial p02 that accompanies the first breath of life. Suggestive evidence now exists that even in utero the size of the ductus arteriosus lumen may be influenced importantly by prostaglandins. The effect of prostaglandins on the smooth muscle tone of the fetal ductus arteriosus can be seen in figure l. In the chronically instrumented fetal lamb, the administration of indomethacin, an inhibitor of prostaglandin synthesis, causes constriction of the fetal ductus arteriosus (fig. 1), whereas prostaglandin EJ infusion reverses this effect (fig. 2). The ductus arteriosus remains a unique structure after birth since its patency may, on the one hand, result in cardiac decompensation and, on the other hand, may provide the only life-sustaining conduit to preserve systemic or
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Introduction
66
FRIEDMAN
FETAL LAMB 124 doys gestation 4 days Post-op. MPA (mmHgl
:~ ~1IIs~.~.~~ ii~~~ ~~~m
Desc. Ao. (mmHg) PDA Dimensions (mm)
ITP
(mmHg) PDA Dimensions (mml
8.03 • •__ 7.23 ~~~ 6.4
Indocin 0.2 mgl kg i.v. (10min)
pulmonary arterial blood flow in the presence of associated cardiac malformations. Appreciable left-to-right shunting across the PDA frequently complicates the clinical course of prematurely born infants. The ductal shunt has been implicated especially in the deterioration of pulmonary function in infants with respiratory distress syndrome in whom severe congestive heart failure is often unresponsive to digitalis and diuretics. Recently, clinical trials at the University of California, San Diego, and at the University of California, San Francisco, have shown that the ductus arteriosus in pre-term infants with cardiopulmonary deterioration and hyaline membrane disease can be constricted and closed by the administration of inhibitors of prostaglandin synthesis [1, 2, 4]. In this report, we intend to present an update on our experience [3].
Downloaded by: University of Cambridge 131.111.164.128 - 3/20/2019 11:48:37 AM
Fig. 1. Representative experiment in which indomethacin produced profound constriction of the fetal ductus arteriosus. PDA dimensions are measured directly with sonomicrometer crystals while pressures are recorded simultaneously from the fetal ascending aorta, main pulmonary artery (MPA), and descending aorta (Desc. Ao.) The constriction is best appreciated in the lower panel. A rise in main pulmonary arterial pressure was associated with ductal constriction. ITP = Intra-tracheal pressure.
Drug Closure of PDA
67
FETAL LAMB
MPA (mmHQ) Desc. Ao. (mmHg) PDA Dimensions (mm)
ITP
(mmHg) PDA Dimensions (mm)
3° 15
°3mmmmmE~mm~~2$rnili~~
~~~~~~~~~~~~~~HHlli
8'7.23°311 _ _ _ t' 6.4
PGE, (0.1 fJg/kg/min
Reversal of Indocin Constriction of PDA
Fig. 2. Representative experiment in which an infusion of PGE1 restored PDA dimensions to normal after constriction had been achieved with indomethacin (0.1 mg/kg i.v.). Little change was observed in MPA pressure during PDA dilatation and aortic pressure rose slightly. Abbreviations as in figure 1.
In our initial clinical experience with sick pre-term infants who received indomethacin to constrict and close the PDA, a large dose (2.5-5 mg/kg) of the drug was delivered orally or per rectum [2]. Within 12-24 h of drug administration, permanent disappearance occurred of all of the clinical symptoms and physical, radiographic, and cardiac ultrasound signs attributable to substantial left-to-right shunting through a PDA. However, several infants transiently exhibited renal dysfunction with a rise in blood urea nitrogen and serum creatinine concentrations and a reduction in urine volume. In the initial clinical trial in San Francisco, salicylates, as well as a smaller dose of indomethacin, were utilized [4]. Salicylates were not found to be particularly effective, and the smaller doses of indomethacin were not associated with transient renal dysfunction.
Downloaded by: University of Cambridge 131.111.164.128 - 3/20/2019 11:48:37 AM
Initial Experience
FRIEDMAN
68
Prostaglandins are virtually ubiquitous in animal tissues and appear to be formed from polyunsaturated fatty acids, and released in most human organs in response to many varied stimuli. It seems likely that these lipids act throughout the body as local mediators or modulators of physiological functions. Many of the prostaglandins have marked effects on pulmonary and systemic blood vessels. It should be stated at the outset that pharmacological closure of the ductus arteriosus in pre-term infants must still be considered experimental. In the experience to be discussed, indomethacin was employed in an attempt to constrict and close the ductus arteriosus in pre-term infants who would have otherwise undergone surgical ligation of their PDA. Indomethacin was chosen because of its known potency as an inhibitor of prostaglandin synthetase and its widespread use for diverse medical indications in the adult population. However, it should be recognized clearly that a large family of drugs exist that have been shown to interfere with the synthesis of prostaglandins. Studies have not yet been performed to identify a single agent with an especially selective action upon ductus arteriosus smooth muscle and little or no action upon other organ systems.
Since our initial experience with the 6 infants described above, indomethacin has been employed in 35 premature infants. It is our current practice clinically to employ an experimental intravenous preparation of sodium indomethacin which ensures delivery of the desired dose. It should be recognized that an oral suspension or a solution of uniform composition of indomethacin does not exist commercially and that potential problems in dosimetry and absorption have not been evaluated critically when the drug is delivered through a nasogastric tube to the preterm infant. During an II-month period, from November, 1976, in collaboration with Drs. ALLEN MERRITI, BERNARD FELDMAN, and LOUIS GLUCK, we have administered indomethacin to 35 preterm infants who would have otherwise undergone surgical ligation of their PDA. During this time period, 24 preterm infants underwent ductal ligation because contraindications were present to indomethacin administration. In all of these infants, the ductal shunt was responsible for deterioration of pulmonary function, or severe congestive heart failure was unresponsive to digitalis and diuretics. In 4 infants, severe episodes of apnea and bradycardia provided the indication for closure of the ductus.
Downloaded by: University of Cambridge 131.111.164.128 - 3/20/2019 11:48:37 AM
Recent Clinical Experience
69
Drug Closure of PDA Table 1. PDA population
Birth wt, g
Onset clin. sings, days
Onset of llled. therapy days
1st dose indolllethacin
Indomethacin treated infants RDS 29 30.1 (2.1) Others' 6 28.2 (1.7)
1361 ± 363 951 ± 187
3.8 ± 1.9 7.6 ± 5.4
4.4 ± 1.5 8.2 ± 2.8
8.7 ± 4.5 13.0 ± 5.7
Ligated infants RDS 17 Others' 7
1326 ± 286 1436 ± 487
4.2 ± 2.1 7.2 ± 2.5
5.6 ± 2.3 8.7 ± 1.4
7.9 ± 2.9 15.0 ± 4.2
CJestage weeks
~ulllber
30.2 (2.2) 31.0 (2.9)
, Apnea and bradycardia, 4; Mikity-Wilson with ventilatory failure, 2. Apnea and bradycardia, 5; illllllature lung disease, 1.
2
10
•
INDOMETHACIN
o LIGATION
8 6 4
I!!z w
2
~
501). 750
751- 1,001- 1,251- 1,501- 1,7511,000 1,250 1,500 1,750 2jl00
IL
o rr: w
BIRTHWEIGHT, 9
'~!~~. . -. . J.L.- ~~~IJ ~~~ 2
2
2
!
2
.oL...L......l...D •
25
26
27
28
29
30
31
32
33
34
35
GESTATIONAL AGE, weeks
Table I and figures 3 and 4 provide a clinical profile of the 42 infants, all but 6 of whom suffered from respiratory distress syndrome. The route of administration and the number of doses of indomethacin (0.2 mg/kg) employed in our study population are illustrated in table II. The majority of infants required more than one dose of indomethacin by any route. In 31 of the 35 indomethacin infants, the PDA constricted promptly and signs and symptoms were alleviated. One of the 4 infants who received indomethacin
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Fig. 3. Birth weight and gestational age of the pre-teflll infants in WhOlll phaflllacological or surgical intervention was elllployed.
70
FRIEDMAN Table II. Indomethacin administration
Route i. v.
p.o. Single Rx course Dose 1 Dose 2 Dose 3
10 3 2
4 5 0
15
9 (Total = 24)
Double Rx course First course Dose 1 Dose 2 Dose 3
Second course Dose 1 Dose 2 Dose 3
4 1 1
3 2 0
6
5
4 1 0
3 3 0
5
6 (Total = 11)
Number
Indomethacin- Treated RDS 261 51 Others
Surgical Ligation RDS Others
1
17 6
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Total Hours IMV
HoursIMV postfirst dose indomethacin
117.5 ± 65.8 80.3 ± 38.8 p- c
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u.!::!
200
0
CONTROL
50
0
«:;: 0
u;
~
_ z -0
25
Cl:c.
>- ., ~...,
LPC 2 mM
0
CJ
C
>>-
LPC
DO
CONTROL
LPC 2
mM
Fig. 3. Effects of LPC on action potentials.
msec
2.2 min
msec
msec
msec
msec
200
msec
400
-100 L..L..._ _' - - _ - ' -_ _- - ' - - _ - - - ' o 200 400 msec
msec
i, _ _ _ _ 67min
o
...."
msec msec msec
msec
msec
",
-100~---'--__:_~--'-'-'--==
o
200
msec
400
Fig. 4. Serial changes in action potentials recorded from canine Purkinje fibers in vitro after exposure to lysophosphatidyl choline (LPC, 2mM) bound to albumin and fatty acid for 2.2 min (upper right panel), the time at which the response was maximal. The lower two panels depict the reversibility evident when subsequent perfusion was maintained with buffer, albumin, and fatty acid but no LPC. As can be seen, recovery was progressive during an interval of 67 min.
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msec
SOBEL/CORR
82
1 to 1.5 mg/ml, LPC completely inhibited both spontaneous and electrically stimulated depolarization (data not shown). When perfusion was maintained without LPC, these parmeters recovered slowly to 89, 46, 86, and 92% of control (values before exposure of the cells to LPC) within 70 min. However, during this recovery period, automaticity was markedly exaggerated, with rates exceeding values durin& the control interval by an average 137%. Illustrative examples of effects of LPC on action potentials are shown in figure 4. Thus LPC exerts profound electrophysiological effects, compatible with potentiation of reentry rhythms, and leads to marked augmentation of automaticity during recovery as well.
These observations indicate that changes in cardiac phospholipid content occur rapidly after the onset of ischemia, with increases in lysophosphoglycerides and a decline in PC and PE evident within 5 min. It appears likely that the accumulated lysophospholipids are derived from partial catabolism of membrane constituents, based on the inverse relationship observed and results from preliminary experiments in which phospholipids were prelabeled with 14C-palmitate prior to the onset of ischemia [14]. In myocardium not subjected to low flow, the overall concentrations of lysophosphoglycerides are less than those required to exert striking electrophysiological effects on isolated canine Purkinje fibers in vitro. However, higher concentrations may contribute to the genesis of malignant dysrhythmias associated with ischemia in vivo judging from their profound effects on dV / dt, resting potential, action potential duration, and automaticity. Accumulation of lysophosphoglycerides might account for several recent observations including correlations between the extent and persistence of malignant ventricular dysrhythmia and enzymatically estimated infarct size in patients [13], and precipitation of dysrhythmia by perfusion of normal myocardium with blood from ischemic zones attributable to as yet uncharacterized components, besides potassium or catecholamines [2]. Since several of the effects elicited by LPC have been identified as factors predisposing to reentry (decreased peak dV/dt, reduction of action potential duration, and diminution of resting potential), and since early malignant dysrhythmia induced by ischemia appears to be due to reentrant mechanisms, accumulation of these compounds may contribute. On the other hand, the striking augmentation of automaticity during the recovery phase, when Purkinje fibers were perfused first with LPC and then with solutions containing no LPC
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Discussion
83
with spontaneous rates of depolarization exceeding control rates by more than 100%, suggests that effects of lower concentrations of lysophospholipids or responses of cells to transitory exposure may potentiate malignant dysrhythmias due to increased automaticity, such as those occurring later after the onset of ischemia. Sudden cardiac death generally occurs in association with extensive underlyng coronary artery disease. Patients resuscitated from primary ventricular fibrillation without overt, transmural myocardial infarction exhibit the highest risk of subsequent sudden death of any subset yet identified. These observations are compatible with the speculation that noxious metabolites, accumulating in proportion to the mass of jeopardized myocardium and the intensity of ischemia, may give rise to the malignant ventricular dysrhythmias seen. The striking disparity between cardiac electrical stability in anoxic hearts perfused with anaerobic solutions (in which slowing of rate is followed ultimately by asystole, generally without ventricular tachyarrhythmia or fibrillation), and the chaotic ventricular dysrhythmias including fibrillation associated with ischemia, is compatible with this speculation. If lysophosphoglycerides represent a class of metabolites capable of mediating these events, it is not surprising that accumulation does not occur in hypoxic, but not ischemic hearts. Thus, lysophosphoglycerides do not accumulate in hearts subjected to low perfusion even though hypoxia results as long as bulk perfusion is maintained at levels prevailing in vivo, where oxygenation is facilitated by perfusion with blood (table I). The present results do not shed light on the cellular or subcellular locus of lysophospholipids accumulating in ischemic hearts. However, these substances may be deleterious even if they are derived from nonmyocardial constituents. Phospholipids or erythrocytes within the vasculature of ischemic zones could be one precursor pool, but this is clearly not an obligatory source based on the results with hearts perfused with blood-free media. Judging from recently recognized relationships between depletion of highenergy phosphates, lysophospholipids, and hemolysis in erythrocytes [3], there may be a connection between depletion of specific pools of A TP in ischemic myocardial cells and activation of phospholipases. It is not yet clear whether the accumulated lysophosphoglycerides observed can become incorporated in membranes of viable cells surrounding severely ischemic zones. However, since lysophospholipids exert detergent-like effects in several systems, including erythrocytes, bacteria, and skeletal muscle cells in culture, they are potentially capable of producing sarcolemmal damage in ischemic myocardium. Assessment of this possibility with pulse-labeling
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The Lysolipid Hypothesis
SOBEL/CORR
84
experiments is complex because of difficulties in isolating, purifying, and characterizing myocardial sarcolemma under conditions minimizing: (1) transfer of lipid constituents between organelles and between different classes of lipids; (2) reacylation, and (3) further catabolism of the lysophospholipids themselves. However, elucidation of the extent to which lysophospholipids elicit injury and clarification of factors affecting activation and inhibition of myocardial phospholipases, lysophospholipid acylases, and acyl transferases should be helpful in defining the possible role of accumulation of lysophospholipids in the genesis of malignant arrhythmias and dissemination of injury induced by ischemia.
2
BARTLETI, G. R: Phosphorus assay in column chromatography. J. biol. Chern. 234: 466--468 (1959).
2
DOWNAR, E.; JANSE, M. J., and DURRER, D.: The effect of ischemic blood on transmembrane potentials of normal porcine ventricular mycardium. Circulation 55: 455-462 (1977).
3
GAZITT, Y.; ORAD, I., and LoITER, A.: Changes in phospholipid susceptibility toward phospholipases induced by ATP depletion in avian and amphibian erythrocyte membranes. Biochim. biophys. Acta 382: 65-72 (1975).
4
HARNARAYAN, c.; BENNETI, M. A.; PENTECOST, B. L., and BREWER, D. B.: Quantitative study of infarcted myocardium in cardiogenic shock. Br. Heart J. 32: 728-732 (1970). HARRIS, A. S.; BISTENI, A.; RUSSELL, R A.; BRIGHAM, J. c., and FIRESTONE, J. E.: Excitatory factors in ventricular tachycardia resulting from myocardial ischemia. Potassium a major excitant. Science 119: 200-203 (1954).
5
6
HERDSON, P. B.; SOMMERS, H. M., and JENNINGS, R B.: A comparative study of the fine structure of normal and ischemic dog myocardium with special reference to early changes following temporary occlusion of a coronary artery. Am. J. Path. 46: 367-386 (1965).
7
HOFFSTEIN, S.; GENNARO, D. E.; Fox, A. C.; HIRSCH, J.; STREULI, F., and WEISSMANN, G.: Colloidal lanthanum as a marker for impaired plasma membrane permeability in ischemic dog myocardium. Am. J. Path. 79: 207-218 (1975).
8
INOUE, K. and KrrAGAWA, T.: Effect of exogenous lysolecithin on liposomal membranes. Its relation to membrane fluidity. Biochim. biophys. Acta 363: 361-372 (1974).
9
KrEKSHUS, J. K. and SOBEL, B. E.: Depressed myocardial creatine phosphokinase activity following experimental myocardial infraction in rabbit. Circulation Res. 27: 403-414 (1970).
10
NEEDLEMAN, P.; MARSHALL, G. R, and SOBEL, B. E.: Hormone interactions in the isolated rabbit heart. Synthesis and coronary vasomotor effects of prostaglandins, angiotensin, and bradykinin. Circulation Res. 37: 802-808 (1975).
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References
The LysoJipid Hypothesis
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13
14
15
16
17
18 19
PAGE, D. L.; CAULFIELD, J. B.; KASTOR, J. A.; DESANCTIS, R. W., and SANDERS, C. A.: Myocardial changes associated with cardiogenic shock. New Engl. J. Med. 285: 133-137 (1971). RAy, T. K.; CRONAN,J.E.,jr.;MAVlS,R.D., andVAGELOS,P. R: The specific acylation of glycerol 3-phosphate to monoacylglycerol 3-phosphate in Escherichia coli. J. bioI. Chern. 245: 6442--6446 (1970). ROBERTS, R; HUSAIN, A.; AMBOS, H. D.; OLIVER, G. C.; COX, J., jr., and SOBEL, B. E.: Relation between infarct size and ventricular arrhythmia. Br. Heart J. 37: 1169-1175 (1975). ROBISON, A. K.; HANSEN, V. A., and SOBEL, B. E.: Accumulation of lysophosphatides, potential mediators of irreversible injury in ischemic myocardium (abstr.). Circulation 56: suppl. III, p. 168 (1977). SHELL, W. E.; LAVELLE, J. F.; COVELL, J. W., and SOBEL, B. E.: Early estimation of myocardial damage in conscious dogs and patients with evolving acute myocardial infarction. J. din. Invest. 52: 2579-2590 (1973). SILBERT, D. F.; ULBRIGHT, T. M., and HONEGGER, J. L.: Utilization of exogenous fatty acids for complex lipid biosynthesis and its effect on de novo fatty acid fonnation in Escherichia coli K-12. Biochemistry, N. Y.12: 164-171 (1973). SOBEL, B. E.; CORR, P. B.; ROBISON, A. K.; GOLDSTEIN, R A.; WITKOWSKI, F. X., and KLEIN, M. S.: Accumulation of lysophosphoglycerides with arrhythmogenic properties in ischemic myocardium. J. din. Invest. 62 (in press, 1978). BOSCH, H. VAN DEN: Phosphoglyceride metabolism. Annu. Rev. Biochem. 43: 243-277 (1974). WILKINSON, P. J. and CATER, D. B.: An electron-microscope study of the effects of lysolecithin on BP8 ascites-tumour cells and phagocytes of mice, compared with the effects of a specific antitumour serum plus complement. J. Path. 97: 219-230 (1969).
B. E. SOBEL, MD, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO 63110 (USA)
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