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Indomethacin and renal function in premature infants with persistent patent ductus arteriosus
October 1979 TheJournalofPEDIATRICS
583
Indomethacin and renal function in premature infants with persistent patent ductus arteriosus Renal function during indomethacin treatment was studied in 12 premature infants with patent ductus arteriosus. Decreases in urinary flow rate, GFR, and CH2o by 56, 27, and 66%, respectively, occurred during Indo therapy. Urinary excretion rates of ions were also reduced: Na by 70%, C1 by 79%, K by 40%. These changes were accompanied by slight decreases in plasma sodium concentration and osmolality. Except for GFR and urinary Na and osmolality, all these functions returned to pretreatment values one to two weeks after stopping the drug.
Raul F. Cifuentes, M.D., Peter M. Olley, M.D., J. Williamson Balfe, M.D., Ingeborg C. Radde, M.D.,* and Steve J. Soldin, Ph.D., T o r o n t o , Ont., C a n a d a
PROSTAGLANDIN SYNTHETASE INHIBITORS have recently been used to close medically a PDA. in premature infants.1-* However, this treatment has been associated with undesirable side effects, most notably transient renal dysfunction.1-3.5 Prior to this study, we believed that extrapolation from renal functional data obtained in experimental animals and/or adult human beings may not be relevant in the evaluation of data in the premature infant. Therefore, we studied premature infants before, during, and after a course of Indo to obtain quan~itar data on the renal response of infants who wou'ld be expected to have incomplete nephrogenesis.
METHODS Twelve premature infants with PDA and CHF were treated with Indo orally or, in two cases, per rectum (0.1 mg/kg, repeated twice at eight-hour intervals). The diagnosis was documented by clinical findings, chest radiographs, electrocardiography, and echocardiography. All infants were kept in incubators in an optimal thermal environment. The infants were treated with From the Research Institute of The Hospital for Sick Children and the Department of Paediatrics, University of Toronto. Supported in part by the Medical Research Council, Canada (Grant No. MA-4635), and The Ontario Heart Foundation. *Reprint address: The Hospitalfor Sickle Children, 555 University Ave., Toronto, Ont., Canada M5G 1XB.
0022-3476/79/100583+05500.50/0 9 1979 The C. V. Mosby Co.
digoxin, and had their fluid intake restricted to 128 _ 3.0 ml/kg/24 hours (mean _ SEM) for 3.2 _ 0.6 days before the trial with Indo. Two of these infants received chlorothiazide and spironolactone during the trial with Indo, and one infant was given furosemide twice a day. While informed written consent was being sought, a basal 24-hour urine collection was obtained. A midpoint venous blood sample was drawn. After Indo was started, a second 24-hour urine and midpoint venous blood specimen was collected; in seven of the infants a third collection was obtained one to two weeks later. In two infants the renal effects were remeasured during a further Indo trial. Abbreviations used PDA: patent ductus arteriosus PG: ~prostaglandin Indo: indomethacin CHF: congestiveheart failure Cer: creatinine clearance CH2o: free water clearance (V -- Costa) Co~m: osmolal clearance FE~: fraction excretion of sodium
100)
LBW: low birth weight Plasma and urine were analyzed for the following: creatinine by high-pressure liquid chromatography, ~ osmolality by freezing point depression with an Advanced Osmometer, and Na and K by standard flame spectrophotometry. Chloride was determined by amperometric-
Vol. 95, No. 4, pp. 583-587
584
Cifuentes et al.
The Journal of Pediatrics October 1979
Table. Urine and plasma values in infants before, during, and after indomethacin therapy (mean ___ SEM) Pretreatment
Urine Volume (ml/kg/24 hr) Osmolality (mOsm/kg H~O) Na(mEq/kg/24hr) K (mEq/kg/24hr) Cl(mEq/kg/24hr) Ca (mEq/kg/24 hr) Mg(mEq/kg/24hr) P (mg/kg/24 hr) Plasma Osmolality (mOsm/kg H oO) Na (mEq/l) K (mEq/1) C1 (mEq/l) Ca (mEq/l) Mg (mEq/1) P (mg/dl) BUN (mg/dl)
lndomethacin
Post-treatment
62.1 162.0 1.16 1.03 1.35 0.250 0.12 7.8
+ 5.5 +_ 13 +_ 0.20 _+ 0.15 _+ 0.31 • 0.076 _+ 0.01 _ 1.7
27.3 218.0 0.35 0.62 0.29 0.052 0.07 4.2
_+ 3.65 • 24* _+ 0.16t _+ 0.10" + 0.11t + 0.010" _+ 0.01t • 0.8*
77.1 113.0 0.55 1.07 0.75 0.204 0.24 10.4
_+ 5.2 + 5* +0.17" ___0.21 ___0.17 _+_0.035 + 0.10 + 2.5
271.0 135.0 5.0 91.0 4.84 1.81 5.8 10
• • _+ _+ _+ + _+ _+
261.0 130.0 5.0 88.0 4.69 1.77 5.9
+ + _ + _+ _+ _+
270.0 139.0 4.8 98.0 4.97 1.83 6.2
_+ 5 -+ It _+ 0.3 • 3* _+ 0.09 _+ 0.06 _+ 0.6
2 1 0.1 2 0.12 0.04 0.3 1
11
3~ 1:~ 0.1 2* 0.12 0.04 0.5
_+ 2
Paired t: *P < 0.05; t P < 0.005; 3~P < 0.001.
coulometric titration/ Total calcium and magnesium concentrations were measured by emission and atomic absorption flame spectrophotometry, respectively#. ~ The birth weight of the infants ranged from 620 to 2,025 gm (mean 1,370 gm) and their gestational age at birth from 27 to 35 weeks. Six infants had perinatal asphyxia; nine developed severe and two had moderate respiratory distress Syndrome. F o u r of the infants had undergone severe cold stress during the immediate neonatal period. Other problems included A B O incompatibility (three patients), recurrent apnea0 hypocalcemia, and bilateral pneumothorax. In nine of the 12 infants the P D A was diagnosed between three and five days o f age, in two at age 8, and in one at age 14 days. C H F was documented between 6 and 8 days of age in six, and up to 25 days of age in the remaining infants. The courses of Indo studied occurred between 10 and 28 days of age (mean 19.0 days) and the follow-up renal function studies were carried out between ages 29 and 44 days. Six o f the infants had two or more courses of Indo therapy, o f which we studied the first in three, the second in one, and the first and second courses in two infants. Statistical analysis was done by paired t test; results were compared between values before and during Indo therapy, and before and after therapy. RESULTS O f the 12 infants treated with Indo, three responded by ductus closure~ and three by reduction of the shunt as
evidenced clinically and by echocardiography. Three of the six infants in w h o m the ductus persisted required surgical ligation. The blood pressure, measured by the D o p p l e r technique, did not change during the Indo trial, being 72 ___ 3, 73___ 2, and 72_+ 1 m m Hg (mean_+ S E M ) before, during, and after the trial, respectively. The heart rate decreased from 149 • 3 to 138 +_ 3 beats per minute (P < 0.001) and returned to pretreatment values (147 ___ 3) after therapy was discontinued. The left atrium/aortic root ratio decreased from 1.56 _+ 0.07 to 1.30 _+ 0.08 during Indo therapy (P < 0.01). The changes in urinary volume before, during, and after Indo therapy are presented in the Table. There was a significant decrease in all infants by a m e a n o f 56%. The urinary output, when'~alculated as a percent o f intake, decreased.from 50.0 ___ 4.1 to 23.5 _+ 3.2% between the pretreatment and Indo periods (P < 0.001). In the third period the urinary output was 54.8 _+ 2.6% of the intake. In the few infants in w h o m the urinary flow rate was measured immediately after discontinuation of the drug, the expected diuresis was observed during the next one to two days/~ The GFR, as measured by the Cc.,, and corrected to square meter of body surface area according to the formula of Haycock et al, 1~ decreased by 27% (Fig. 1). The effects of the drug on urine and plasma osmolality and ion concentrations are presented in the Table. The urinary excretion rates of all ions decreased during Indo therapy, but the changes in K, Ca, and P were less than
Volume 95 Number 4
Indomethacin and renal function with PDA
ml/min/m 2
FE No
%
GFR
585
2sJ 24.0
1.2
1.0
18.0
Rq
12.0
0.8
0.6 0.4
",6.0 00
,-
0.2
9 @tpe
0
Pre
Indo p <0.05
Pre
Post p < 0,05
000
Indo
Post
p < 0.05
p
Fig. 1. Glomerular filtration rate (GFR) in ml/rnin/m2and fractional~excretionrate of sodium (FEx,) in percent before (Pre), during (Iudo), and after (Pos0 treatment with I n d o m e t h a c i n . ~ - - ~ = Mean +_ SEM. The P values indicated are from comparisons with the "Pre" value. w
those of Na, C1, and Mg. The three infants who received diuretics during the pretreatment and Indo periods had similar excretion rates for water and ions compared to infants who did not receive such therapy, and thus their results are included in the analysis of data. In the post-treatment period only osmolality and urinary Na excretion rates were still decreased when compared to pretreatment values (P < 0.05). The FEx~ during Indo therapy was lower than during the pretreatment period, and in the post-treatment period decreased to even lower values in every infant. Both plasma Na and C1 concentrations were higher during the post-treatment compared to the pretreatment period. The free water clearance (C,_~o) decreased by 65%. One to two weeks later, the CH~ohad returned to values similar to those measured before treatment. The Corm decreased also during Indo therapy; in the post-treatment period it decreased further (Fig. 2). DISCUSSION Several clinical trials using Indo to close a PDA have been reported, and guidelines for its use suggested. H The renal side effects noted included oliguria2 -~ rising BUN? ~ decreased urinary sodium excretion, * and increased serum creatinine concentration.1. 2 These effects were transient and it was suggested that a dose-response relationship existed? The kidney synthesizes PGE,, PGF2a, and PGD~, predominantly in the papilla and medulla. PGE1 increases water excretion in man and animals, an action present
I
also during fetal life?'-'-~ Conversely, Indo decreases water excretion18 18 by reducing the inhibitory action of PG on vasopressin, 1~while vasopressin stimulates PG production in a feedback system. The urinary osmolality in the pretreatment period was slightly higher than the normal range established for similarly fed low-birth-weight infants? 8 reflecting the renal response to the moderate fluid restriction. In the post-treatment period, both urinary osmolality and Co~, were lower than in the pretreatment period, suggesting greater solute retention. The infants may have entered a stage of greater anabolism, and this may partly explain the finding of increased solute retention. We attribute the fall in GFR in our premature infants specifically to the action of Indo, since clinically CHF improved and shunting was reduced, as evidenced by the decrease in the left atrium/aortic root ratio. In addition, fluid intake was only moderately restricted to approximately 130 ml/kg/24 hours for an average of three days prior to Indo, and thus we presume the infants had reached a relatively stable level of hydration. We have found (unpublished observations) in studies of very LBW infants of similar postnatal age that reduction of fluid intake from 200 to 150 ml/kg/24 hour leads to stable urine output within 24 hours. GFR has been reported to decrease in adults given indo,17 _,0 or to remain unchanged? ~8. _~Although the role of PGs in the maintenance of basal renal blood flow is controversial, acute administration of PGs or their synthetase inhibitors alter renal blood flow and intrarenal blood distribution in the
5 86
Cifuentes et al.
The Journal of.Pediatrics October 1979
7.0 m
,5" LL.
7.0
CH20
6.0
6.0
5.0
5.0
4.0
4.0
3.0
3.0
2.0
2.0
1.0
1.0
Costa
R
0
u 0 0
e~e
I::
E
0
9
-1.0
Pre
~176176
0
S9 Indo p
Post
Pre
Indo
Post
Fig. 2. Free water clearance (C. o) and osmolal clearance (Co~m),both in ml/min/dl GFR before (Pre), during (Indo), and after (Post) treatment with Indomethacin. ~ [ ~ = Mean _-!-SEM. experimental animal. 1-~-1~.... ._,3Whether the decrease in GFR was due to change in renal plasma flow, in intrarenal blood distribution, in basement membrane permeability, or due to a combination of these, remains to be clarified. One to two weeks after Indo therapy, the GFR in our infants had increased significantly compared to the pretreatment period. This was consistent with the expected age-related increase in GFR normally occurring in premature infants,-~ and provides further evidence that the Indo effect on GFR is reversible. Prostaglandins E1 and E~ induce natriuresis by renal vasodilatationr -~-1~. -~ while Indo reduces urinary sodium excretionY 17.26.~.~ In LBW infants, the .~FEx~ and the urinary Na excretion rates have been shown to be higher in the first few weeks of life than later7 ~After Indo (one to two weeks later), the FEx, and the urinary sodium excretion rates were even lower than in the two previous periods. This effect could be explained partly on the basis of maturation of the renal tubular reabsorptive capacity for Na. Indomethacin produced a slight but consistent decrease in plasma Na concentration and osmolality, confirming previous reports in premature infants. ~ 3 The lower urinary Na excretion and the hyponatremia sugges(that water retention exceeds that of sodium. Since we have shown that C.~o was decreased more than ~Co~m during administration of Indo, we suggest that the enhancement
of water reabsorption is occurring in the distal nephron. We did not observe changes in arterial blood pressure during Indo therapy, in agreement with the experience of others. 1~ -~~Arterial hypertension has been observed with Indo treatment in infants with PDA ~ and in animals. 16- -~1 Heart rate decreased during Indo administration,-~which may reflect improved cardiac function. Prostaglandin E~ can induce kaliuresis, 13 whereas Indo decreases the urinary excretion rates of potassium. ~6 17 We found that the excretion rates of all elements tested (Na, K, C1, Ca, Mg, and P) were reduced, but the magnitude of the change for K was much less than that of Na or C1. Nephrogenesis in the premature infant is not complete until 36 weeks of gestati0~i and it has been proposed that PGs play a role in renal development in the rat7 ~ Structural renal changes have been observed in the rat after high doses of Indo for at least eight daysY However, in the three infants in our series who died either shortly after Indo therapy (two infants) or five months later, no renal abnormalities were seen by light microscopy. Longterm follow'Zup 'of Indo-treated infants has shown no residual defects in renal function.-~ Our study suggests that the renal response to Indo therapy in premature infants follows a similar pattern described for adults and experimental animals. The renal functional changes were rapidly reversed and no permanent .impairment was observed. We believe that the
Volume 95 Number 4
transient renal abnormalities do not preclude the use o f Indo for closure of P D A in LBW infants if clinically indicated. We acknowledge with gratitude the skillful assistance of Miss J. Chabot, R.N., Research Nurse attached to the Study, and the excellent technical help -of Mrs. J. Sheepers, R.T., and Mrs. D~ Davis, B.Sc. REFERENCES
1. Friedman WF, Hirschkiau M J, Printz MP, Pitlick PT, and Kirkp~ttrick SE: Pharmacological closure of patent ductus arteriosus in the prematur e infant, N Engl J Med 295:526, 1976. 2. Heymann MA, Rudolph.AM, and Silverman NH: Closure of the ductus arteriosus in premature infants by inhibition of prostaglandin synthesis, N Engl J Med 295:530, 1976. 3. Neal WA, Kyle JM, and Mullett MD: Failure ofindomethacin therapy to induce closure of patent ductus arteriosus in premature infants with respiratory distress syndrome, J PEDIATR 91:621, 1977. 4. Grant M, Rowlands D, Swyer P, Rowe R, Coceani F, and Olley P: Closure of the ductus arteriosus in premature infants using prostaglandin synthesis inhibition, Proceedings of the Canadian CardiovaScular Society, October, 1977, Toronto. (abstr). 5. Winther J, Printz MP, Mendoza SA, Kirkpatrick SE, and Friedman WF: The influence of indomethacin on neonatal renal function, Pediatr Res 11:402, 1977 (abstr). 6. Soldin SJ, and Hill JG: Rapid specific micromethod for the determination of creatinine in biological fluids b y high performance liquid chromatography, Clin Chem 24:747, 1978. 7. Cotlove E: Determination of chloride in biological materials, in Gl!ck D, editor: Methods of biochemical analysis, vol. 12, New YoLk, 1964, John Wiley & Sons, Inc., p 277. 8. Maclntyre I: Flame photometry, Adv Clin Chem 4:11 1961. , 9. Aicock N, MacIntyre I, and Radde IC: The determination of magnesium in biological fluids and tissues by flame spectrophotometty, J Clin Pathol !3:506, 1960. 10, Haycock GB; Schwartz GJ, and Wisotsky DH: Geometric method for measuring body surface area: A height-weight formula validated in infants, children and adults, J PEDIATR 93:62, 1978. 11. Gersony WM: Commentary: Patent ductus arteriosus and the respiratory distress syndrome-a perspective, J PEDIATR 91:624, 1977. 12. Johnston HH, Herzog JP, and Lauler DP: Effect of prostaglandin E1 on renal hemodynamics, sodium and water excretion, Am J Physiol 213:939, 1967.
Indomethacin and renal f u n c t i o n with P D A
587
13. Bed T, and Schrier RW: Mechanism of effect of PGE~ on renal water excretion, J Clin Invest 52:4631 1973. 14. Gross JB, and Bartter FC: Effects of prostaglandins E,, A~ and F2,, on renal handling of salt and water, Am J Physiol 225:218, 1973. !5. Walker DW, and Mitchell MD: Prostaglandins in urine of fetal lamb, Nature 271:161, 1978. 16. Feigen LP, Klainer E, Chapnik BM, and Kadowitz PJ: The effect of indomethacin on renal function in pentobarbitalanesthetized dogs, J Pharmacol Exp Ther 198:457, 1976. 17. Bowden RE, Gill JR Jr, Radfar M, Taylor AA, and Keiser HR: Prostaglandin synthetase inhibitors in Bartter's syndrome, JAMA 239:117, 1978. 18. Anderson RJ, Berl T, McDonald KM, and Schrier RW: Evidence for an in vivo antagonism between vasopressin and prostaglandin in the mammalian kidney, J Ctin lnvest 56:420, 1975. 19. Saigal S, and Sinclair JC: Urine solute excretion in growing low birth weight infants, in 9 L, Friis-Hansen B, and Kildeberg p, editors: Intensive care in the newborn, New Yoi'k, 1976, Masson Publishing USA, Inc. p. 119. 20. Donker AJM, Arisz L, Brentjens JRH, van der Hem GK, and Hollemans HJG: The effect of indomethacin on kidney function and plasma renin activity in man, Nephron 17:288, 1976. 21. DiBona GF, Zambraski EJ, Aguilera AJ, and Kaloyanides GJ: Neurogenic control of renal tubular sodium reabsorption in the dog, Circ Res Suppl 40:127, 1977. 22. Ten-agno NA, Terragno DA, and McGiff JC: Contribution ofprostaglandins to the renal circulation in conscious, anesthetized, and laparotomized dogs, Circ Res 40:590, i977.9 23. Beilin LJ, and Bhatiacharya J: The effect of prostaglandin syntl~esis inhibitors on renal blood flow distribution in conscious rabbits, J Physiol 269:395, 1977. 24. Ross B, Cowett RM, and Oh W: Renal functions of low birth Weight infants during the first tWO months of life, Pediatr Res 11:1162, 1977. 25. Fine LG, and Trizna W: Influence of prostaglandins on sodium transport of isolated medullary nephron segments, Am J Physiol 232:383, 1977. 26. Pace-Aseiak C: Activity profiles of prostaglandin 15- and 9-hydroxydehydrogenase and 13-reductase in the develOping rat kidney, J Biol Chem 250:2795, 1975. 27. Sessa A, Allaria PM, Conte F, Cioffi A, and D'Amico G: Ukra-s!ructural changes of the glomeruli of the rat induced by indomethacin, Nephron 10:238, 1973. 28. Merritt TA, White CL, Hirschklau M J, Friedman WF, and Gluck L: Infant follow up after indomethacin closure of the patent ductus arteriosus, Pediatr Res 11:395, 1977 (abstr).
583
Indomethacin and renal function in premature infants with persistent patent ductus arteriosus Renal function during indomethacin treatment was studied in 12 premature infants with patent ductus arteriosus. Decreases in urinary flow rate, GFR, and CH2o by 56, 27, and 66%, respectively, occurred during Indo therapy. Urinary excretion rates of ions were also reduced: Na by 70%, C1 by 79%, K by 40%. These changes were accompanied by slight decreases in plasma sodium concentration and osmolality. Except for GFR and urinary Na and osmolality, all these functions returned to pretreatment values one to two weeks after stopping the drug.
Raul F. Cifuentes, M.D., Peter M. Olley, M.D., J. Williamson Balfe, M.D., Ingeborg C. Radde, M.D.,* and Steve J. Soldin, Ph.D., T o r o n t o , Ont., C a n a d a
PROSTAGLANDIN SYNTHETASE INHIBITORS have recently been used to close medically a PDA. in premature infants.1-* However, this treatment has been associated with undesirable side effects, most notably transient renal dysfunction.1-3.5 Prior to this study, we believed that extrapolation from renal functional data obtained in experimental animals and/or adult human beings may not be relevant in the evaluation of data in the premature infant. Therefore, we studied premature infants before, during, and after a course of Indo to obtain quan~itar data on the renal response of infants who wou'ld be expected to have incomplete nephrogenesis.
METHODS Twelve premature infants with PDA and CHF were treated with Indo orally or, in two cases, per rectum (0.1 mg/kg, repeated twice at eight-hour intervals). The diagnosis was documented by clinical findings, chest radiographs, electrocardiography, and echocardiography. All infants were kept in incubators in an optimal thermal environment. The infants were treated with From the Research Institute of The Hospital for Sick Children and the Department of Paediatrics, University of Toronto. Supported in part by the Medical Research Council, Canada (Grant No. MA-4635), and The Ontario Heart Foundation. *Reprint address: The Hospitalfor Sickle Children, 555 University Ave., Toronto, Ont., Canada M5G 1XB.
0022-3476/79/100583+05500.50/0 9 1979 The C. V. Mosby Co.
digoxin, and had their fluid intake restricted to 128 _ 3.0 ml/kg/24 hours (mean _ SEM) for 3.2 _ 0.6 days before the trial with Indo. Two of these infants received chlorothiazide and spironolactone during the trial with Indo, and one infant was given furosemide twice a day. While informed written consent was being sought, a basal 24-hour urine collection was obtained. A midpoint venous blood sample was drawn. After Indo was started, a second 24-hour urine and midpoint venous blood specimen was collected; in seven of the infants a third collection was obtained one to two weeks later. In two infants the renal effects were remeasured during a further Indo trial. Abbreviations used PDA: patent ductus arteriosus PG: ~prostaglandin Indo: indomethacin CHF: congestiveheart failure Cer: creatinine clearance CH2o: free water clearance (V -- Costa) Co~m: osmolal clearance FE~: fraction excretion of sodium
100)
LBW: low birth weight Plasma and urine were analyzed for the following: creatinine by high-pressure liquid chromatography, ~ osmolality by freezing point depression with an Advanced Osmometer, and Na and K by standard flame spectrophotometry. Chloride was determined by amperometric-
Vol. 95, No. 4, pp. 583-587
584
Cifuentes et al.
The Journal of Pediatrics October 1979
Table. Urine and plasma values in infants before, during, and after indomethacin therapy (mean ___ SEM) Pretreatment
Urine Volume (ml/kg/24 hr) Osmolality (mOsm/kg H~O) Na(mEq/kg/24hr) K (mEq/kg/24hr) Cl(mEq/kg/24hr) Ca (mEq/kg/24 hr) Mg(mEq/kg/24hr) P (mg/kg/24 hr) Plasma Osmolality (mOsm/kg H oO) Na (mEq/l) K (mEq/1) C1 (mEq/l) Ca (mEq/l) Mg (mEq/1) P (mg/dl) BUN (mg/dl)
lndomethacin
Post-treatment
62.1 162.0 1.16 1.03 1.35 0.250 0.12 7.8
+ 5.5 +_ 13 +_ 0.20 _+ 0.15 _+ 0.31 • 0.076 _+ 0.01 _ 1.7
27.3 218.0 0.35 0.62 0.29 0.052 0.07 4.2
_+ 3.65 • 24* _+ 0.16t _+ 0.10" + 0.11t + 0.010" _+ 0.01t • 0.8*
77.1 113.0 0.55 1.07 0.75 0.204 0.24 10.4
_+ 5.2 + 5* +0.17" ___0.21 ___0.17 _+_0.035 + 0.10 + 2.5
271.0 135.0 5.0 91.0 4.84 1.81 5.8 10
• • _+ _+ _+ + _+ _+
261.0 130.0 5.0 88.0 4.69 1.77 5.9
+ + _ + _+ _+ _+
270.0 139.0 4.8 98.0 4.97 1.83 6.2
_+ 5 -+ It _+ 0.3 • 3* _+ 0.09 _+ 0.06 _+ 0.6
2 1 0.1 2 0.12 0.04 0.3 1
11
3~ 1:~ 0.1 2* 0.12 0.04 0.5
_+ 2
Paired t: *P < 0.05; t P < 0.005; 3~P < 0.001.
coulometric titration/ Total calcium and magnesium concentrations were measured by emission and atomic absorption flame spectrophotometry, respectively#. ~ The birth weight of the infants ranged from 620 to 2,025 gm (mean 1,370 gm) and their gestational age at birth from 27 to 35 weeks. Six infants had perinatal asphyxia; nine developed severe and two had moderate respiratory distress Syndrome. F o u r of the infants had undergone severe cold stress during the immediate neonatal period. Other problems included A B O incompatibility (three patients), recurrent apnea0 hypocalcemia, and bilateral pneumothorax. In nine of the 12 infants the P D A was diagnosed between three and five days o f age, in two at age 8, and in one at age 14 days. C H F was documented between 6 and 8 days of age in six, and up to 25 days of age in the remaining infants. The courses of Indo studied occurred between 10 and 28 days of age (mean 19.0 days) and the follow-up renal function studies were carried out between ages 29 and 44 days. Six o f the infants had two or more courses of Indo therapy, o f which we studied the first in three, the second in one, and the first and second courses in two infants. Statistical analysis was done by paired t test; results were compared between values before and during Indo therapy, and before and after therapy. RESULTS O f the 12 infants treated with Indo, three responded by ductus closure~ and three by reduction of the shunt as
evidenced clinically and by echocardiography. Three of the six infants in w h o m the ductus persisted required surgical ligation. The blood pressure, measured by the D o p p l e r technique, did not change during the Indo trial, being 72 ___ 3, 73___ 2, and 72_+ 1 m m Hg (mean_+ S E M ) before, during, and after the trial, respectively. The heart rate decreased from 149 • 3 to 138 +_ 3 beats per minute (P < 0.001) and returned to pretreatment values (147 ___ 3) after therapy was discontinued. The left atrium/aortic root ratio decreased from 1.56 _+ 0.07 to 1.30 _+ 0.08 during Indo therapy (P < 0.01). The changes in urinary volume before, during, and after Indo therapy are presented in the Table. There was a significant decrease in all infants by a m e a n o f 56%. The urinary output, when'~alculated as a percent o f intake, decreased.from 50.0 ___ 4.1 to 23.5 _+ 3.2% between the pretreatment and Indo periods (P < 0.001). In the third period the urinary output was 54.8 _+ 2.6% of the intake. In the few infants in w h o m the urinary flow rate was measured immediately after discontinuation of the drug, the expected diuresis was observed during the next one to two days/~ The GFR, as measured by the Cc.,, and corrected to square meter of body surface area according to the formula of Haycock et al, 1~ decreased by 27% (Fig. 1). The effects of the drug on urine and plasma osmolality and ion concentrations are presented in the Table. The urinary excretion rates of all ions decreased during Indo therapy, but the changes in K, Ca, and P were less than
Volume 95 Number 4
Indomethacin and renal function with PDA
ml/min/m 2
FE No
%
GFR
585
2sJ 24.0
1.2
1.0
18.0
Rq
12.0
0.8
0.6 0.4
",6.0 00
,-
0.2
9 @tpe
0
Pre
Indo p <0.05
Pre
Post p < 0,05
000
Indo
Post
p < 0.05
p
Fig. 1. Glomerular filtration rate (GFR) in ml/rnin/m2and fractional~excretionrate of sodium (FEx,) in percent before (Pre), during (Iudo), and after (Pos0 treatment with I n d o m e t h a c i n . ~ - - ~ = Mean +_ SEM. The P values indicated are from comparisons with the "Pre" value. w
those of Na, C1, and Mg. The three infants who received diuretics during the pretreatment and Indo periods had similar excretion rates for water and ions compared to infants who did not receive such therapy, and thus their results are included in the analysis of data. In the post-treatment period only osmolality and urinary Na excretion rates were still decreased when compared to pretreatment values (P < 0.05). The FEx~ during Indo therapy was lower than during the pretreatment period, and in the post-treatment period decreased to even lower values in every infant. Both plasma Na and C1 concentrations were higher during the post-treatment compared to the pretreatment period. The free water clearance (C,_~o) decreased by 65%. One to two weeks later, the CH~ohad returned to values similar to those measured before treatment. The Corm decreased also during Indo therapy; in the post-treatment period it decreased further (Fig. 2). DISCUSSION Several clinical trials using Indo to close a PDA have been reported, and guidelines for its use suggested. H The renal side effects noted included oliguria2 -~ rising BUN? ~ decreased urinary sodium excretion, * and increased serum creatinine concentration.1. 2 These effects were transient and it was suggested that a dose-response relationship existed? The kidney synthesizes PGE,, PGF2a, and PGD~, predominantly in the papilla and medulla. PGE1 increases water excretion in man and animals, an action present
I
also during fetal life?'-'-~ Conversely, Indo decreases water excretion18 18 by reducing the inhibitory action of PG on vasopressin, 1~while vasopressin stimulates PG production in a feedback system. The urinary osmolality in the pretreatment period was slightly higher than the normal range established for similarly fed low-birth-weight infants? 8 reflecting the renal response to the moderate fluid restriction. In the post-treatment period, both urinary osmolality and Co~, were lower than in the pretreatment period, suggesting greater solute retention. The infants may have entered a stage of greater anabolism, and this may partly explain the finding of increased solute retention. We attribute the fall in GFR in our premature infants specifically to the action of Indo, since clinically CHF improved and shunting was reduced, as evidenced by the decrease in the left atrium/aortic root ratio. In addition, fluid intake was only moderately restricted to approximately 130 ml/kg/24 hours for an average of three days prior to Indo, and thus we presume the infants had reached a relatively stable level of hydration. We have found (unpublished observations) in studies of very LBW infants of similar postnatal age that reduction of fluid intake from 200 to 150 ml/kg/24 hour leads to stable urine output within 24 hours. GFR has been reported to decrease in adults given indo,17 _,0 or to remain unchanged? ~8. _~Although the role of PGs in the maintenance of basal renal blood flow is controversial, acute administration of PGs or their synthetase inhibitors alter renal blood flow and intrarenal blood distribution in the
5 86
Cifuentes et al.
The Journal of.Pediatrics October 1979
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Fig. 2. Free water clearance (C. o) and osmolal clearance (Co~m),both in ml/min/dl GFR before (Pre), during (Indo), and after (Post) treatment with Indomethacin. ~ [ ~ = Mean _-!-SEM. experimental animal. 1-~-1~.... ._,3Whether the decrease in GFR was due to change in renal plasma flow, in intrarenal blood distribution, in basement membrane permeability, or due to a combination of these, remains to be clarified. One to two weeks after Indo therapy, the GFR in our infants had increased significantly compared to the pretreatment period. This was consistent with the expected age-related increase in GFR normally occurring in premature infants,-~ and provides further evidence that the Indo effect on GFR is reversible. Prostaglandins E1 and E~ induce natriuresis by renal vasodilatationr -~-1~. -~ while Indo reduces urinary sodium excretionY 17.26.~.~ In LBW infants, the .~FEx~ and the urinary Na excretion rates have been shown to be higher in the first few weeks of life than later7 ~After Indo (one to two weeks later), the FEx, and the urinary sodium excretion rates were even lower than in the two previous periods. This effect could be explained partly on the basis of maturation of the renal tubular reabsorptive capacity for Na. Indomethacin produced a slight but consistent decrease in plasma Na concentration and osmolality, confirming previous reports in premature infants. ~ 3 The lower urinary Na excretion and the hyponatremia sugges(that water retention exceeds that of sodium. Since we have shown that C.~o was decreased more than ~Co~m during administration of Indo, we suggest that the enhancement
of water reabsorption is occurring in the distal nephron. We did not observe changes in arterial blood pressure during Indo therapy, in agreement with the experience of others. 1~ -~~Arterial hypertension has been observed with Indo treatment in infants with PDA ~ and in animals. 16- -~1 Heart rate decreased during Indo administration,-~which may reflect improved cardiac function. Prostaglandin E~ can induce kaliuresis, 13 whereas Indo decreases the urinary excretion rates of potassium. ~6 17 We found that the excretion rates of all elements tested (Na, K, C1, Ca, Mg, and P) were reduced, but the magnitude of the change for K was much less than that of Na or C1. Nephrogenesis in the premature infant is not complete until 36 weeks of gestati0~i and it has been proposed that PGs play a role in renal development in the rat7 ~ Structural renal changes have been observed in the rat after high doses of Indo for at least eight daysY However, in the three infants in our series who died either shortly after Indo therapy (two infants) or five months later, no renal abnormalities were seen by light microscopy. Longterm follow'Zup 'of Indo-treated infants has shown no residual defects in renal function.-~ Our study suggests that the renal response to Indo therapy in premature infants follows a similar pattern described for adults and experimental animals. The renal functional changes were rapidly reversed and no permanent .impairment was observed. We believe that the
Volume 95 Number 4
transient renal abnormalities do not preclude the use o f Indo for closure of P D A in LBW infants if clinically indicated. We acknowledge with gratitude the skillful assistance of Miss J. Chabot, R.N., Research Nurse attached to the Study, and the excellent technical help -of Mrs. J. Sheepers, R.T., and Mrs. D~ Davis, B.Sc. REFERENCES
1. Friedman WF, Hirschkiau M J, Printz MP, Pitlick PT, and Kirkp~ttrick SE: Pharmacological closure of patent ductus arteriosus in the prematur e infant, N Engl J Med 295:526, 1976. 2. Heymann MA, Rudolph.AM, and Silverman NH: Closure of the ductus arteriosus in premature infants by inhibition of prostaglandin synthesis, N Engl J Med 295:530, 1976. 3. Neal WA, Kyle JM, and Mullett MD: Failure ofindomethacin therapy to induce closure of patent ductus arteriosus in premature infants with respiratory distress syndrome, J PEDIATR 91:621, 1977. 4. Grant M, Rowlands D, Swyer P, Rowe R, Coceani F, and Olley P: Closure of the ductus arteriosus in premature infants using prostaglandin synthesis inhibition, Proceedings of the Canadian CardiovaScular Society, October, 1977, Toronto. (abstr). 5. Winther J, Printz MP, Mendoza SA, Kirkpatrick SE, and Friedman WF: The influence of indomethacin on neonatal renal function, Pediatr Res 11:402, 1977 (abstr). 6. Soldin SJ, and Hill JG: Rapid specific micromethod for the determination of creatinine in biological fluids b y high performance liquid chromatography, Clin Chem 24:747, 1978. 7. Cotlove E: Determination of chloride in biological materials, in Gl!ck D, editor: Methods of biochemical analysis, vol. 12, New YoLk, 1964, John Wiley & Sons, Inc., p 277. 8. Maclntyre I: Flame photometry, Adv Clin Chem 4:11 1961. , 9. Aicock N, MacIntyre I, and Radde IC: The determination of magnesium in biological fluids and tissues by flame spectrophotometty, J Clin Pathol !3:506, 1960. 10, Haycock GB; Schwartz GJ, and Wisotsky DH: Geometric method for measuring body surface area: A height-weight formula validated in infants, children and adults, J PEDIATR 93:62, 1978. 11. Gersony WM: Commentary: Patent ductus arteriosus and the respiratory distress syndrome-a perspective, J PEDIATR 91:624, 1977. 12. Johnston HH, Herzog JP, and Lauler DP: Effect of prostaglandin E1 on renal hemodynamics, sodium and water excretion, Am J Physiol 213:939, 1967.
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13. Bed T, and Schrier RW: Mechanism of effect of PGE~ on renal water excretion, J Clin Invest 52:4631 1973. 14. Gross JB, and Bartter FC: Effects of prostaglandins E,, A~ and F2,, on renal handling of salt and water, Am J Physiol 225:218, 1973. !5. Walker DW, and Mitchell MD: Prostaglandins in urine of fetal lamb, Nature 271:161, 1978. 16. Feigen LP, Klainer E, Chapnik BM, and Kadowitz PJ: The effect of indomethacin on renal function in pentobarbitalanesthetized dogs, J Pharmacol Exp Ther 198:457, 1976. 17. Bowden RE, Gill JR Jr, Radfar M, Taylor AA, and Keiser HR: Prostaglandin synthetase inhibitors in Bartter's syndrome, JAMA 239:117, 1978. 18. Anderson RJ, Berl T, McDonald KM, and Schrier RW: Evidence for an in vivo antagonism between vasopressin and prostaglandin in the mammalian kidney, J Ctin lnvest 56:420, 1975. 19. Saigal S, and Sinclair JC: Urine solute excretion in growing low birth weight infants, in 9 L, Friis-Hansen B, and Kildeberg p, editors: Intensive care in the newborn, New Yoi'k, 1976, Masson Publishing USA, Inc. p. 119. 20. Donker AJM, Arisz L, Brentjens JRH, van der Hem GK, and Hollemans HJG: The effect of indomethacin on kidney function and plasma renin activity in man, Nephron 17:288, 1976. 21. DiBona GF, Zambraski EJ, Aguilera AJ, and Kaloyanides GJ: Neurogenic control of renal tubular sodium reabsorption in the dog, Circ Res Suppl 40:127, 1977. 22. Ten-agno NA, Terragno DA, and McGiff JC: Contribution ofprostaglandins to the renal circulation in conscious, anesthetized, and laparotomized dogs, Circ Res 40:590, i977.9 23. Beilin LJ, and Bhatiacharya J: The effect of prostaglandin syntl~esis inhibitors on renal blood flow distribution in conscious rabbits, J Physiol 269:395, 1977. 24. Ross B, Cowett RM, and Oh W: Renal functions of low birth Weight infants during the first tWO months of life, Pediatr Res 11:1162, 1977. 25. Fine LG, and Trizna W: Influence of prostaglandins on sodium transport of isolated medullary nephron segments, Am J Physiol 232:383, 1977. 26. Pace-Aseiak C: Activity profiles of prostaglandin 15- and 9-hydroxydehydrogenase and 13-reductase in the develOping rat kidney, J Biol Chem 250:2795, 1975. 27. Sessa A, Allaria PM, Conte F, Cioffi A, and D'Amico G: Ukra-s!ructural changes of the glomeruli of the rat induced by indomethacin, Nephron 10:238, 1973. 28. Merritt TA, White CL, Hirschklau M J, Friedman WF, and Gluck L: Infant follow up after indomethacin closure of the patent ductus arteriosus, Pediatr Res 11:395, 1977 (abstr).