FETAL
AND
MEDICINE
NEONATAL RichardE. Behrman,Editor
Failure of indomethacin therapy to induce closure of patent ductus arteriosus in premature infants with respiratory distress syndrome William A. Neal, M.D.,* James M. Kyle, and Martha D. Mullett, M.D., Morgantown,
W. Va.
MANAGEMENT of premature infants with respiratory distress syndrome complicated by patent ductus arteriosus continues to pose a challenge in the selection of patients for surgical ligation of the ductus and for appropriate timing of the operation. The exciting possibility of pharmacologic closure of the ductus with indomethacin inhibition of prostaglandin synthesis was first suggested by Sharpe.' Support for this hypothesis was detailed in two reports of indomethacin-induced PDA closure in premature infants with RDS.-" :~ A recent update of the combined experience of these two West Coast centers is even more encouraging considering the extremely high incidence of successful pharmacologic treatment and the relatively low associated morbidity. ~ We present our less favorable experience with indomethacin therapy in premature infants with RDS and PDA and briefly examine some of the possible reasons for the discrepancy in results. MATERIALS
absence of severe anemia a n d / o r hypoxia), and hepatomegaly. When these findings were present laboratory studies were performed to exclude hyperbilirubinemia ( > 12 mg/dl), renal insufficiency, serum electrolyte imbalance, gastrointestinal bleeding, and coagulopathy. Parental informed consent was obtained prior to administration of indomethacin in accordance with the Committee on Research Involving Human Subjects of West Virginia University. Indomethacin was administered orally (via nasogastric tube) in nine patients and rectally in two patients. The route of administration, amount given, and number of administrations is tabulated in Table I. Clinical and laboratory evidence of toxicity was recorded following indomethacin treatment, as were characteristics of the PDA murmur and presence or absence of congestive heart failure.
See related article, p. 624.
AND METHODS
Eleven premature infants with severe RDS (ventilator dependence), gestational ages from 27 to 33 weeks, were selected for indomethacin therapy using the same criteria for selection that we follow for surgical ligation of the PDA. These include continuous murmur beneath the left clavicle, brisk peripheral pulses, and evidence of congestive heart failure unresponsive to medical management: cardiomegaly on chest roentgenogram, persistent elevation of heart rate greater than 160/minute (in the From the Department of Pediatrics, West Virginia University. *Reprint address: Department (~fPediatrics, West Virginia University. Morgantown. WV 26506.
Abbreviations used RDS: respiratory distress syndrome. PDA: patent ductus arteriosus BUN: blood urea nitrogen CHF: congestive heart failure RESULTS All but two patients demonstrated transient cessation or diminished intensity of the murmur within 24 hours following administration of indomethacin, interpreted as ductal responsiveness to the drug. In only two of the 11 infants was closure of the PDA permanent. Two addiThe Journal of P E D I A T R 1 C S Vol. 91, No. 4, pp. 621-623
621
622
Neal, Kyle, and Mullett
The Journal of Pediatrics October 1977
Table L Clinical data of patients treated with indomethacin
Onset CHF (days)
Ag e Indomethacin given (days)
Dose~ (mg/kg)
32
7
10,24
0.33
1.20
30
18
18
0.57*
3
0.95
28
7
7,14
0.26
4 5
1.90 0.83
33 27
21 7
30,32,34 7,14,21
0.40 0.48
6
0.82
28
14
14
0.88
7
1.15
29
10
14,21,23
1.10"
8
1.30
31
7
14
0.25
9
1.63
32
7
11,18,23
0.40
10
0.89
27
9
11,12
0.80
11
1.28
31
31
40,42,43
0.50
Patient
Birth weight (kg)
Gestational age (wk)
1
1.50
2
Results Permanent closure Transient closure Transient closure No change Permanent closure Intensity murmur decreased Intensity murmur decreased Intensity murmur decreased Intensity murmur decreased Intensity murmur decreased No change
Complications Hyponatremia Guaiac-positive stools Guaiac-positive gastric aspirate None Mild azotemia
End result Died, hydrocephalus, intracranial hemorrhage Died, hydrocephalus, intracranial hemorrhage, BPD Died, BPD Died, BPD Died, BPD
Transient oliguria, Died, sepsis hyponatremia None
Surgical ligation PDA, died, BPD
None
Spontaneous closure PDA, recovered
None
Surgical ligation PDA, residual chronic lung disease
None
Surgical ligation PDA, recovered
None
Surgical ligation PDA, recovered
CHF = Congestedheart failure; BPD = bronchopulmonarydysplasia; PDA = patent ductus arteriosus. *Per rectum. tCalculated by weightat time of.first administration.
tional !nfants experienced transient closure of the ductus, but subsequently developed evidence of recurrence of a left-t0-right ductal shunt 48 to 72 hours later. The PDA murmur persisted in the seven remaining patients. Surgical ligation of the PDA was performed in four patients (Table I: Patients 7, 9, 10, and 11). Seven patients in the series died, most likely of causes unrelated to the medication. Postmortem examination, performed on six of the seven nonsurvivors, confirmed the presence of a large PDA in each infant. The cause of death was attributed to hydrocephalus secondary to intracranial hemorrhage in two infants, to bronchopulmonary dysplasia in four patients, and to septicemia in one infant. SPOntaneous closure of a PDA occurred in one survivor five weeks following indomethacin therapy. There were no detectable serious complications of indomethacin therapy. Two infants had evidence of transient renal insufficiency, one of whom was oliguric for 36 hours and another mildly azotemic (BUN increased
from 20 to 36 mg/dl), but with normal output of urine. Two patients developed transient hyponatremia (127 and 128 meq/1, respec!Nely), and two patients had minimal gastrointestinal bleeding that did not result in measurable decrease in the hemoglobin concentration or hematocrit value. DISCUSSION Friedman and Heymann~ recently reported successful indomethacin-induced constriction of the ductus in 49 of 50 premature infants studied. Only two of our 11 patients responded sufficiently to indomethacin therapy to alleviate symptoms related to the ductus. Though we c a n n o t fully explain this discrepancy, there may be important differences between the groups o f patients studied. Of the original 15 patients described by Heymann and associates ~ only five had severe hyaline membrane disease. The mean age of onset of CHF was 6.3 days, and eight of their patients received the first dose of indo-
Volume 91 Number 4
methacin prior to ten days of age. All 11 of our patients had severe RDS. In our infants the m e a n age of onset of C H F was 12.5 days; only two of our patients were given the first dose of indomethacin prior to ten days of age. Thus, our patients clearly had more severe lung disease, manifested signs and symptoms of C H F later, and received indomethacin at an older age. W e acknowledge that the rigid criteria we require for the diagnosis of intractible CHF, detailed in a previous report," results in selection of a group of patients at the severe end of the spectrum of neonatal lung disease complicated by large left-to-right ductal shunts. All of the original infants studied by F r i e d m a n and associates -~ had severe RDS. They developed signs of prominent left-to-right shunting across a PDA within three to nine days, and were considered candidates for PDA ligation within 72 hours after the onset of decongestive therapy. Presumably indomethacin was administered shortly thereafter. The mean gestational age of this group of patients was 32 weeks, as compared with slightly less than 30 weeks in our patients. It is intriguing to speculate that indomethacin therapy is more likely to effect permanent closure of the ductus arteriosus the greater the gestational age of the infant, and
Failure of indomethacin to close PDA in R D S
623
the sooner after birth it is administered. Our data strongly suggests that "late" indomethacin therapy administered to the small premature infant with severe RDS and C H F secondary to PDA is ineffective. We are indebted to Drs. Gilbert Ratcliff, Jr., and Joseph Werthammer, Huntington, West Virginia, for their participation in this study (Patient 10). REFERENCES
1. Sharpe GL: Indomethacin and closure of the ductus arteriosus, Lancet 1:696, 1975. 2. Friedman WF, Hirschklau M J, Printz MP, Pitlick PT, and Kirkpatrick SE: Pharmacologic closure of patent ductus arteriosus in the premature infant, N Engl J Med 295:526, 1976. 3. Heymann MA, Rudolph AM, and Silverman NH: Closure of the ductus arteriosus in infants by inhibition of prostaglandin synthesis, N Engl J Med 295:530, 1976. 4. Friedman WF, Heymann MA, and Rudolph AM: Commentary: New thoughts on an old problem--patent ductus arteriosus in the premature infant, J PEDIATR90:338, 1977. 5. Neal WA, Bessinger FB, Hunt CE, and Lucas RV: Patent ductus arteriosus complicating respiratory distress syndrome, J PEDIATR86:127, 1975,
AND
MEDICINE
NEONATAL RichardE. Behrman,Editor
Failure of indomethacin therapy to induce closure of patent ductus arteriosus in premature infants with respiratory distress syndrome William A. Neal, M.D.,* James M. Kyle, and Martha D. Mullett, M.D., Morgantown,
W. Va.
MANAGEMENT of premature infants with respiratory distress syndrome complicated by patent ductus arteriosus continues to pose a challenge in the selection of patients for surgical ligation of the ductus and for appropriate timing of the operation. The exciting possibility of pharmacologic closure of the ductus with indomethacin inhibition of prostaglandin synthesis was first suggested by Sharpe.' Support for this hypothesis was detailed in two reports of indomethacin-induced PDA closure in premature infants with RDS.-" :~ A recent update of the combined experience of these two West Coast centers is even more encouraging considering the extremely high incidence of successful pharmacologic treatment and the relatively low associated morbidity. ~ We present our less favorable experience with indomethacin therapy in premature infants with RDS and PDA and briefly examine some of the possible reasons for the discrepancy in results. MATERIALS
absence of severe anemia a n d / o r hypoxia), and hepatomegaly. When these findings were present laboratory studies were performed to exclude hyperbilirubinemia ( > 12 mg/dl), renal insufficiency, serum electrolyte imbalance, gastrointestinal bleeding, and coagulopathy. Parental informed consent was obtained prior to administration of indomethacin in accordance with the Committee on Research Involving Human Subjects of West Virginia University. Indomethacin was administered orally (via nasogastric tube) in nine patients and rectally in two patients. The route of administration, amount given, and number of administrations is tabulated in Table I. Clinical and laboratory evidence of toxicity was recorded following indomethacin treatment, as were characteristics of the PDA murmur and presence or absence of congestive heart failure.
See related article, p. 624.
AND METHODS
Eleven premature infants with severe RDS (ventilator dependence), gestational ages from 27 to 33 weeks, were selected for indomethacin therapy using the same criteria for selection that we follow for surgical ligation of the PDA. These include continuous murmur beneath the left clavicle, brisk peripheral pulses, and evidence of congestive heart failure unresponsive to medical management: cardiomegaly on chest roentgenogram, persistent elevation of heart rate greater than 160/minute (in the From the Department of Pediatrics, West Virginia University. *Reprint address: Department (~fPediatrics, West Virginia University. Morgantown. WV 26506.
Abbreviations used RDS: respiratory distress syndrome. PDA: patent ductus arteriosus BUN: blood urea nitrogen CHF: congestive heart failure RESULTS All but two patients demonstrated transient cessation or diminished intensity of the murmur within 24 hours following administration of indomethacin, interpreted as ductal responsiveness to the drug. In only two of the 11 infants was closure of the PDA permanent. Two addiThe Journal of P E D I A T R 1 C S Vol. 91, No. 4, pp. 621-623
621
622
Neal, Kyle, and Mullett
The Journal of Pediatrics October 1977
Table L Clinical data of patients treated with indomethacin
Onset CHF (days)
Ag e Indomethacin given (days)
Dose~ (mg/kg)
32
7
10,24
0.33
1.20
30
18
18
0.57*
3
0.95
28
7
7,14
0.26
4 5
1.90 0.83
33 27
21 7
30,32,34 7,14,21
0.40 0.48
6
0.82
28
14
14
0.88
7
1.15
29
10
14,21,23
1.10"
8
1.30
31
7
14
0.25
9
1.63
32
7
11,18,23
0.40
10
0.89
27
9
11,12
0.80
11
1.28
31
31
40,42,43
0.50
Patient
Birth weight (kg)
Gestational age (wk)
1
1.50
2
Results Permanent closure Transient closure Transient closure No change Permanent closure Intensity murmur decreased Intensity murmur decreased Intensity murmur decreased Intensity murmur decreased Intensity murmur decreased No change
Complications Hyponatremia Guaiac-positive stools Guaiac-positive gastric aspirate None Mild azotemia
End result Died, hydrocephalus, intracranial hemorrhage Died, hydrocephalus, intracranial hemorrhage, BPD Died, BPD Died, BPD Died, BPD
Transient oliguria, Died, sepsis hyponatremia None
Surgical ligation PDA, died, BPD
None
Spontaneous closure PDA, recovered
None
Surgical ligation PDA, residual chronic lung disease
None
Surgical ligation PDA, recovered
None
Surgical ligation PDA, recovered
CHF = Congestedheart failure; BPD = bronchopulmonarydysplasia; PDA = patent ductus arteriosus. *Per rectum. tCalculated by weightat time of.first administration.
tional !nfants experienced transient closure of the ductus, but subsequently developed evidence of recurrence of a left-t0-right ductal shunt 48 to 72 hours later. The PDA murmur persisted in the seven remaining patients. Surgical ligation of the PDA was performed in four patients (Table I: Patients 7, 9, 10, and 11). Seven patients in the series died, most likely of causes unrelated to the medication. Postmortem examination, performed on six of the seven nonsurvivors, confirmed the presence of a large PDA in each infant. The cause of death was attributed to hydrocephalus secondary to intracranial hemorrhage in two infants, to bronchopulmonary dysplasia in four patients, and to septicemia in one infant. SPOntaneous closure of a PDA occurred in one survivor five weeks following indomethacin therapy. There were no detectable serious complications of indomethacin therapy. Two infants had evidence of transient renal insufficiency, one of whom was oliguric for 36 hours and another mildly azotemic (BUN increased
from 20 to 36 mg/dl), but with normal output of urine. Two patients developed transient hyponatremia (127 and 128 meq/1, respec!Nely), and two patients had minimal gastrointestinal bleeding that did not result in measurable decrease in the hemoglobin concentration or hematocrit value. DISCUSSION Friedman and Heymann~ recently reported successful indomethacin-induced constriction of the ductus in 49 of 50 premature infants studied. Only two of our 11 patients responded sufficiently to indomethacin therapy to alleviate symptoms related to the ductus. Though we c a n n o t fully explain this discrepancy, there may be important differences between the groups o f patients studied. Of the original 15 patients described by Heymann and associates ~ only five had severe hyaline membrane disease. The mean age of onset of CHF was 6.3 days, and eight of their patients received the first dose of indo-
Volume 91 Number 4
methacin prior to ten days of age. All 11 of our patients had severe RDS. In our infants the m e a n age of onset of C H F was 12.5 days; only two of our patients were given the first dose of indomethacin prior to ten days of age. Thus, our patients clearly had more severe lung disease, manifested signs and symptoms of C H F later, and received indomethacin at an older age. W e acknowledge that the rigid criteria we require for the diagnosis of intractible CHF, detailed in a previous report," results in selection of a group of patients at the severe end of the spectrum of neonatal lung disease complicated by large left-to-right ductal shunts. All of the original infants studied by F r i e d m a n and associates -~ had severe RDS. They developed signs of prominent left-to-right shunting across a PDA within three to nine days, and were considered candidates for PDA ligation within 72 hours after the onset of decongestive therapy. Presumably indomethacin was administered shortly thereafter. The mean gestational age of this group of patients was 32 weeks, as compared with slightly less than 30 weeks in our patients. It is intriguing to speculate that indomethacin therapy is more likely to effect permanent closure of the ductus arteriosus the greater the gestational age of the infant, and
Failure of indomethacin to close PDA in R D S
623
the sooner after birth it is administered. Our data strongly suggests that "late" indomethacin therapy administered to the small premature infant with severe RDS and C H F secondary to PDA is ineffective. We are indebted to Drs. Gilbert Ratcliff, Jr., and Joseph Werthammer, Huntington, West Virginia, for their participation in this study (Patient 10). REFERENCES
1. Sharpe GL: Indomethacin and closure of the ductus arteriosus, Lancet 1:696, 1975. 2. Friedman WF, Hirschklau M J, Printz MP, Pitlick PT, and Kirkpatrick SE: Pharmacologic closure of patent ductus arteriosus in the premature infant, N Engl J Med 295:526, 1976. 3. Heymann MA, Rudolph AM, and Silverman NH: Closure of the ductus arteriosus in infants by inhibition of prostaglandin synthesis, N Engl J Med 295:530, 1976. 4. Friedman WF, Heymann MA, and Rudolph AM: Commentary: New thoughts on an old problem--patent ductus arteriosus in the premature infant, J PEDIATR90:338, 1977. 5. Neal WA, Bessinger FB, Hunt CE, and Lucas RV: Patent ductus arteriosus complicating respiratory distress syndrome, J PEDIATR86:127, 1975,
