PEDIATRICS Vol. 121 No. 1 January 2008, pp. 142-147 (doi:10.1542/peds.2007-0925)
ARTICLE |
Impact of Patent Ductus Arteriosus and Subsequent Therapy With Indomethacin on Cerebral Oxygenation in Preterm Infants
Department of Neonatology, University Medical Center/Wilhelmina Children's Hospital, Utrecht, Netherlands
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVES. A hemodynamically important patent ductus arteriosus is a common problem in the first week of life in the preterm infant. Although patent ductus arteriosus induces alterations in organ perfusion, scarce information is available of the impact of patent ductus arteriosus and its subsequent treatment on the oxygen supply and oxygen extraction of the brain. We investigated the impact of patent ductus arteriosus and its treatment with indomethacin on regional cerebral oxygen saturation and fractional tissue oxygen extraction by using near-infrared spectroscopy.
PATIENTS AND METHODS. Twenty infants with patent ductus arteriosus (gestational age: <32 weeks), subsequently treated with indomethacin, were monitored for mean arterial blood pressure, arterial oxygen saturation, near-infrared spectroscopy–determined regional cerebral oxygen saturation, and fractional tissue oxygen extraction ([arterial oxygen saturation – regional cerebral oxygen saturation]/arterial oxygen saturation). Ten-minute periods were selected and averaged during patent ductus arteriosus, at 10, 20, 30, 60, and 120 minutes, and at 6,12, 24, and 36 hours after starting indomethacin treatment (to ductal closure) for mean arterial blood pressure, arterial oxygen saturation, regional cerebral oxygen saturation, and fractional tissue oxygen extraction. The patients with patent ductus arteriosus were matched for gestational age, birth weight, postnatal age, and severity of respiratory distress syndrome with infants without patent ductus arteriosus, who served as control subjects.
RESULTS. Mean arterial blood pressure and regional cerebral oxygen saturation were significantly lower and fractional tissue oxygen extraction significantly higher compared with the control infants during patent ductus arteriosus (mean arterial blood pressure: 33 ± 5 vs 38 ± 6 mmHg; regional cerebral oxygen saturation: 62% ± 9% vs 72% ± 10%; fractional tissue oxygen extraction: 0.34 ± 0.1 vs 0.25 ± 0.1, respectively). Regional cerebral oxygen saturation and fractional tissue oxygen extraction were lower and higher, respectively, up to 24 hours after the start of indomethacin but normalized to control values afterward. Indomethacin had no additional negative effect on cerebral oxygenation.
CONCLUSIONS. A hemodynamically significant patent ductus arteriosus has a negative effect on cerebral oxygenation in the premature infant. Subsequent and adequate treatment of a patent ductus arteriosus may prevent diminished cerebral perfusion and subsequent decreased oxygen delivery, which reduces the change of damage to the vulnerable immature brain.
Key Words: preterm infant • near-infrared spectroscopy • cerebral oxygenation • patent ductus arteriosus • indomethacin
Abbreviations: PDA—persistent ductus arteriosus • NIRS—near-infrared spectroscopy • GA—gestational age • SaO2—arterial oxygen saturation • rScO2—regional cerebral oxygen saturation • FTOE—fractional tissue oxygen extraction • MABP—mean arterial blood pressure
In preterm infants, a hemodynamically important patent ductus arteriosus (PDA) that requires therapy is a common problem in the first week of life. Excessive pulmonary flow increases the ventilatory dependency and decreases systemic flow, causing alterations in cerebral perfusion. Clinical parameters, such as hyperactive precordium, wide pulse pressure, cardiac murmur, and tachycardia, are not very reliable signs to properly diagnose PDA.1 To prove whether a hemodynamically important ductus arteriosus exists, echocardiography should be used.
Because PDA may compromise cerebral perfusion, it is a risk factor for periventricular/intraventricular hemorrhage and white matter damage. Although several studies are performed to investigate cerebral hemodynamics during PDA, but in particular during treatment with indomethacin, information of the impact of PDA itself and of subsequent treatment with indomethacin on cerebral oxygenation and especially on the cerebral oxygen extraction and on autoregulatory ability of the brain in the preterm infant is scarce.2,3 Because infants with PDA have lower blood pressures and "ductal steal" phenomena leading to less blood flow directed to organs such as the brain, we hypothesize that cerebral oxygenation will be less optimal and oxygen extraction will increase. We further hypothesize that these disturbances disappear after therapy with indomethacin, although indomethacin may have a transient negative effect on the cerebral oxygenation.4
Therefore, we simultaneously monitored arterial blood pressure, arterial oxygen saturation, regional cerebral saturation, and fractional tissue oxygen extraction, by using near-infrared spectroscopy (NIRS), in preterm infants during a hemodynamically significant PDA and during treatment with indomethacin up to ductal closure. Each infant with PDA was matched with an infant without PDA of the same postnatal age, gestational age (GA), birth weight, and severity of respiratory distress syndrome.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patient Population
Forty infants were studied. Twenty infants with a gestational age (GA) of <32 completed weeks consecutively admitted to the NICU of the Wilhelmina Children's Hospital, suffering from a PDA and subsequently treated with indomethacin, were included into the study. Each infant with PDA was matched with an infant without clinical signs of PDA. Matching criteria were same GA, postnatal age, ventilatory support, and severity of respiratory distress syndrome. Infants with periventricular or intraventricular hemorrhage at or more than grade 2 according to the grading of Papile et al5 or congenital malformations were excluded. Informed parental consent was obtained for all of the patients. The medical ethical committee of the University Medical Centre Utrecht approved the present study.
Clinical Data
Obstetric and intrapartum data were collected from the hospital records. Neonatal data were collected prospectively. Treatment decisions were made by the attending neonatologist. All of the mechanical ventilated infants were sedated with morphine at 10 to 20 µg/kg per hour. The arterial oxygen saturation (SaO2) was monitored using pulse oximetry on a limb and the arterial blood pressure by an indwelling arterial catheter (umbilical, tibial, or radial artery) in all infants. Blood pressure support was started according to the decision of the attending neonatologist as indicated by the guidelines used in our NICU. A blood pressure support scoring system, depending on the intensity of the treatment, was used to assess the intensity of blood pressure support: score 0 indicates no support; score 1 indicates volume expansion and/or dopamine level of 
5 µg/kg per minute; score 2 indicates a dopamine level of >5 and 10 µg/kg per minute; score 3 indicates a dopamine level of >10 µg/kg per minute or a dopamine and dobutamine level of 10 µg/kg per minute; score 4 indicates a dopamine plus dobutamine level of >10 µg/kg per minute; and score 5 indicates additional adrenaline and/or corticosteroids.6
Diagnosis of PDA
The diagnosis of PDA was based on clinical indices and confirmed by echocardiographic investigation (left atrium/aorta ratio: >1.4; internal ductal diameter: >1.4 mm/kg; left pulmonary artery end diastolic flow: >0.2 m/second).
Monitoring of Cerebral Tissue Oxygenation and Oxygen Extraction
We used the NIRS-determined regional cerebral oxygen saturation (rScO2) as a reliable estimator for changes in regional cerebral oxygenation.7 Because absolute values are provided here, rScO2 is less dependent of movement artifacts, and important comparisons over time are possible.8,9
We used an INVOS 4100 near-infrared spectrometer (Somanetics Corp, Troy, MI): a transducer containing a light-emitting diode and 2 distant sensors was attached to the frontoparietal side of the neonatal skull. rScO2 was calculated from the differential signals obtained from these 2 sensors, expressed as the venous-weighted percentage of oxygenated hemoglobin (oxygenated hemoglobin/total hemoglobin[oxygenated hemoglobin + deoxygenated hemoglobin]).9,10
To investigate the balance between oxygen delivery and oxygen consumption, a relative fractional tissue oxygen extraction (FTOE) measurement can be formulated as a ratio: (SaO2 – rScO2)/SaO2. Because it is a ratio, an increase might either indicate a reduced oxygen delivery to the brain with a constant oxygen consumption of the brain or a higher oxygen consumption than oxygen delivery. The opposite is true in the case of a decrease in FTOE, either reflecting a decrease of oxygen extraction of the brain because of less use of oxygen or a constant oxygen consumption of the brain with an increased oxygen delivery to the brain.9,11
Study Design
As part of a prospective clinical study in which consecutively admitted preterm infants (GA: <32 weeks) were simultaneously monitored for arterial blood pressure, heart rate, SaO2, rScO2, and FTOE starting as soon as possible after birth up to 72 hours of life depending on the availability of an NIRS device and parental consent, each infant with the diagnosis PDA (see above) and subsequently treated with indomethacin was enrolled in the present study. The end point of the study was defined as 12 hours after the third dose of indomethacin, leading to ductal closure proven by echocardiographic investigation. Indomethacin was administered by the following scheme: 3 times 0.2 mg/kg every 12 hours as an intravenous infusion of 4 mL in 60 minutes. Contraindications of treatment with indomethacin were sepsis, necrotizing enterocolitis, low platelets (<75 x 109/L), renal failure (oliguria or blood creatinine: >150 µmol/L), and unstable periventricular or intraventricular hemorrhage. The simultaneously collected data were stored on a personal computer for offline analysis (Poly 5; Inspektor Research Systems, Amsterdam, Netherlands).
In the 20 control patients used as a match (see above-listed criteria), a hemodynamically significant PDA was excluded in case of an absence of clinical signs but at the slightest doubt also by echocardiographic investigation. An echocardiographic investigation was performed in 9 control infants because of low arterial blood pressure (n = 5) and because of prolonged ventilatory dependency not explained for pulmonary reasons (n = 4).
In both groups, the arterial hemoglobin concentration was measured daily or more frequently if indicated. Arterial blood gasses were measured every 4 hours or more frequently if necessary or less frequently after 24 hours of life if the clinical situation was stable.
Cranial ultrasound studies were performed before starting treatment of PDA with indomethacin and repeated every 24 hours during the course (or more frequently if indicated by the attending neonatologist). To reduce the data to manageable proportions, to reduce the signal/noise ratio, and to be able to make comparisons over time, 10-minute periods were selected and averaged for MABP, SaO2, rScO2, and FTOE when the diagnosis of PDA was made before starting indomethacin and at 10, 20, 30, 60, and 120 minutes and 6, 12, 24, and 36 hours after starting indomethacin. In the matched-control infant, the 10-minute period selection started on the same postnatal age, further following the same time schedule as indicated by its PDA counterpart. In 2 patients no matched control subjects were available of the same postnatal age (76 hours). For these 2 patients, 2 control infants were selected with a postnatal age of 41 hours, which was the mean postnatal age at the time of confirmation of a significant duct in the PDA group.
Statistical Analysis
Data are summarized as mean values ± SD or as median values and ranges where appropriate. Student's t test or the 
2 test, as appropriate, compared patient characteristics and differences in the blood pressure support score between both groups. The Mann-Whitney U test and analysis of variance were used to assess differences between the groups at the various time points; differences among MABP, rScO2, and FTOE within groups (shown as box-and-whisker plots) were evaluated by analysis of variance for repeated measurements to assess changes within groups over time. Adjustments for multiple comparisons were made by a posthoc test (Scheffe's procedure). A P value of <.05 was considered statistically significant. For statistical analysis, SPSS 12.0 (SPSS Inc, Chicago, IL) was used.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Clinical Characteristics
The clinical characteristics of the PDA and control infants are shown in Table 1. GA and birth weight were not significantly different between PDA and control infants (28.6 ± 1. 5 vs 28.5 ± 1.5 weeks; 1154 ± 268 vs 1055 ± 216 g, respectively). The mean postnatal age at diagnosis of PDA was 41 hours (range: 17–76 hours). All except 1 infant with PDA and 2 infants in the control group, who were treated with nasal continuous positive airway pressure, were on mechanical ventilation during the study period. Blood pressure support, especially for scores 2 and 3, was more needed in infants with PDA as compared with control infants (P < .05).
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Patterns of Mean Arterial Blood Pressure, rScO2, and FTOE
Figure 1 depicts the patterns of mean arterial blood pressure (MABP), rScO2, and FTOE during the study period. In infants with PDA, MABP and rScO2 were lower and FTOE was higher compared with the control subjects (MABP: 33 ± 5 vs 38 ± 6 mmHg; rScO2: 62% ± 9% vs 72% ± 10%; FTOE: 0.34 ± 0.1 vs 0.25 ± 0.1, respectively; all P < .05). After the start of therapy with indomethacin, MABP was still only significantly lower at 6 hours after indomethacin. rScO2 and FTOE remained significantly lower and higher, respectively, up to 24 hours after the start of indomethacin as compared with the control subjects (P < .05); afterward, MABP and rScO2 increased and FTOE decreased to values of the control group. Interestingly, indomethacin treatment did not further negatively influence cerebral oxygenation and extraction. The heart rate and SaO2 were not different between the groups at any point of time. In 18 of the 20 infants, PDA was closed at 36 hours, which was confirmed by echocardiographic investigation. The other 2 infants successfully received a prolonged course of indomethacin (4 days at 0.1 mg/kg per 24 hours).
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In Fig 2, a representative individual case has been shown providing a typical pattern of rScO2 and its relation to MABP during the development of a PDA and its subsequent treatment with indomethacin. In this 27-week-old premature infant, the rScO2 values decreased to exceptional low values (<40%) during the actual PDA.
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Patterns of Hemoglobin and PCO2
The hemoglobin concentration was not different, neither within nor between groups, and was always in the reference range. Also, PCO2 was not different between groups at any time point and was always in the reference range (46 ± 6 vs 44 ±.6 mmHg, respectively, in infants with PDA compared with control subjects), and there was no significant correlation between PCO2 and rScO2 in both groups at any point of time.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The results of our study show lower blood pressures during a hemodynamically important ductus arteriosus and a lower regional cerebral oxygenation with an increased cerebral oxygen extraction. This probably indicated a reduced oxygen delivery induced by ductal steal and a consequent decrease of cerebral perfusion as compared with control infants without a PDA. Subsequent treatment with indomethacin gave rise to a sustained increase in rScO2 and normalization of cerebral oxygenation as indicated by the increase in rScO2 to values found in the control infants. Our study also showed that treatment with indomethacin had no further negative effect on cerebral oxygenation, reported in several earlier studies,2,4 as indicated by the stable rScO2 and FTOE values during the first 2 hours after the start of indomethacin therapy. We cannot totally refute that the use of more inotropic drugs in the infants with PDA were partly responsible for the lower cerebral oxygenation values because of vasoconstriction by these drugs. However, Seri et al12 and Zhang et al13 showed that dopamine infusion at <10 µg/kg per minute does not affect regional cerebral hemodynamics.
An increasing number of studies have provided us with reference values of NIRS-measured regional cerebral oxygenation expressed as the tissue oxygenation index or as rScO2 (which was used in our study) for the extremely premature infant.8,9 rScO2 values reported in pediatric and neonatal patient populations usually range between 60% and 85%.8,14 In a population of very preterm infants in stable condition with GAs of <32 weeks in which we monitored rScO2 for the first 3 days of life, the mean value (±SD) of rScO2 was 71% (±7%).8 It has been suggested that there are methodologic flaws when using NIRS-monitored cerebral oxygenation in the clinical setting, especially when repeated measurements are done (at different places of the skull), leading to quite large differences in rScO2, even up to 15%.15,16 However, Menke et al17 showed that rScO2 measurements showed a good reproducibility and acceptable interobserver variance when used clinically, better than the NIRS-measured total cerebral hemoglobin or the difference between oxygenated and deoxygenated cerebral hemoglobin often used in research settings. In our hands, the reproducibility in preterm infants is quite acceptable, but it takes some time (10 minutes) after refixation of the optode before the rScO2 is stable again (limits of agreement of –6% to 6% by the Bland-Altman method18 and PMA Lemmers, MD; Frank van Bel, MD PhD, unpublished data, 2007). We, therefore, assume that the rScO2 values obtained in the present study are reliable estimates of the actual cerebral oxygenation and that distinct individual changes indeed indicate changes in cerebral oxygenation of the infant under investigation. A recent study in adult and pediatric patients reported that changes of >25% below the rScO2 baseline value or values below an rScO2 of 50% were associated with an increased risk for brain damage and longer hospitalization.19
With the above-mentioned considerations in mind, we believe that the combined effect of PDA-induced lower blood pressures and a left-to-right ductal steal lead to a potential critical situation with respect to the oxygenation of the immature brain, indicated by the lower rScO2 and the compensatory increase of FTOE. Although we do not know what the critical lower values for oxygenation of the preterm brain are, it has been reported that a PDA has been related to periventricular or intraventricular hemorrhages in preterm infants, which may negatively influence the neurodevelopmental outcome.20,21 Moreover, the immature brain is even more vulnerable for damage because of the easy-to-disturb autoregulatory ability of the cerebrovascular bed.22,23 Although the detected rScO2 values during PDA were 10% to 14% lower, only a few infants had values of <50% (see also Fig 1), suggested as a critical lower limit in relation to brain damage.19 This was probably because we recognized this particular rScO2 pattern to be related to PDA. Therefore, we diagnosed PDA early with echocardiography and treated these infants relatively early with indomethacin. We, therefore, postulate that monitoring cerebral oxygenation using NIRS-measured rScO2 in unstable extremely premature infants in the first days of life may help to detect diminished cerebral perfusion and consequent decreased oxygen delivery to the immature brain, as may be the case during PDA. In our NICU, therefore, we are quite active in diagnosing and treating PDA.
Our observation that treatment with indomethacin did not initially further decrease cerebral oxygenation was interesting. Earlier studies, also from our own group, found a distinct fall in cerebral oxygen delivery and oxygenation in the first hours after the start of indomethacin.2–4 We postulate that the longer infusion time used in the present study (60 minutes) explains the absence of further changes in cerebral oxygenation. This suggestion is supported by a study of Christmann et al,24 who compared the effects on organ perfusion in preterm infants during bolus infusion of indomethacin with continuous infusion of indomethacin over 36 hours. In most studies mentioned above, indomethacin was administered as a bolus or with a maximal infusion time of 30 minutes.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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We suggest that monitoring cerebral oxygenation and oxygen extraction by using NIRS-derived rScO2 and FTOE reveals decreases in cerebral oxygenation, possibly because of the existence of a PDA. Subsequent echocardiographic investigation to prove or exclude PDA and, if appropriate, adequate treatment may prevent diminished cerebral perfusion and subsequent decreased oxygen delivery, reducing damage to the vulnerable immature brain.
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FOOTNOTES |
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Accepted Jun 27, 2007.
Address correspondence to Petra M. A. Lemmers, MD, Department of Neonatology, Room KE.04.123.1, Wilhelmina Children's Hospital, University Medical Center, PO Box 85090, 3508 AB Utrecht, Netherlands. E-mail: p.lemmers{at}umcutrecht.nl
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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