Effect of indomethacin on superior mesenteric artery blood flow velocity in preterm infants Frank Van Bel, MD, Diny Van Zoeren, MD, Jaap Schipper, MD, Gerard L. Guit, MD, and Jan Baan, PhD From the Departments of Pediatrics .and Radiology, University Hospital of Leiden, the Netherlands
In 15 preterm infants with symptomatic patent ductus arteriosus, blood flow velocity changes in the superior mesenteric artery were investigated with Doppler ultrasound just before and during the first 12 hours after a single dose of indomethacin. Indomethacin administration led to an instantaneous decrease in all infants of temporal mean flow velocity in the superior mesenteric artery, which was maximal 10 minutes after administration of indomethacin, followed by a more sustained recovery, slightly greater than baseline values, 12 hours after indomethacin treatment. Simultaneously determined temporal mean flow velocity of the anterior cerebral artery, used as an indicator of changes in cerebral blood flow, had a similar pattern as in the mean flow velocity in the superior mesenteric artery (r = 0.49; p 1.1511 and a diastolic reverse flow in the pulmonary artery). Infants with abnormalities, other than PDA, that could possibly alter intestinal or cerebral blood flow velocity were not included in this study, with the exception of the
presence of mild hypercapnia. 12, 13 Informed parental consent was obtained in all cases. The study was approved by the scientific board of the department of pediatrics. The study design was as follows: Doppler ultrasound measurements of the SMA and cerebral blood flow velocity were performed just before, and at 2, 10, and 60 minutes, and at 2, 4, and 12 hours after indomethacin administration. The rationale of this protocol, at least with respect to the cerebral Doppler measurements, was based on earlier work. 3 Simultaneously with the ultrasound studies, arterial pressure was measured; pH, Paco2, and hematocrit were determined; and transcutaneously measured partial oxygen
Volume 116 Number 6
Effect o f indomethacin on S M A blood flow velocity
Table. Infant characteristics (n =
967
170
15)
M e a n _+ SD ( r a n g e )
Birth weight (gm) Gestational age (wk) Age at treatment (days) Time to clinical closure (hr)
1170 _+ 299 (775-1700) 29.0 _+ 2.4 (25-33) 9 + 8 (3-35) 4* (1-12)
15~1
.......................
~E 140"
". . . . . . . . . . . . . . .
"" ~'-- ~.i...._i ....................................................
*Mediantime to clinicalclosure. 2S
tension and heart rate registered. Immediately after every postindomethacin Doppler investigation, a brief physical examination was performed to assess ductal closure clinically. Within 24 hours after the indomethacin administration, a pediatric cardiologist, who was unaware of the study results, assessed, using clinical and echocardiographic examination, whether the ductus had closed. Real-time duplex Doppler ultrasound and M-mode ecbocardiographic studies were performed with an Ultramark-4 ultrasound system (Advanced Technology Laboratories, Inc., Bothell, Wash.). All scans were performed with a 7.5 MHz transducer for real-time imaging, whereas the Doppler transducer was 5 MHz. The sample volume of the Doppler system used ranged from 1.5 mm to 2.5 mm; a 100 Hz high-pass filter was used to reduce noise from the pulsating arterial wall.
Doppler ultrasound investigation for measurement of blood flow velocity in SMA. The SMA is the second major branch of the abdominal aorta; its origin is just below the celiac trunk, from the ventral wall of the aorta. The proximal segment of the SMA usually has an anterior course (angle between SMA and abdominal aorta of approximately 90~ which allows Doppler insonation under a small angle with the use of a longitudinal abdominal approach (Fig. l, A). The beam of the sample volume used always included practically the whole vessel lumen, but insonation of the vessel wall was avoided to prevent disturbance of the velocity signal by vessel wall movements. The position of the sample volume can be optimized further by acoustic and visual control to obtain a blood flow velocity wave form of the SMA of maximal quality (Fig. 1, B). 14
Doppler ultrasound investigation of changes in cerebral blood flow. For serial investigation of changes in cerebral blood flow, the blood flow velocity in the anterior cerebral artery was performed with use of the anterior fontanel as an acoustic window, as previously described. 3 Briefly, the ACA was insonated at its curve around the corpus callosum, where the angle of insonation is approximately 0 degrees. Optimization of the sample volume position was obtained by acoustic and visual control to obtain a reliable blood flow velocity wave form of the ACA with maximal amplitudes. A minimum of 5 to 10 sequential cardiac cycles of the blood flow velocity wave forms of the SMA and ACA were subjected to real-time spectral analysis. The temporal mean
} 3oJ[
i t
Minutes
Hours
~ndomethacin
Fig. 9. Mean values +_ SD of heart rate and MABP in 15 infants (solid line) as function of time. Infants with clinical ductus closure (n = 10); 9 9 infants whose ductus remained open (n = 5); 9 . . . . . O.
flow velocities of the SMA (MFV-SMA) and of the ACA (MFV-ACA) were then determined by integration of the area under the curve. The MFV-SMA was used as a qualitative measure of changes in superior mesenteric blood flow. The MFV-ACA can be used as a qualitative measure of changes in actual cerebral blood flow, provided that cerebral perfusion pressure is relatively constant and hematocrit values are in the physiologic range. I5' 16 The ratio of mean arterial blood pressure (as a measure of effective pressure difference over the vascular bed perfused by the SMA), and the MFV-SMA was used as an independent estimator of relative vascular resistance in the perfusion region of the SMA. Similarly, the ratio of MABP and MFVACA was used as an independent estimator of relative cerebral vascular resistance. During the Doppler investigations, the infants were in a resting state, lying supine and in the anti-Trendelenburg position (15 degrees). To exclude the possible influence of postprandial changes on intestinal blood supply, the infants were not fed orally. 17 Neonatal data were collected prospectively. Pat02 and pH values were obtained from an indwelling arterial catheter or from arterialized blood samples. Arterial oxygen tensions are derived from Tcp02. Blood pressure measurements were made directly by arterial pressure transducer or indirectly via oscillometry (Dinamap, Critikon, Inc., Tampa, Fla.). If necessary, packed cell transfusions were given to keep the hematocrit greater than 40%. Statistical analysis. Results are reported as mean +_ SD. Differences between mean values of all variables at different times were assessed with the use of analysis of variance for repeated measures, followed by a Student t test for paired comparisons, with the Bonferroni correction when a significant difference was found. Differences between mean val-
968
~:~
Van Bel et al.
The Journal o f Pediatrics June 1990
9
3
................
_ _
-,
n1
25 ", m I")"~'~ ',
~ ~ f f " ~/' ' " " ' " ' " ' " ' " " ' " " " " - ' ' ' \
.
10
i ~ Minutes // 1 [ndomethacin p
In 15 preterm infants with symptomatic patent ductus arteriosus, blood flow velocity changes in the superior mesenteric artery were investigated with Doppler ultrasound just before and during the first 12 hours after a single dose of indomethacin. Indomethacin administration led to an instantaneous decrease in all infants of temporal mean flow velocity in the superior mesenteric artery, which was maximal 10 minutes after administration of indomethacin, followed by a more sustained recovery, slightly greater than baseline values, 12 hours after indomethacin treatment. Simultaneously determined temporal mean flow velocity of the anterior cerebral artery, used as an indicator of changes in cerebral blood flow, had a similar pattern as in the mean flow velocity in the superior mesenteric artery (r = 0.49; p 1.1511 and a diastolic reverse flow in the pulmonary artery). Infants with abnormalities, other than PDA, that could possibly alter intestinal or cerebral blood flow velocity were not included in this study, with the exception of the
presence of mild hypercapnia. 12, 13 Informed parental consent was obtained in all cases. The study was approved by the scientific board of the department of pediatrics. The study design was as follows: Doppler ultrasound measurements of the SMA and cerebral blood flow velocity were performed just before, and at 2, 10, and 60 minutes, and at 2, 4, and 12 hours after indomethacin administration. The rationale of this protocol, at least with respect to the cerebral Doppler measurements, was based on earlier work. 3 Simultaneously with the ultrasound studies, arterial pressure was measured; pH, Paco2, and hematocrit were determined; and transcutaneously measured partial oxygen
Volume 116 Number 6
Effect o f indomethacin on S M A blood flow velocity
Table. Infant characteristics (n =
967
170
15)
M e a n _+ SD ( r a n g e )
Birth weight (gm) Gestational age (wk) Age at treatment (days) Time to clinical closure (hr)
1170 _+ 299 (775-1700) 29.0 _+ 2.4 (25-33) 9 + 8 (3-35) 4* (1-12)
15~1
.......................
~E 140"
". . . . . . . . . . . . . . .
"" ~'-- ~.i...._i ....................................................
*Mediantime to clinicalclosure. 2S
tension and heart rate registered. Immediately after every postindomethacin Doppler investigation, a brief physical examination was performed to assess ductal closure clinically. Within 24 hours after the indomethacin administration, a pediatric cardiologist, who was unaware of the study results, assessed, using clinical and echocardiographic examination, whether the ductus had closed. Real-time duplex Doppler ultrasound and M-mode ecbocardiographic studies were performed with an Ultramark-4 ultrasound system (Advanced Technology Laboratories, Inc., Bothell, Wash.). All scans were performed with a 7.5 MHz transducer for real-time imaging, whereas the Doppler transducer was 5 MHz. The sample volume of the Doppler system used ranged from 1.5 mm to 2.5 mm; a 100 Hz high-pass filter was used to reduce noise from the pulsating arterial wall.
Doppler ultrasound investigation for measurement of blood flow velocity in SMA. The SMA is the second major branch of the abdominal aorta; its origin is just below the celiac trunk, from the ventral wall of the aorta. The proximal segment of the SMA usually has an anterior course (angle between SMA and abdominal aorta of approximately 90~ which allows Doppler insonation under a small angle with the use of a longitudinal abdominal approach (Fig. l, A). The beam of the sample volume used always included practically the whole vessel lumen, but insonation of the vessel wall was avoided to prevent disturbance of the velocity signal by vessel wall movements. The position of the sample volume can be optimized further by acoustic and visual control to obtain a blood flow velocity wave form of the SMA of maximal quality (Fig. 1, B). 14
Doppler ultrasound investigation of changes in cerebral blood flow. For serial investigation of changes in cerebral blood flow, the blood flow velocity in the anterior cerebral artery was performed with use of the anterior fontanel as an acoustic window, as previously described. 3 Briefly, the ACA was insonated at its curve around the corpus callosum, where the angle of insonation is approximately 0 degrees. Optimization of the sample volume position was obtained by acoustic and visual control to obtain a reliable blood flow velocity wave form of the ACA with maximal amplitudes. A minimum of 5 to 10 sequential cardiac cycles of the blood flow velocity wave forms of the SMA and ACA were subjected to real-time spectral analysis. The temporal mean
} 3oJ[
i t
Minutes
Hours
~ndomethacin
Fig. 9. Mean values +_ SD of heart rate and MABP in 15 infants (solid line) as function of time. Infants with clinical ductus closure (n = 10); 9 9 infants whose ductus remained open (n = 5); 9 . . . . . O.
flow velocities of the SMA (MFV-SMA) and of the ACA (MFV-ACA) were then determined by integration of the area under the curve. The MFV-SMA was used as a qualitative measure of changes in superior mesenteric blood flow. The MFV-ACA can be used as a qualitative measure of changes in actual cerebral blood flow, provided that cerebral perfusion pressure is relatively constant and hematocrit values are in the physiologic range. I5' 16 The ratio of mean arterial blood pressure (as a measure of effective pressure difference over the vascular bed perfused by the SMA), and the MFV-SMA was used as an independent estimator of relative vascular resistance in the perfusion region of the SMA. Similarly, the ratio of MABP and MFVACA was used as an independent estimator of relative cerebral vascular resistance. During the Doppler investigations, the infants were in a resting state, lying supine and in the anti-Trendelenburg position (15 degrees). To exclude the possible influence of postprandial changes on intestinal blood supply, the infants were not fed orally. 17 Neonatal data were collected prospectively. Pat02 and pH values were obtained from an indwelling arterial catheter or from arterialized blood samples. Arterial oxygen tensions are derived from Tcp02. Blood pressure measurements were made directly by arterial pressure transducer or indirectly via oscillometry (Dinamap, Critikon, Inc., Tampa, Fla.). If necessary, packed cell transfusions were given to keep the hematocrit greater than 40%. Statistical analysis. Results are reported as mean +_ SD. Differences between mean values of all variables at different times were assessed with the use of analysis of variance for repeated measures, followed by a Student t test for paired comparisons, with the Bonferroni correction when a significant difference was found. Differences between mean val-
968
~:~
Van Bel et al.
The Journal o f Pediatrics June 1990
9
3
................
_ _
-,
n1
25 ", m I")"~'~ ',
~ ~ f f " ~/' ' " " ' " ' " ' " ' " " ' " " " " - ' ' ' \
.
10
i ~ Minutes // 1 [ndomethacin p
