- Email: [email protected]
Randomized trial of dobutamine versus dopamine in preterm infants with low systemic blood flow
Randomized trial of dobutamine versus dopamine in preterm infants with low systemic blood flow David Osborn, MM, FRACP, Nick Evans, MRCPCH, DM, and Martin Kluckow, FRACP, PhD Objective: Our purpose was to determine if dobutamine or dopamine results in greater improvements in systemic blood flow in very preterm infants with low flow during the first 24 hours of life. Study design: A 2-center, randomized, double-blind study. Infants (n = 42) with low superior vena cava (SVC) flow (<41 mL/kg/min) in the first 12 hours were randomly assigned to receive 10 mL/kg normal saline solution, followed by 10 µg/kg/minute of dobutamine or dopamine. If low flow persisted or recurred, the inotrope was increased to 20 µg/kg/minute, with crossover to the other inotrope if treatment failed to maintain flow. Results: Volume produced a more significant increase in SVC flow than dopamine (+43%). At the highest dose, dobutamine resulted in a significantly greater increase in SVC flow than dopamine (mean, +9.9 vs –3.2 mL/kg/min, P = .02). Dopamine resulted in a significantly greater increase in blood pressure. Infants receiving dobutamine only at 24 hours had a greater right ventricular output than infants receiving dopamine (mean, 295 vs 167 mL/kg/min, P < .001). Forty percent failed to increase or maintain SVC flow in response to either inotrope. No significant differences in mortality or morbidity were found. Conclusions: Dobutamine produced a greater increase in blood flow than dopamine. (J Pediatr 2002;140:183-91) Of surviving babies born very prematurely, 20% have some degree of neurodevelopmental disability.1 Peri/intraventricular hemorrhage (P/IVH) is a major risk factor for neurodevelopmental disability.2 Studies have shown that low blood flow to the brain on the first day of life almost always precedes late P/IVH in
extremely premature infants,3,4 with P/IVH occurring after blood flow improves.3 Most studies of inotropes in preterm infants have used dopamine and dobutamine.5-10 No difference has been found between the ability of dopamine and dobutamine to lower neonatal mor-
From Royal Prince Alfred Hospital, Camperdown, Royal North Shore Hospital, St Leonards, and the University of Sydney, NSW, Australia.
Supported by the National Health and Medical Research Council of Australia and The North Shore Heart Research Foundation, Sydney, Australia. Submitted for publication Feb 12, 2001; revisions received May 22, 2001, Aug 8, 2001, and Oct 4, 2001; accepted Oct 4, 2001. Reprint requests: Dr David Osborn, The Department of Neonatal Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW, Australia 2050. Copyright © 2002, Mosby, Inc. All rights reserved. 0022-3476/2002/$35.00 + 0 9/21/120834 doi:10.1067/mpd.2002.120834
bidity or mortality rates including P/IVH, although the studies to date are small and not sufficiently powered to detect important differences in clinical outcomes.11 Blood pressure (BP) has been the criteria for entry in these studies and the primary outcome. Although dopamine increases systemic BP more than dobutamine, no difference has been shown in their ability to increase cardiac output. However, BP is poorly correlated with systemic blood flow in preterm infants in the first days of life.12,13 Where cardiac output has been measured, ventricular outputs have been used.8,9 Ventricular outputs in the first days of life may significantly overestimate systemic blood flow because of shunts across the ductus arteriosus (DA) and foramen ovale.14 BP DA HR MAP P/IVH PVL RVO SVC VR
Blood pressure Ductus arteriosus Heart rate Mean airway pressure Peri/intraventricular hemorrhage Periventricular leucomalacia Right ventricular output Superior vena cava Vascular resistance
We have described and validated a novel method of measuring systemic blood flow in premature infants in the first days of life by measuring superior vena cava flow (SVC flow), which measures flow from the upper body and brain.3,15 Low SVC flow is common in the first 24 hours of life and is associated with a larger-diameter DA and higher systemic vascular resistance (VR). Almost all infants with late P/IVH had preceding low SVC flows (<41 mL/kg/min). We speculate that low flow may result from an immature myocardium unable to adapt to high ex183
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trauterine VR. As dopamine tends to increase16 and dobutamine decrease systemic VR,17-19 we hypothesized that in preterm infants with low systemic blood flow and a constricting DA during the first postnatal day, dobutamine would result in greater improvements in systemic blood flow than dopamine.
METHODS Study Design The study was a 2-center, prospective, randomized, double-blind study of volume and dobutamine versus volume and dopamine. The study was part of a sequential, two-intervention study in a cohort of infants born <30 weeks’ gestation. The studies had independent criteria for intervention and independent randomization procedures. The first intervention examined the hemodynamic effects of early indomethacin given to infants with a large DA. The results of this will be described in a separate report. The study was carried out in the Royal Prince Alfred and Royal North Shore Hospital Neonatal Intensive Care Units, Sydney, Australia, between October 1998 and December 1999. The ethics committees of Central Sydney and Northern Sydney Area Health Services approved the study. A single consent was obtained to encompass cardiovascular monitoring and inclusion in either of the 2 intervention studies where enrolment criteria were met.
Infants Infants born <30 weeks’ gestation and <24 hours of age were eligible. Infants were enrolled in the trial of volume and inotrope if at any time in the first 24 hours low SVC flow (<41 mL/kg/min) was identified on echocardiographic monitoring. Informed consent was obtained antenatally where possible. Infants were excluded if parental consent was refused, grade 3 or 4 P/IVH was found on initial head ultrasound, major congenital or cardiac abnormality was identified, the infant was considered by the clinician to be nonviable, or if ino184
THE JOURNAL OF PEDIATRICS FEBRUARY 2002 trope or indomethacin had been given previously.
ment of infants, including those who did not respond, was at the clinician’s discretion.
Study Protocol Infants had echocardiographic monitoring routinely at 3, 8 to 10, and 24 hours of age. If a large DA (color Doppler diameter >1.6 mm)20 was identified before 12 hours of age, then the infants were enrolled in a randomized, double-blind, crossover study of indomethacin versus placebo with crossover at 1 hour if there was inadequate ductal constriction (first intervention study). Therefore, infants in this study with low SVC flow randomly assigned to volume and inotrope would either have a spontaneously constricting DA or had received indomethacin. Low systemic blood flow was defined as SVC flow <41 mL/kg/minute from previous data in healthy preterm babies.15 Treatment failure was defined as SVC flow remaining below or subsequently falling below 41 mL/kg/min. was increased and maintained. Double blinding was achieved by preparing trial packs comprising two identical infusion syringes labeled “1” and “2” in the pharmacy. Dobutamine and dopamine were allocated randomly at identical concentrations to syringe 1 and syringe 2. Syringe 1 was always given first, followed by syringe 2 if required. Blocks of 6 syringes were allocated to a single center. Infants with low SVC flow initially received 10 mL/kg of normal saline solution over 20 minutes followed immediately by syringe 1 at 10 µg/kg/min. Infants in whom SVC flow failed to increase to >40 mL/kg/minute or subsequently fell to <41 mL/kg/minute before 24 hours of age had syringe 1 infusion increased to 20 µg/kg/minute. Crossover to syringe 2 (the other inotrope) occurred if low SVC flow was subsequently identified, initially at 10 µg/kg/minute, then 20 µg/kg/minute if required. Infants who responded and maintained a response to a study inotrope had the infusion continued to at least 24 hours of age. Subsequent treat-
Echocardiographic Monitoring Echocardiographic monitoring was performed routinely at 3, 8 to 10, and 24 hours of age. Echocardiography was performed on infants enrolled in interventions immediately before and after normal saline solution and immediately before and 30 minutes after commencement of inotrope, or change in dose of inotrope or syringe. All measurements were performed blind to treatment allocation. An Acuson (Mountain View, Calif) 128/XP 10 ultrasound scanner was used with a 7-MHz vector array transducer incorporating color flow and pulsed wave Doppler. The scan was recorded onto VHS videotape and the measurements then taken from the videotape. Structural normality of the heart was established on the initial scan. SVC flow was determined as described previously.15 Other measurements included color Doppler diameter of the DA shunt and right ventricular output (RVO), measured with the use of techniques described elsewhere.14
Clinical and Physiologic Data Oxygen requirements, ventilatory settings, and intra-arterial BP were recorded at the time of each scan. Invasive arterial monitoring with umbilical or peripheral arterial catheters was available in 39 of the 42 infants enrolled. Cerebral ultrasound was performed with a 7-MHz transducer at 3, 8 to 10, and 24 hours. Any P/IVH was noted and classified according to Papile grading. Routine ultrasound was performed between days 4 and 7 and on day 28. Late P/IVH was defined as any P/IVH that was not present on the scan at 3 hours after birth.
Sample Size and Statistical Analysis To detect a difference in change in SVC flow of 10 mL/kg/minute between
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VOLUME 140, NUMBER 2 Table I. Comparison of clinical characteristics and baseline hemodynamic data (mean ± SD) of infants randomly assigned to volume and dobutamine versus volume and dopamine
Dobutamine Number Gestation (wk) Birth weight (g) Male Incomplete/no steroids Cesarean delivery High-frequency ventilation Surfactant Pneumothorax Inspired oxygen (%) MAP (cm H2O) HR (bpm) Mean BP Ductal diameter (mm) RVO (mL/kg/min) SVC flow (mL/kg/min)
Dopamine
22 26.0 (2.1) 982 (324) 12 (54%) 12 (54%) 10 (45%) 2 (9%) 17 (77%) 2 (9%) 35 (20) 8.6 (2.4) 142 (12) 29.9 (4.8) 1.5 (0.7) 130.2 (42.3) 30.8 (7.2)
P value
20 25.7 (1.5) 859 (190) 9 (45%) 10 (50%) 12 (60%) 1 (5%) 17 (85%) 1 (5%) 40 (21) 8.3 (2.1) 141 (13) 26.0 (7.1) 1.7 (0.6) 126.7 (49.7) 33.8 (5.4)
.6 .1 .5 .5 .8 1.0 .4 .5 .4 .7 .8 .05 .3 .8 .1
Table II. Response and maintenance of response to dobutamine and dopamine
Response* Dobutamine n/total Saline solution (10 mL/kg) Syringe 1 10 µg/kg/min 20 µg/kg/min Success on syringe 1 Syringe 2 10 µg/kg/min 20 µg/kg/min Success on syringe 2 Success on either syringe
Dopamine n/total
Maintained response* P
12/22
11/20
1.0
12/22 5/11
12/20 3/12
.7 .3
3/7 0/7
0/5 1/5
.2 1.0
Dobutamine n/total
Dopamine n/total
P value
10/22 5/11 15/22
7/20 2/12 9/20
1/7 0/7 1/8 16/22 (73%)
0/5 0/5 0/6 9/20 (45%)
.5 .3 .2 1.0 1.0 1.0 .1
*SVC flow >40 mL/kg/minute.
the 2 inotropes with 80% power at the 95% significance level, a total of 34 infants would be required. Data were analyzed as the change in the variable from before to after intervention. Analysis of change at the highest dose of inotrope is taken from the scan immediately before commencement of inotrope to the scan 30 minutes after the highest dose was reached. Data were analyzed with a PC-based statistics package (SPSS for Windows, SPSS,
Chicago, Ill), with the t test and χ2 or Fisher exact test used where appropriate. Statistical significance is taken as a value of P < .05.
RESULTS Between October 1998 and November 1999, 160 infants from 23 to 29 weeks’ gestation were admitted to the neonatal units (100 to Royal Prince Al-
fred Hospital and 60 to Royal North Shore Hospital). Consent was not obtained or an investigator not available for 32 (20%) infants. The mean gestation (27.1 vs 26.8 weeks) and birth weight (1078 g vs 986 g) of nonenrolled infants were not significantly higher than enrolled infants. Of 128 infants with consent who underwent echocardiographic monitoring, 2 infants were excluded because of grade 3 to 4 P/IVH on the initial scan. One infant died be185
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Table III. Change, while on syringe 1
Dobutamine, 10 µg/kg/min (n = 22)
A Before HR (bpm) Mean BP RVO (mL/kg/min) SVC flow (mL/kg/min)
138 (11) 30.6 (5.1) 157.5 (62.4) 42.3 (18.6)
152 (10) 28.6 (7.9) 130.8 (57.7) 31.5 (6.9)
C HR (bpm) Mean BP RVO (mL/kg/min) SVC flow (mL/kg/min)
Change
154 (12) 31.1 (7.6) 163.7 (54.3) 47.3 (19.6)
17 (11) 0.6 (4.3) 6.2 (34.6) 5.0 (11.8)
Dobutamine, 20 µg/kg/min (n = 11)
B HR (bpm) Mean BP RVO (mL/kg/min) SVC flow (mL/kg/min)
After
159 (11) 29.5 (9.3) 134.6 (48.4) 41.9 (24.5)
7 (8) 0.9 (3.2) 3.8 (23.5) 10.4 (20.0)
Dobutamine, highest dose (n = 22) 138 (11) 30.6 (5.1) 157.5 (62.4) 42.3 (18.6)
158 (12) 31.6 (8.1) 163.7 (50.1) 52.2 (22.6)
21 (10) 1.0 (4.7) 6.1 (38.0) 9.9 (16.2)
From before to after inotrope at 10 µg/kg/min (A), 20 µg/kg/min (B), and from before inotrope to after highest dose reached (C) for infants randomly assigned to dobutamine compared with dopamine (mean ± SD)
fore random assignment to volume and inotrope. Forty-two of the 126 infants were identified as having low SVC flow at a median age 7.5 hours (range, 3.111.3) and randomly assigned to volume and inotrope. Infants with low flow were of significantly lower gestation (25.8 vs 27.4 weeks, P < .001) and birth weight (915 vs 1029 g, P = .03). They were significantly more likely to have incomplete antenatal steroid therapy (51% vs 28%, P = .009), less likely to be born to mothers taking antihypertensive medication (5% vs 25%, P = .004), more likely to require mechanical ventilation (100% vs 84%, P = .004), and more likely to have a large DA (84% vs 64%, P = .02).
Baseline Data Infants were randomly assigned to volume and dobutamine initially (n = 22) and to volume and dopamine initially (n = 20). The infants were of similar gestation and birth weight and were matched for sex (Table I). Antenatal factors and postnatal respiratory morbidity were similar between the two groups. Baseline hemodynamic vari186
ables showed a small but significantly lower mean BP (29.9 vs 26.0 mm Hg) in the dopamine group, a difference that was not reflected in the baseline flow measurements. Three infants did not have invasive BP monitoring.
Volume Volume given as 10 mL/kg normal saline solution over 20 minutes produced a significant increase in blood flow (Fig 1). SVC flow increased from 32.2 to 46.2 mL/kg/minute (mean, +43%) and RVO from 129 to 151 mL/kg/minute (mean, +22%). There was a small reduction in heart rate (HR) (141 to 137 bpm, P = .04) and an increase in systolic BP (34.9 to 36.9 mm Hg, P = .05), with 23 (55%) infants having increased SVC flow over 40 mL/mg/minute after volume. Syringe 1, which contained the first inotrope, was then immediately commenced in all infants.
Inotrope All 42 infants had measurements immediately before and 30 minutes after syringe 1 was given at 10 µg/kg/minute.
Eleven infants receiving dobutamine and 12 receiving dopamine had the infusion increased to 20 µg/kg/minute. Six of 7 infants who failed dobutamine at 20 µg/kg/min and 9 of 11 who failed dopamine crossed to the other inotrope. Infants who did not complete the protocol included 1 infant who died after receiving 10 µg/kg/minute dobutamine (cardiorespiratory failure). Two infants died (cardiorespiratory and respiratory failure) and one was withdrawn (severe pulmonary hypertension) after receiving 20 µg/kg/minute dopamine. One infant died (from sepsis) after crossing over to dopamine at 10 µg/kg/minute. Two infants who crossed over (one to each inotrope) were profoundly hypotensive and did not have echocardiography performed while receiving 10 µg/kg/min. Table II documents response and maintenance of response to volume and inotrope at each dose. There was a nonsignificant trend for dobutamine to produce a greater increase in SVC flow than dopamine at both 10 µg/kg/min (mean increase, 20% vs 10%) and 20 µg/kg/minute (mean increase, 27% vs 6%) (Table III, Fig 2).
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Dopamine, 10 µg/kg/min (n = 20) Before
After
137 (16) 26.9 (8.9) 146.4 (53.3) 49.5 (22.7)
Change
159 (18) 32.0 (8.1) 148.6 (49.5) 49.8 (19.4)
P value
22 (18) 5.1 (7.0) 2.2 (41.6) 0.3 (16.4)
.3 .02 .7 .3
12 (11) 5.5 (6.5) 2.6 (40.0) 0.7 (12.0)
.3 .06 .9 .2
31 (19) 8.2 (8.5) –4.6 (57.7) –3.2 (17.5)
.04 .003 .5 .02
Dopamine, 20 µg/kg/min (n = 12) 159 (14) 28.9 (6.8) 117.7 (36.2) 31.6 (5.9)
171 (16) 34.4 (9.8) 120.2 (45.0) 32.3 (10.2)
Dopamine, highest dose (n = 20) 137 (16) 26.9 (8.9) 146.4 (53.3) 49.5 (22.7)
168 (19) 35.1 (8.8) 141.7 (56.2) 46.2 (21.9)
Table IV. Hemodynamic data at 24 hours of life in infants who continued to receive a single trial inotrope at 24 hours of age
Dobutamine Number Infusion rate 10 µg/kg/min 20 µg/kg/min Gestation (wk) Birth weight (g) MAP (cm H2O) HR (bpm) Mean BP (n = 24) RVO (mL/kg/min) SVC flow (mL/kg/min)
Dopamine
16 5 11 26.3 (2.1) 1014 (348) 6.5 (1.5) 160 (12) 39.8 (4.9) 294.5 (81.3) 85.6 (24.7)
P value
11 7 4 25.8 (1.1) 900 (171) 8.2 (2.3) 145 (12) 35.4 (4.9) 169.2 (51.9) 68.0 (30.2)
.4 .3 .03 .004 .04 <.001 .1
Mean ± SD.
There were small and similar increases in RVO for both inotropes. At the highest dose of inotrope reached on syringe 1 (Table III, Fig 3), dobutamine produced a significantly greater increase in SVC flow than dopamine (+9.9 vs –3.2 mL/kg/min, P = .02 [t test], P = .03 [Mann-Whitney U test]). This represents a mean increase in SVC flow for infants receiving dobutamine of 35% (range, –15% to +319%) versus a 1% decrease (range, –70% to +94%) for in-
fants receiving dopamine. In contrast, dopamine produced a significantly greater increase in mean BP than dobutamine.
Crossover to Other Inotrope Six infants who failed dobutamine crossed over to dopamine and 9 crossed from dopamine to dobutamine. Infants who changed to dobutamine had a significant fall in BP compared with the increase for infants changing to dopamine
(mean BP, –12.3 vs +7.8 mm Hg, P = .02). The change in SVC flow was not significantly different for infants changing to dobutamine compared with those changing to receive dopamine (11.5 vs 1.2 mL/kg/min, P = .1).
Response to Treatment at 24 Hours of Age On syringe 1, 15 infants (68%) responded and maintained a response to 187
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Fig 1. Scatterplot shows effect on SVC flow (mL/kg/min) from before to immediately after 10 mL/kg normal saline solution in all 42 infants.
volume and dobutamine compared with 9 (45%) to volume and dopamine. Of 15 infants who crossed to the other inotrope, 4 responded (3 to dobutamine and 1 to dopamine) but only one maintained the response (to dobutamine). Forty percent of all randomly assigned infants failed to maintain a response to either inotrope (Table II). Twenty-six of 42 infants (62%) continued to receive a single study inotrope at 24 hours (16 receiving dobutamine and 11 receiving dopamine; Table IV). One infant who initially responded to dopamine had low SVC flows at 24 hours of age. One infant who failed both inotropes continued to receive dopamine, 7 infants died before 24 hours, and 8 infants were receiving a combination of inotropes. The 16 infants receiving dobutamine at 24 hours had a significantly lower mean airway pressure (MAP) and trend to lower inspired oxygen compared with the 11 infants receiving dopamine. Infants receiving dobutamine had a significantly higher systolic and mean BP and a substantially and significantly higher RVO. SVC flows were not significantly different.
Clinical Outcomes There was no significant difference for any clinical outcome between infants randomly assigned initially to volume and dobutamine compared with volume 188
Fig 2. Scatterplots show response in SVC flow (mL/kg/min) from immediately before to 30 minutes after inotrope at 10 µg/kg/minute (A, B) and 20 µg/kg/minute (C, D) for infants randomly assigned to dobutamine (A, C) and dopamine (B, D).
and dopamine. The rates of death before discharge (64% vs 45 %, P = .2), any P/IVH (41% vs 45%, P = .8), grade 2 to 4 P/IVH (9% vs 35%, P = .06), or grade 3 to 4 P/IVH (14% vs 30%, P = .3) were not significantly different. Three infants randomly assigned to dobutamine had periventricular leucomalacia (PVL) and 3 necrotizing enterocolitis, compared with 1 infant randomly assigned to dopamine who had necrotizing enterocolitis. Rates of combined mortality and severe cerebral ischemic lesions (grade 3–4 P/IVH or PVL) were similar (64% vs 50%, P = .4). The 17 infants who did not respond to either treatment were of similar gestation (25.5 vs 26.1 weeks) and birth weight (860 vs 966 g) compared with the 25 infants who responded. They
were significantly less likely to have received a complete course of antenatal steroids (24% vs 64%, P = .01) and more likely to have respiratory distress syndrome (100% vs 68%, P = .01). The rate of combined death, grade 2 to 4 P/IVH, and PVL was higher in these infants compared with those who did respond (76% vs 44%, P = .04).
DISCUSSION This study of inotropes in premature newborn infants treated on the basis of low blood flow used return to normal flows as the criteria for successful treatment. Previous studies comparing dobutamine and dopamine have used BP as the criteria for enrollment and
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VOLUME 140, NUMBER 2 successful treatment.5-10 In the first days of life, low BP is poorly correlated to low systemic blood flow, therefore many of the babies enrolled in these studies would not have had low systemic blood flow.12,13 Where cardiac output has been assessed by echocardiography, the effect of inotropes on ventricular output has been determined.8,9 However, in the first day of life, shunts across the DA are common and can result in left ventricular output overestimating systemic blood flow by up to 100%.14 The flow returning to the heart through the SVC offers a solution to this problem in that it is not affected by these shunts and represents flow to the upper body, approximately 80% of which goes to the brain.21 Right ventricular output can be affected by atrial shunts, but these shunts tend not to be large early on, so it is incorporated into this study as a further measure of total systemic blood flow. All 42 infants with low flows received volume, which resulted in a significant increase in blood flow to the brain and upper body. Because all infants went on to receive inotropes immediately, this study did not examine whether this response was maintained. A previous small observational study also showed a large short-term increase in cardiac output in preterm infants with low cardiac output who received volume.22 Studies in hypotensive preterm infants suggest that many infants fail to respond or have a short-lived response to volume expansion.23,24 Clinical studies have not shown that early use of colloid or saline solution for volume expansion in preterm infants prevents P/IVH or subsequent abnormal neurodevelopment, so it may be that this effect would not be sustained if only volume was given.25,26 This study confirms our a priori hypothesis. Dobutamine produced a significantly greater increase in SVC flow than dopamine at the highest dose of inotrope reached. However, trends to better blood flow responses to dobutamine at both 10 and 20 µg/kg/minute were not significant. In addition, for infants
Fig 3. Scatterplots show response in SVC flow (mL/kg/min) from before commencement of inotrope to 30 minutes after highest dose of inotrope reached (E, dobutamine; F, dopamine) and from before commencement of volume to after highest dose of inotrope reached (G, volume and dobutamine; H, volume and dopamine). who continued to receive the initial study inotrope at 24 hours, those infants receiving dobutamine had a significant and substantially greater RVO and trend to higher SVC flow. Roze et al8 found a similar increase in left ventricular output in infants receiving dobutamine and decreased output in infants receiving dopamine. Interestingly, infants receiving dobutamine at 24 hours had a lower MAP and higher mean BP. This suggests a clinical benefit from dobutamine, although this may be biased due to the selection of these infants. In contrast, dopamine produced a significant increase in BP that was accompanied by little change in blood flow. Of relevance to the interpretation of previous randomized studies of dobutamine
and dopamine in preterm infants, this study demonstrates that improving BP does not necessarily improve blood flow. This is important because the observation that dopamine is superior at improving BP is widely used to justify dopamine as the inotrope of first choice. Our previous observation that high systemic VR is associated with lower SVC flow would suggest that increasing BP by increasing systemic VR may be counterproductive during the first day of life.3 Babies in this study who were initially randomly assigned to dopamine achieved much of their improvement in flow at 10 µg/kg/minute. Increasing to 20 µg/kg/minute in those with an inadequate response produced little additional increase in flow. In contrast, additional effect was seen between 10 189
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and 20 µg/kg/minute for babies receiving dobutamine. This is consistent with the observation that at higher doses, the pressor effect of dopamine increases BP, with little benefit for organ blood flow. A limitation of this study was the titration of the dose of inotrope at 10 and 20 µg/kg/minute that may not have optimized the dose of dopamine given. Previous studies have titrated the dose of inotropes against a continuous measure of BP.5-10 The titration of inotropes against an echocardiographic measure of blood flow limited our ability to titrate dopamine in a way that has been previously advocated to optimize individual patient response.27 However, the doses used encompass those used in these previous studies and current clinical practice. The crossover from dopamine to dobutamine produced a substantial drop in BP, with little change in blood flow. This may have been due to vasodilation in a previously vasoconstricted infant. This study and a previous study7 used volume loading before dobutamine and demonstrated little change in HR and improved BP. Current evidence suggests hemodynamic benefit from volume loading before dobutamine. However, neither inotrope was effective at improving blood flow in a large number of infants with low flows; 40% of infants did not respond to either inotrope. These infants were less likely to have received a complete course of antenatal steroids and more likely to have respiratory distress syndrome, reinforcing the importance of antenatal steroids in preventing neonatal mortality and morbidity.28 The morbidity and mortality rates of this group of infants with low blood flow is very high. This study was not designed or powered to examine long-term clinical outcomes. Despite dobutamine increasing blood flow to a greater extent than dopamine, there does not appear to have been any obvious clinical benefit in terms of death or P/IVH. Caution should be taken in interpreting the clinical outcomes of this study in view of the crossover design, 190
THE JOURNAL OF PEDIATRICS FEBRUARY 2002 which resulted in a third of infants receiving both inotropes. The crossover design was used to explore the effect of the inotropes on blood flow and to ensure that each infant received the inotrope that best improved blood flow. A meta-analysis of previous studies also shows no difference in neonatal morbidity or mortality rates between infants randomly assigned to either dobutamine or dopamine.11 There is insufficient evidence of improved clinical outcomes to recommend a single best strategy for cardiovascular support of preterm infants. Volume expansion produces improvements in blood flow, but there is no evidence of longer-term clinical benefit.25,26 Although dopamine is more effective at raising BP,11 dobutamine is more effective at improving blood flow. No important difference in morbidity or mortality has been demonstrated between the inotropes.11 However, studies to date are too small to be sufficiently powered to detect clinically important differences. Empirically, our physiologic goal in improving BP is to improve organ blood flow, so a pragmatic approach to cardiovascular support during the first postnatal day might be to give volume and dobutamine up to 20 µg/kg/minute initially. Because there was a trend to some additional benefit from dopamine in the infants who crossed over, there may be benefit from the addition of dopamine up to 10 µg/kg/minute. In view of the results of this study and the previously described inverse relation between systemic VR and blood flow,3 we would suggest higher doses of dopamine be avoided unless severe pressor-resistant hypotension occurs. We would suggest caution even in the latter situation because there are no data on the effects of very high pressor doses on organ or systemic blood flow. Infants with severe P/IVH are more likely to have BP passive changes in cerebral blood flow29 and oxygenation30 in the first days of life. The relation between low cerebral blood flow, a pressure-passive cerebral circulation,
and subsequent P/IVH is yet to be elucidated. Pryds et al29 found that not only did infants with severe P/IVH have absence of cerebral blood flow reactivity, they also had 20% lower global cerebral blood flow. It is yet to be determined whether the pressure passivity is the primary problem or whether it is also a result of preceding hypoperfusion. This study found that dobutamine, which resulted in little change in BP, produced greater increases in SVC flow compared with dopamine, which resulted in a substantial increase in BP. This suggests that the underlying problem is low systemic blood flow and not low BP. Future trials of cardiovascular support in preterm infants should identify infants with low systemic blood flow. They should include systemic blood flow as an outcome. Trials with sufficient power to detect important differences in clinically important outcomes (death, P/IVH, and neurodevelopment) are required. In view of the high failure rate for either inotrope during the first day of life, new strategies must be explored. These might include low-dose adrenaline,31,32 stress-dose steroids,33,34 or newer agents such as phosphodiesterase III inhibitors amrinone or milrinone, which lower VR and are positively inotropic.35 These observations pertain to the very premature newborn in the first day of life, and extrapolation of the findings beyond the immediate postnatal period to other clinical scenarios such as septic shock and more mature infants should be done with caution.
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National Institute of Child Health and Human Development Neonatal Research Network, 1993–1994. Pediatrics 2000;105:1216-26. Kluckow M, Evans N. Low superior vena cava flow and intraventricular haemorrhage in preterm infants. Arch Dis Child 2000;82:F188-94. Meek JH, Tyszczuk T, Elwell CE, Wyatt JS. Low cerebral blood flow is a risk factor for severe intraventricular haemorrhage. Arch Dis Child 1999;81:F15-8. Greenough A, Emery EF. Randomized trial comparing dopamine and dobutamine in preterm infants. Eur J Pediatr 1993;152:925-7. Hentschel R, Hensel D, Brune T, Rabe H, Jorch G. Impact on blood pressure and intestinal perfusion of dobutamine or dopamine in hypotensive preterm infants. Biol Neonate 1995;68:318-24. Klarr JM, Faix RG, Pryce CJE, BhattMehta V. Randomized, blind trial of dopamine versus dobutamine for treatment of hypotension in preterm infants with respiratory distress syndrome. J Pediatr 1994;125:117-22. Roze JC, Tohier C, Maingueneau C, Lefevre M, Mouzard A. Response to dobutamine and dopamine in the hypotensive very preterm infant. Arch Dis Child 1993;69:59-63. Chatterjee A, Bussey ME, Leuschen MP. The pharmacodynamics of inotropic drugs in premature neonates [abstract]. Pediatr Res 1993;33:206A. Ruelas-Orozco G, Vargas-Origel A. Assessment of therapy for arterial hypotension in critically ill preterm infants. Am J Perinatol 2000;17:95-9. Subhedar NV, Shaw NJ. Dopamine versus dobutamine for hypotensive preterm infants (Cochrane Review). In: The Cochrane Library, Issue 4, 2000. Oxford: Update Software. Kluckow M, Evans N. Relationship between blood pressure and cardiac output in preterm infants requiring mechanical ventilation. J Pediatr 1996;129:506-12. Pladys P, Wodey E, Beuchee A, Branger B, Betremieux P. Left ventricle output and mean arterial blood pressure in preterm infants during the 1st day of life. Eur J Pediatr 1999;158: 817-24.
14. Evans N, Kluckow M. Early determinants of right and left ventricular output in ventilated preterm infants. Arch Dis Child 1996;74:F88-94. 15. Kluckow M, Evans N. Superior vena cava flow in newborn infants: a novel marker of systemic blood flow. Arch Dis Child 2000;82:F182-7. 16. Seri I. Cardiovascular, renal, and endocrine actions of dopamine in neonates and children. J Pediatr 1995;126: 333-44. 17. Smolich JJ, Sano T, Penny DJ. Blunting of pulmonary but not systemic vasodilator responses to dobutamine in newborn lambs. Pediatr Res 2000;47: 107-13. 18. Cheung PY, Barrington KJ, Bigam D. The hemodynamic effects of dobutamine infusion in the chronically instrumented newborn piglet. Crit Care Med 1999;27:558-64. 19. Schranz D, Stopfkuchen H, Jungst BK, Clemens R, Emmrich P. Hemodynamic effects of dobutamine in children with cardiovascular failure. Eur J Pediatr 1982;139:4-7. 20. Evans N, Kluckow M. Early ductal shunting and intraventricular haemorrhage in ventilated preterm infants. Arch Dis Child 1996;75:F183-6. 21. Drayton MR, Skidmore R. Vasoactivity of the major intracranial arteries in newborn infants. Arch Dis Child 198762:236-40. 22. Pladys P, Wodey E, Betremieux P, Beuchee A, Ecoffey C. Effects of volume expansion on cardiac output in the preterm infant. Acta Paediatr 1997; 86:1241-5. 23. So KW, Fok TF, Ng PC, Wong WW, Cheung KL. Randomised controlled trial of colloid or crystalloid in hypotensive preterm infants. Arch Dis Child 1997;76:F43-6. 24. Gill AB, Weindling AM. Randomised controlled trial of plasma protein fraction versus dopamine in hypotensive very low birthweight infants. Arch Dis Child 1993;69:284-7. 25. Northern Neonatal Nursing Initiative [NNNI] Trial Group. A randomized trial comparing the effect of prophylactic intravenous fresh frozen plasma, gelatin or glucose on early mortality and
26.
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morbidity in preterm babies. Eur J Pediatr 1996;155:580-8. Northern Neonatal Nursing Initiative Trial Group. Randomised trial of prophylactic early fresh-frozen plasma or gelatin or glucose in preterm babies: outcome at 2 years. Lancet 1996;348: 229-32. Padbury JF. Neonatal dopamine pharmacodynamics: lessons from the bedside. J Pediatr 1998;133:719-20. Crowley P. Prophylactic corticosteroids for preterm birth (Cochrane Review). In: The Cochrane Library, Issue 4, 2000. Oxford: Update Software. Pryds O, Greisen G, Lou H, FriisHansen B. Heterogeneity of cerebral vasoreactivity in preterm infants supported by mechanical ventilation. J Pediatr 1989;11:638-45. Tsuji M, Saul IP, du Plessis A, Eichenwald E, Sobh J, Crocker R, et al. Cerebral intravascular oxygenation correlates with mean arterial pressure in critically ill premature infants. Pediatrics 2000;106:625-32. Phillipos EZ, Robertson MA. A randomized double blinded controlled trial of dopamine (DO) versus epinephrine (EPI) for inotropic support in premature infants <1750 grams [abstract]. Pediatr Res 2000;47:425A. Phillipos EZ, Barrington KJ, Robertson MA. Dopamine (D) versus epinephrine (E) for inotropic support in the neonate: a randomized, double blinded controlled trial [abstract]. Pediatr Res 1996;39:238A. Bourchier D, Weston PJ. Randomised trial of dopamine compared with hydrocortisone for the treatment of hypotensive very low birthweight infants. Arch Dis Child 1997;76:F174-8. Osiovich H, Phillipos EE, Lemke RP. A short course of hydrocortisone in hypotensive neonates <1250 g in the first 24 hours of life: a randomized, double blind controlled trial [abstract]. Pediatr Res 2000;47:422A. Lindsay CA, Barton P, Lawless S, Kitchen L, Zorka A, Garcia J, et al. Pharmacokinetics and pharmacodynamics of milrinone lactate in pediatric patients with septic shock. J Pediatr 1998;132:329-34.
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extremely premature infants,3,4 with P/IVH occurring after blood flow improves.3 Most studies of inotropes in preterm infants have used dopamine and dobutamine.5-10 No difference has been found between the ability of dopamine and dobutamine to lower neonatal mor-
From Royal Prince Alfred Hospital, Camperdown, Royal North Shore Hospital, St Leonards, and the University of Sydney, NSW, Australia.
Supported by the National Health and Medical Research Council of Australia and The North Shore Heart Research Foundation, Sydney, Australia. Submitted for publication Feb 12, 2001; revisions received May 22, 2001, Aug 8, 2001, and Oct 4, 2001; accepted Oct 4, 2001. Reprint requests: Dr David Osborn, The Department of Neonatal Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW, Australia 2050. Copyright © 2002, Mosby, Inc. All rights reserved. 0022-3476/2002/$35.00 + 0 9/21/120834 doi:10.1067/mpd.2002.120834
bidity or mortality rates including P/IVH, although the studies to date are small and not sufficiently powered to detect important differences in clinical outcomes.11 Blood pressure (BP) has been the criteria for entry in these studies and the primary outcome. Although dopamine increases systemic BP more than dobutamine, no difference has been shown in their ability to increase cardiac output. However, BP is poorly correlated with systemic blood flow in preterm infants in the first days of life.12,13 Where cardiac output has been measured, ventricular outputs have been used.8,9 Ventricular outputs in the first days of life may significantly overestimate systemic blood flow because of shunts across the ductus arteriosus (DA) and foramen ovale.14 BP DA HR MAP P/IVH PVL RVO SVC VR
Blood pressure Ductus arteriosus Heart rate Mean airway pressure Peri/intraventricular hemorrhage Periventricular leucomalacia Right ventricular output Superior vena cava Vascular resistance
We have described and validated a novel method of measuring systemic blood flow in premature infants in the first days of life by measuring superior vena cava flow (SVC flow), which measures flow from the upper body and brain.3,15 Low SVC flow is common in the first 24 hours of life and is associated with a larger-diameter DA and higher systemic vascular resistance (VR). Almost all infants with late P/IVH had preceding low SVC flows (<41 mL/kg/min). We speculate that low flow may result from an immature myocardium unable to adapt to high ex183
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trauterine VR. As dopamine tends to increase16 and dobutamine decrease systemic VR,17-19 we hypothesized that in preterm infants with low systemic blood flow and a constricting DA during the first postnatal day, dobutamine would result in greater improvements in systemic blood flow than dopamine.
METHODS Study Design The study was a 2-center, prospective, randomized, double-blind study of volume and dobutamine versus volume and dopamine. The study was part of a sequential, two-intervention study in a cohort of infants born <30 weeks’ gestation. The studies had independent criteria for intervention and independent randomization procedures. The first intervention examined the hemodynamic effects of early indomethacin given to infants with a large DA. The results of this will be described in a separate report. The study was carried out in the Royal Prince Alfred and Royal North Shore Hospital Neonatal Intensive Care Units, Sydney, Australia, between October 1998 and December 1999. The ethics committees of Central Sydney and Northern Sydney Area Health Services approved the study. A single consent was obtained to encompass cardiovascular monitoring and inclusion in either of the 2 intervention studies where enrolment criteria were met.
Infants Infants born <30 weeks’ gestation and <24 hours of age were eligible. Infants were enrolled in the trial of volume and inotrope if at any time in the first 24 hours low SVC flow (<41 mL/kg/min) was identified on echocardiographic monitoring. Informed consent was obtained antenatally where possible. Infants were excluded if parental consent was refused, grade 3 or 4 P/IVH was found on initial head ultrasound, major congenital or cardiac abnormality was identified, the infant was considered by the clinician to be nonviable, or if ino184
THE JOURNAL OF PEDIATRICS FEBRUARY 2002 trope or indomethacin had been given previously.
ment of infants, including those who did not respond, was at the clinician’s discretion.
Study Protocol Infants had echocardiographic monitoring routinely at 3, 8 to 10, and 24 hours of age. If a large DA (color Doppler diameter >1.6 mm)20 was identified before 12 hours of age, then the infants were enrolled in a randomized, double-blind, crossover study of indomethacin versus placebo with crossover at 1 hour if there was inadequate ductal constriction (first intervention study). Therefore, infants in this study with low SVC flow randomly assigned to volume and inotrope would either have a spontaneously constricting DA or had received indomethacin. Low systemic blood flow was defined as SVC flow <41 mL/kg/minute from previous data in healthy preterm babies.15 Treatment failure was defined as SVC flow remaining below or subsequently falling below 41 mL/kg/min. was increased and maintained. Double blinding was achieved by preparing trial packs comprising two identical infusion syringes labeled “1” and “2” in the pharmacy. Dobutamine and dopamine were allocated randomly at identical concentrations to syringe 1 and syringe 2. Syringe 1 was always given first, followed by syringe 2 if required. Blocks of 6 syringes were allocated to a single center. Infants with low SVC flow initially received 10 mL/kg of normal saline solution over 20 minutes followed immediately by syringe 1 at 10 µg/kg/min. Infants in whom SVC flow failed to increase to >40 mL/kg/minute or subsequently fell to <41 mL/kg/minute before 24 hours of age had syringe 1 infusion increased to 20 µg/kg/minute. Crossover to syringe 2 (the other inotrope) occurred if low SVC flow was subsequently identified, initially at 10 µg/kg/minute, then 20 µg/kg/minute if required. Infants who responded and maintained a response to a study inotrope had the infusion continued to at least 24 hours of age. Subsequent treat-
Echocardiographic Monitoring Echocardiographic monitoring was performed routinely at 3, 8 to 10, and 24 hours of age. Echocardiography was performed on infants enrolled in interventions immediately before and after normal saline solution and immediately before and 30 minutes after commencement of inotrope, or change in dose of inotrope or syringe. All measurements were performed blind to treatment allocation. An Acuson (Mountain View, Calif) 128/XP 10 ultrasound scanner was used with a 7-MHz vector array transducer incorporating color flow and pulsed wave Doppler. The scan was recorded onto VHS videotape and the measurements then taken from the videotape. Structural normality of the heart was established on the initial scan. SVC flow was determined as described previously.15 Other measurements included color Doppler diameter of the DA shunt and right ventricular output (RVO), measured with the use of techniques described elsewhere.14
Clinical and Physiologic Data Oxygen requirements, ventilatory settings, and intra-arterial BP were recorded at the time of each scan. Invasive arterial monitoring with umbilical or peripheral arterial catheters was available in 39 of the 42 infants enrolled. Cerebral ultrasound was performed with a 7-MHz transducer at 3, 8 to 10, and 24 hours. Any P/IVH was noted and classified according to Papile grading. Routine ultrasound was performed between days 4 and 7 and on day 28. Late P/IVH was defined as any P/IVH that was not present on the scan at 3 hours after birth.
Sample Size and Statistical Analysis To detect a difference in change in SVC flow of 10 mL/kg/minute between
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VOLUME 140, NUMBER 2 Table I. Comparison of clinical characteristics and baseline hemodynamic data (mean ± SD) of infants randomly assigned to volume and dobutamine versus volume and dopamine
Dobutamine Number Gestation (wk) Birth weight (g) Male Incomplete/no steroids Cesarean delivery High-frequency ventilation Surfactant Pneumothorax Inspired oxygen (%) MAP (cm H2O) HR (bpm) Mean BP Ductal diameter (mm) RVO (mL/kg/min) SVC flow (mL/kg/min)
Dopamine
22 26.0 (2.1) 982 (324) 12 (54%) 12 (54%) 10 (45%) 2 (9%) 17 (77%) 2 (9%) 35 (20) 8.6 (2.4) 142 (12) 29.9 (4.8) 1.5 (0.7) 130.2 (42.3) 30.8 (7.2)
P value
20 25.7 (1.5) 859 (190) 9 (45%) 10 (50%) 12 (60%) 1 (5%) 17 (85%) 1 (5%) 40 (21) 8.3 (2.1) 141 (13) 26.0 (7.1) 1.7 (0.6) 126.7 (49.7) 33.8 (5.4)
.6 .1 .5 .5 .8 1.0 .4 .5 .4 .7 .8 .05 .3 .8 .1
Table II. Response and maintenance of response to dobutamine and dopamine
Response* Dobutamine n/total Saline solution (10 mL/kg) Syringe 1 10 µg/kg/min 20 µg/kg/min Success on syringe 1 Syringe 2 10 µg/kg/min 20 µg/kg/min Success on syringe 2 Success on either syringe
Dopamine n/total
Maintained response* P
12/22
11/20
1.0
12/22 5/11
12/20 3/12
.7 .3
3/7 0/7
0/5 1/5
.2 1.0
Dobutamine n/total
Dopamine n/total
P value
10/22 5/11 15/22
7/20 2/12 9/20
1/7 0/7 1/8 16/22 (73%)
0/5 0/5 0/6 9/20 (45%)
.5 .3 .2 1.0 1.0 1.0 .1
*SVC flow >40 mL/kg/minute.
the 2 inotropes with 80% power at the 95% significance level, a total of 34 infants would be required. Data were analyzed as the change in the variable from before to after intervention. Analysis of change at the highest dose of inotrope is taken from the scan immediately before commencement of inotrope to the scan 30 minutes after the highest dose was reached. Data were analyzed with a PC-based statistics package (SPSS for Windows, SPSS,
Chicago, Ill), with the t test and χ2 or Fisher exact test used where appropriate. Statistical significance is taken as a value of P < .05.
RESULTS Between October 1998 and November 1999, 160 infants from 23 to 29 weeks’ gestation were admitted to the neonatal units (100 to Royal Prince Al-
fred Hospital and 60 to Royal North Shore Hospital). Consent was not obtained or an investigator not available for 32 (20%) infants. The mean gestation (27.1 vs 26.8 weeks) and birth weight (1078 g vs 986 g) of nonenrolled infants were not significantly higher than enrolled infants. Of 128 infants with consent who underwent echocardiographic monitoring, 2 infants were excluded because of grade 3 to 4 P/IVH on the initial scan. One infant died be185
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Table III. Change, while on syringe 1
Dobutamine, 10 µg/kg/min (n = 22)
A Before HR (bpm) Mean BP RVO (mL/kg/min) SVC flow (mL/kg/min)
138 (11) 30.6 (5.1) 157.5 (62.4) 42.3 (18.6)
152 (10) 28.6 (7.9) 130.8 (57.7) 31.5 (6.9)
C HR (bpm) Mean BP RVO (mL/kg/min) SVC flow (mL/kg/min)
Change
154 (12) 31.1 (7.6) 163.7 (54.3) 47.3 (19.6)
17 (11) 0.6 (4.3) 6.2 (34.6) 5.0 (11.8)
Dobutamine, 20 µg/kg/min (n = 11)
B HR (bpm) Mean BP RVO (mL/kg/min) SVC flow (mL/kg/min)
After
159 (11) 29.5 (9.3) 134.6 (48.4) 41.9 (24.5)
7 (8) 0.9 (3.2) 3.8 (23.5) 10.4 (20.0)
Dobutamine, highest dose (n = 22) 138 (11) 30.6 (5.1) 157.5 (62.4) 42.3 (18.6)
158 (12) 31.6 (8.1) 163.7 (50.1) 52.2 (22.6)
21 (10) 1.0 (4.7) 6.1 (38.0) 9.9 (16.2)
From before to after inotrope at 10 µg/kg/min (A), 20 µg/kg/min (B), and from before inotrope to after highest dose reached (C) for infants randomly assigned to dobutamine compared with dopamine (mean ± SD)
fore random assignment to volume and inotrope. Forty-two of the 126 infants were identified as having low SVC flow at a median age 7.5 hours (range, 3.111.3) and randomly assigned to volume and inotrope. Infants with low flow were of significantly lower gestation (25.8 vs 27.4 weeks, P < .001) and birth weight (915 vs 1029 g, P = .03). They were significantly more likely to have incomplete antenatal steroid therapy (51% vs 28%, P = .009), less likely to be born to mothers taking antihypertensive medication (5% vs 25%, P = .004), more likely to require mechanical ventilation (100% vs 84%, P = .004), and more likely to have a large DA (84% vs 64%, P = .02).
Baseline Data Infants were randomly assigned to volume and dobutamine initially (n = 22) and to volume and dopamine initially (n = 20). The infants were of similar gestation and birth weight and were matched for sex (Table I). Antenatal factors and postnatal respiratory morbidity were similar between the two groups. Baseline hemodynamic vari186
ables showed a small but significantly lower mean BP (29.9 vs 26.0 mm Hg) in the dopamine group, a difference that was not reflected in the baseline flow measurements. Three infants did not have invasive BP monitoring.
Volume Volume given as 10 mL/kg normal saline solution over 20 minutes produced a significant increase in blood flow (Fig 1). SVC flow increased from 32.2 to 46.2 mL/kg/minute (mean, +43%) and RVO from 129 to 151 mL/kg/minute (mean, +22%). There was a small reduction in heart rate (HR) (141 to 137 bpm, P = .04) and an increase in systolic BP (34.9 to 36.9 mm Hg, P = .05), with 23 (55%) infants having increased SVC flow over 40 mL/mg/minute after volume. Syringe 1, which contained the first inotrope, was then immediately commenced in all infants.
Inotrope All 42 infants had measurements immediately before and 30 minutes after syringe 1 was given at 10 µg/kg/minute.
Eleven infants receiving dobutamine and 12 receiving dopamine had the infusion increased to 20 µg/kg/minute. Six of 7 infants who failed dobutamine at 20 µg/kg/min and 9 of 11 who failed dopamine crossed to the other inotrope. Infants who did not complete the protocol included 1 infant who died after receiving 10 µg/kg/minute dobutamine (cardiorespiratory failure). Two infants died (cardiorespiratory and respiratory failure) and one was withdrawn (severe pulmonary hypertension) after receiving 20 µg/kg/minute dopamine. One infant died (from sepsis) after crossing over to dopamine at 10 µg/kg/minute. Two infants who crossed over (one to each inotrope) were profoundly hypotensive and did not have echocardiography performed while receiving 10 µg/kg/min. Table II documents response and maintenance of response to volume and inotrope at each dose. There was a nonsignificant trend for dobutamine to produce a greater increase in SVC flow than dopamine at both 10 µg/kg/min (mean increase, 20% vs 10%) and 20 µg/kg/minute (mean increase, 27% vs 6%) (Table III, Fig 2).
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Dopamine, 10 µg/kg/min (n = 20) Before
After
137 (16) 26.9 (8.9) 146.4 (53.3) 49.5 (22.7)
Change
159 (18) 32.0 (8.1) 148.6 (49.5) 49.8 (19.4)
P value
22 (18) 5.1 (7.0) 2.2 (41.6) 0.3 (16.4)
.3 .02 .7 .3
12 (11) 5.5 (6.5) 2.6 (40.0) 0.7 (12.0)
.3 .06 .9 .2
31 (19) 8.2 (8.5) –4.6 (57.7) –3.2 (17.5)
.04 .003 .5 .02
Dopamine, 20 µg/kg/min (n = 12) 159 (14) 28.9 (6.8) 117.7 (36.2) 31.6 (5.9)
171 (16) 34.4 (9.8) 120.2 (45.0) 32.3 (10.2)
Dopamine, highest dose (n = 20) 137 (16) 26.9 (8.9) 146.4 (53.3) 49.5 (22.7)
168 (19) 35.1 (8.8) 141.7 (56.2) 46.2 (21.9)
Table IV. Hemodynamic data at 24 hours of life in infants who continued to receive a single trial inotrope at 24 hours of age
Dobutamine Number Infusion rate 10 µg/kg/min 20 µg/kg/min Gestation (wk) Birth weight (g) MAP (cm H2O) HR (bpm) Mean BP (n = 24) RVO (mL/kg/min) SVC flow (mL/kg/min)
Dopamine
16 5 11 26.3 (2.1) 1014 (348) 6.5 (1.5) 160 (12) 39.8 (4.9) 294.5 (81.3) 85.6 (24.7)
P value
11 7 4 25.8 (1.1) 900 (171) 8.2 (2.3) 145 (12) 35.4 (4.9) 169.2 (51.9) 68.0 (30.2)
.4 .3 .03 .004 .04 <.001 .1
Mean ± SD.
There were small and similar increases in RVO for both inotropes. At the highest dose of inotrope reached on syringe 1 (Table III, Fig 3), dobutamine produced a significantly greater increase in SVC flow than dopamine (+9.9 vs –3.2 mL/kg/min, P = .02 [t test], P = .03 [Mann-Whitney U test]). This represents a mean increase in SVC flow for infants receiving dobutamine of 35% (range, –15% to +319%) versus a 1% decrease (range, –70% to +94%) for in-
fants receiving dopamine. In contrast, dopamine produced a significantly greater increase in mean BP than dobutamine.
Crossover to Other Inotrope Six infants who failed dobutamine crossed over to dopamine and 9 crossed from dopamine to dobutamine. Infants who changed to dobutamine had a significant fall in BP compared with the increase for infants changing to dopamine
(mean BP, –12.3 vs +7.8 mm Hg, P = .02). The change in SVC flow was not significantly different for infants changing to dobutamine compared with those changing to receive dopamine (11.5 vs 1.2 mL/kg/min, P = .1).
Response to Treatment at 24 Hours of Age On syringe 1, 15 infants (68%) responded and maintained a response to 187
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Fig 1. Scatterplot shows effect on SVC flow (mL/kg/min) from before to immediately after 10 mL/kg normal saline solution in all 42 infants.
volume and dobutamine compared with 9 (45%) to volume and dopamine. Of 15 infants who crossed to the other inotrope, 4 responded (3 to dobutamine and 1 to dopamine) but only one maintained the response (to dobutamine). Forty percent of all randomly assigned infants failed to maintain a response to either inotrope (Table II). Twenty-six of 42 infants (62%) continued to receive a single study inotrope at 24 hours (16 receiving dobutamine and 11 receiving dopamine; Table IV). One infant who initially responded to dopamine had low SVC flows at 24 hours of age. One infant who failed both inotropes continued to receive dopamine, 7 infants died before 24 hours, and 8 infants were receiving a combination of inotropes. The 16 infants receiving dobutamine at 24 hours had a significantly lower mean airway pressure (MAP) and trend to lower inspired oxygen compared with the 11 infants receiving dopamine. Infants receiving dobutamine had a significantly higher systolic and mean BP and a substantially and significantly higher RVO. SVC flows were not significantly different.
Clinical Outcomes There was no significant difference for any clinical outcome between infants randomly assigned initially to volume and dobutamine compared with volume 188
Fig 2. Scatterplots show response in SVC flow (mL/kg/min) from immediately before to 30 minutes after inotrope at 10 µg/kg/minute (A, B) and 20 µg/kg/minute (C, D) for infants randomly assigned to dobutamine (A, C) and dopamine (B, D).
and dopamine. The rates of death before discharge (64% vs 45 %, P = .2), any P/IVH (41% vs 45%, P = .8), grade 2 to 4 P/IVH (9% vs 35%, P = .06), or grade 3 to 4 P/IVH (14% vs 30%, P = .3) were not significantly different. Three infants randomly assigned to dobutamine had periventricular leucomalacia (PVL) and 3 necrotizing enterocolitis, compared with 1 infant randomly assigned to dopamine who had necrotizing enterocolitis. Rates of combined mortality and severe cerebral ischemic lesions (grade 3–4 P/IVH or PVL) were similar (64% vs 50%, P = .4). The 17 infants who did not respond to either treatment were of similar gestation (25.5 vs 26.1 weeks) and birth weight (860 vs 966 g) compared with the 25 infants who responded. They
were significantly less likely to have received a complete course of antenatal steroids (24% vs 64%, P = .01) and more likely to have respiratory distress syndrome (100% vs 68%, P = .01). The rate of combined death, grade 2 to 4 P/IVH, and PVL was higher in these infants compared with those who did respond (76% vs 44%, P = .04).
DISCUSSION This study of inotropes in premature newborn infants treated on the basis of low blood flow used return to normal flows as the criteria for successful treatment. Previous studies comparing dobutamine and dopamine have used BP as the criteria for enrollment and
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VOLUME 140, NUMBER 2 successful treatment.5-10 In the first days of life, low BP is poorly correlated to low systemic blood flow, therefore many of the babies enrolled in these studies would not have had low systemic blood flow.12,13 Where cardiac output has been assessed by echocardiography, the effect of inotropes on ventricular output has been determined.8,9 However, in the first day of life, shunts across the DA are common and can result in left ventricular output overestimating systemic blood flow by up to 100%.14 The flow returning to the heart through the SVC offers a solution to this problem in that it is not affected by these shunts and represents flow to the upper body, approximately 80% of which goes to the brain.21 Right ventricular output can be affected by atrial shunts, but these shunts tend not to be large early on, so it is incorporated into this study as a further measure of total systemic blood flow. All 42 infants with low flows received volume, which resulted in a significant increase in blood flow to the brain and upper body. Because all infants went on to receive inotropes immediately, this study did not examine whether this response was maintained. A previous small observational study also showed a large short-term increase in cardiac output in preterm infants with low cardiac output who received volume.22 Studies in hypotensive preterm infants suggest that many infants fail to respond or have a short-lived response to volume expansion.23,24 Clinical studies have not shown that early use of colloid or saline solution for volume expansion in preterm infants prevents P/IVH or subsequent abnormal neurodevelopment, so it may be that this effect would not be sustained if only volume was given.25,26 This study confirms our a priori hypothesis. Dobutamine produced a significantly greater increase in SVC flow than dopamine at the highest dose of inotrope reached. However, trends to better blood flow responses to dobutamine at both 10 and 20 µg/kg/minute were not significant. In addition, for infants
Fig 3. Scatterplots show response in SVC flow (mL/kg/min) from before commencement of inotrope to 30 minutes after highest dose of inotrope reached (E, dobutamine; F, dopamine) and from before commencement of volume to after highest dose of inotrope reached (G, volume and dobutamine; H, volume and dopamine). who continued to receive the initial study inotrope at 24 hours, those infants receiving dobutamine had a significant and substantially greater RVO and trend to higher SVC flow. Roze et al8 found a similar increase in left ventricular output in infants receiving dobutamine and decreased output in infants receiving dopamine. Interestingly, infants receiving dobutamine at 24 hours had a lower MAP and higher mean BP. This suggests a clinical benefit from dobutamine, although this may be biased due to the selection of these infants. In contrast, dopamine produced a significant increase in BP that was accompanied by little change in blood flow. Of relevance to the interpretation of previous randomized studies of dobutamine
and dopamine in preterm infants, this study demonstrates that improving BP does not necessarily improve blood flow. This is important because the observation that dopamine is superior at improving BP is widely used to justify dopamine as the inotrope of first choice. Our previous observation that high systemic VR is associated with lower SVC flow would suggest that increasing BP by increasing systemic VR may be counterproductive during the first day of life.3 Babies in this study who were initially randomly assigned to dopamine achieved much of their improvement in flow at 10 µg/kg/minute. Increasing to 20 µg/kg/minute in those with an inadequate response produced little additional increase in flow. In contrast, additional effect was seen between 10 189
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and 20 µg/kg/minute for babies receiving dobutamine. This is consistent with the observation that at higher doses, the pressor effect of dopamine increases BP, with little benefit for organ blood flow. A limitation of this study was the titration of the dose of inotrope at 10 and 20 µg/kg/minute that may not have optimized the dose of dopamine given. Previous studies have titrated the dose of inotropes against a continuous measure of BP.5-10 The titration of inotropes against an echocardiographic measure of blood flow limited our ability to titrate dopamine in a way that has been previously advocated to optimize individual patient response.27 However, the doses used encompass those used in these previous studies and current clinical practice. The crossover from dopamine to dobutamine produced a substantial drop in BP, with little change in blood flow. This may have been due to vasodilation in a previously vasoconstricted infant. This study and a previous study7 used volume loading before dobutamine and demonstrated little change in HR and improved BP. Current evidence suggests hemodynamic benefit from volume loading before dobutamine. However, neither inotrope was effective at improving blood flow in a large number of infants with low flows; 40% of infants did not respond to either inotrope. These infants were less likely to have received a complete course of antenatal steroids and more likely to have respiratory distress syndrome, reinforcing the importance of antenatal steroids in preventing neonatal mortality and morbidity.28 The morbidity and mortality rates of this group of infants with low blood flow is very high. This study was not designed or powered to examine long-term clinical outcomes. Despite dobutamine increasing blood flow to a greater extent than dopamine, there does not appear to have been any obvious clinical benefit in terms of death or P/IVH. Caution should be taken in interpreting the clinical outcomes of this study in view of the crossover design, 190
THE JOURNAL OF PEDIATRICS FEBRUARY 2002 which resulted in a third of infants receiving both inotropes. The crossover design was used to explore the effect of the inotropes on blood flow and to ensure that each infant received the inotrope that best improved blood flow. A meta-analysis of previous studies also shows no difference in neonatal morbidity or mortality rates between infants randomly assigned to either dobutamine or dopamine.11 There is insufficient evidence of improved clinical outcomes to recommend a single best strategy for cardiovascular support of preterm infants. Volume expansion produces improvements in blood flow, but there is no evidence of longer-term clinical benefit.25,26 Although dopamine is more effective at raising BP,11 dobutamine is more effective at improving blood flow. No important difference in morbidity or mortality has been demonstrated between the inotropes.11 However, studies to date are too small to be sufficiently powered to detect clinically important differences. Empirically, our physiologic goal in improving BP is to improve organ blood flow, so a pragmatic approach to cardiovascular support during the first postnatal day might be to give volume and dobutamine up to 20 µg/kg/minute initially. Because there was a trend to some additional benefit from dopamine in the infants who crossed over, there may be benefit from the addition of dopamine up to 10 µg/kg/minute. In view of the results of this study and the previously described inverse relation between systemic VR and blood flow,3 we would suggest higher doses of dopamine be avoided unless severe pressor-resistant hypotension occurs. We would suggest caution even in the latter situation because there are no data on the effects of very high pressor doses on organ or systemic blood flow. Infants with severe P/IVH are more likely to have BP passive changes in cerebral blood flow29 and oxygenation30 in the first days of life. The relation between low cerebral blood flow, a pressure-passive cerebral circulation,
and subsequent P/IVH is yet to be elucidated. Pryds et al29 found that not only did infants with severe P/IVH have absence of cerebral blood flow reactivity, they also had 20% lower global cerebral blood flow. It is yet to be determined whether the pressure passivity is the primary problem or whether it is also a result of preceding hypoperfusion. This study found that dobutamine, which resulted in little change in BP, produced greater increases in SVC flow compared with dopamine, which resulted in a substantial increase in BP. This suggests that the underlying problem is low systemic blood flow and not low BP. Future trials of cardiovascular support in preterm infants should identify infants with low systemic blood flow. They should include systemic blood flow as an outcome. Trials with sufficient power to detect important differences in clinically important outcomes (death, P/IVH, and neurodevelopment) are required. In view of the high failure rate for either inotrope during the first day of life, new strategies must be explored. These might include low-dose adrenaline,31,32 stress-dose steroids,33,34 or newer agents such as phosphodiesterase III inhibitors amrinone or milrinone, which lower VR and are positively inotropic.35 These observations pertain to the very premature newborn in the first day of life, and extrapolation of the findings beyond the immediate postnatal period to other clinical scenarios such as septic shock and more mature infants should be done with caution.
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