Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs
Indomethacin is a drug used in preterm babies to prevent brain hemorrhage or to help close off PDA (patent ductus arteriosus - when a channel between the lungs and heart does not close off after birth as it should). Indomethacin often causes fluid retention and reduced flow of urine, which can sometimes cause deterioration in kidney (renal) function. The drug dopamine is sometimes used along with indomethacin to try and prevent negative impact on the kidneys. The review found there is not enough evidence from trials to show there is any value in giving dopamine to babies being treated with indomethacin.
2. Rationale for using dopamine in association with indomethacin, putative
benefits and risks:
If oliguria can be prevented and overall fluid status improved, then
other outcomes could also be affected. Dopamine is often administered in
the hope that its actions on specific dopaminergic receptors in the renal
vasculature will increase renal perfusion by selectively mediating renal
vasodilatation (Goldberg 1972), thus leading
to increased renal blood flow, increased glomerular filtration rate and
increased urine output. However, there is no reliable evidence that dopaminergic
vasodilatation occurs in the neonatal mammalian or human renal circulation
(Cheung 1996). Potential interactions of dopamine
with indomethacin also exist. One study showed that in healthy human adults
the renal vasodilation of low dose dopamine was prevented by indomethacin
(Manoogian 1988). It may be that the usual
physiologic cascade which follows dopaminergic stimulation in renal vascular
muscle involves release of prostacyclin and, therefore, might be affected
by indomethacin treatment.
3. Need for this review and planned subgroup analyses:
Despite the potential serious side effects of indomethacin on kidney,
gut and brain, indomethacin is frequently used for the medical treatment
of PDA. Furosemide has been used in an attempt to prevent oliguria in indomethacin-treated
preterm infants, but in a systematic review Brion 2001 found no evidence
of benefit. A systematic review of the effects of dopamine in indomethacin-treated
infants has not been reported, and is needed.
The effects of indomethacin on renal and gut blood flow might well differ depending on the blood flow to these areas prior to indomethacin, and therefore might exacerbate the reduction in renal and gastrointestinal blood flow which is related to the PDA. Therefore, we plan a subgroup analysis in patients receiving indomethacin as prophylaxis and in those receiving indomethacin as treatment of PDA.
Secondary objective: To assess effects of dopamine on the above variables in two subgroups: (1) patients given indomethacin as prophylaxis of intraventricular hemorrhage, and (2) patients given indomethacin as treatment of PDA
Secondary outcomes
• Gastrointestinal bleeding
• Intestinal perforation
• Necrotizing enterocolitis
• Cerebral blood flow (measured using validated methodology, such as
Near Infra-Red Spectroscopy)
• Cardiac output (measured using validated methodology, such as doppler
ultrasound)
• Urine output, renal function (creatinine values or fractional sodium
excretion)
• Low serum thyroxine, more than two SD below a reference mean for
age, analyzed within 1 week after starting the study intervention
Trials without a simultaneous control group (e.g. those with historical controls) were rejected.
Inclusion criteria and therapeutic interventions for each trial were reviewed to see how they differed between trials. The outcomes in each trial were examined to see how comparable they were between studies.
Statistics: For categorical outcomes, we calculated typical estimates for relative risk and risk difference and used as denominator the total number of randomized patients. 95% confidence intervals were used. For continuous outcomes the weighted mean difference was calculated. Fixed effect models were assumed for meta-analysis.
Our search yielded six studies, including three randomized controlled trials (Baenziger 1999; Fajardo 1992; Seri 1984). A fourth trial which has only appeared as an abstract is awaiting assessment, as it is unclear whether the treatment and control groups were contemporaneous (Cochran 1989). Two additional non-randomized studies were excluded: Tulassay 1983 is a study in which the authors used historical controls. Seri 1988 is a study in which infants received dopamine on the basis of clinical condition: controls did not require dopamine, whereas patients in the treatment group received dopamine for edema, moderate oliguria, poor peripheral perfusion and/or mild systemic hypotension. Thus, this latter study is not a randomized or quasi-randomized study.
All three randomized studies qualifying for this review were single center trials among indomethacin-treated NICU patients with symptomatic PDA. All were small studies, leading to a total enrollment in published randomized trials of 75 infants.
OUTCOMES
Each of the trials appears to have a primary objective of investigating
the effects of dopamine on the renal dysfunction associated with indomethacin
therapy of a PDA. Other important clinical outcomes are not reported in
any trial (mortality before discharge, intraventricular hemorrhage, periventricular
leukomalacia). The method used for assessing ductal closure is not stated
in any study. The methods used for assessing changes in renal function
appear to be appropriate.
SUBJECTS
Two studies were limited to preterm infants (Fajardo
1992, Seri 1984), whereas in Baenziger
1999, although most of the patients were premature, the gestational
ages extended up to 38 weeks and three days. There were no clear pre-stated
limits for Seri 1984, but all patients were less
than 35 weeks gestation.
Clinical diagnosis of a PDA was followed by ultrasound confirmation in Baenziger 1999 and Fajardo 1992, together with confirmation of hemodynamic significance by a left atrial to aortic root ratio of >1.3. No echocardiography appears to have been performed in Seri 1984.
DRUG DOSES.
The majority of patients in Baenziger 1999
and Fajardo 1992 received indomethacin at a
dose of 0.2 mg/kg per dose, every 12 hours, for three doses. Fajardo
1992 varied the second and third indomethacin doses based on postnatal
age at the time of starting (0.1 mg/kg for infants < two days of age,
0.25 mg/kg for infants > seven days).
In Seri 1984 two doses of indomethacin of 0.3 mg/kg were given with a 12 hour interval; this does not reflect current dosing used in the majority of NICUs.
Dopamine was administered at a dose of 4 microg/kg/min in Baenziger 1999. The dose was 2 microg/kg/min in Fajardo 1992 for all 14 infants randomly assigned to the dopamine group; when no effect was apparent, a further 10 non-randomized infants were studied at a dose of 4 microg/kg/min. Seri 1984 studied five infants at a dose of 2 microg/kg/min and three infants at 4 microg/kg/min; the choice of dose appears to have been based on blood pressure.
Renal function
There are data for the three secondary outcomes describing aspects
of renal function. Dopamine was associated with a minor increase in urine
output [WMD 0.68 ml/kg/hour (95% CI 0.22, 1.14) n=69]. There is no evidence
of effect of dopamine on serum creatinine [(WMD 2.04 micromoles/liter (95%
CI -17.90, 21.97) n=59]. There is no demonstrated effect on fractional
sodium excretion [WMD 0.47% (95% CI -0.74, 1.68) n=69]. The incidence of
oliguria (urine output < 1 ml/kg/hour) in Baenziger
1999 was not shown to be affected by dopamine administration (RR 0.73,
CI 0.35, 1.54). Clinically important degrees of renal impairment are not
reported in any of the studies.
PDA closure
There was no evidence of effect of dopamine on the frequency of failure
to close the ductus arteriosus (RR 1.11, CI 0.56, 2.19)
The mechanism of oliguria caused by indomethacin is not well understood. Other cyclooxygenase inhibitors appear to cause less oliguria (Bergamo 1989), and in newborn infants these other agents have less effect on renal blood flow than does indomethacin (Pezzati 1999). Differential effects of various cyclooxygenase inhibitors on the kidney may depend on the ratio of their activity on the two cyclooxygenase isozymes, COX-1, which preferentially mediates renal side effects (Vane 1998), and COX-2, which preferentially mediates the antiinflammatory response (Smith 1995). Indomethacin is more active against COX-1 than ibuprofen, which may explain the increased frequency and severity of renal side effects. In newborn piglets indomethacin administration affects a number of regional circulations (renal, gastrointestinal and cerebral) more than other cyclooxygenase inhibitors (Chemtob 1991, Speziale 1999); actions of indomethacin other than cyclo-oxygenase inhibition may be in part responsible, such as the propensity for causing an increase in concentrations for lipoxygenase products. The majority of infants who receive indomethacin have some decrease in urine flow, and the best predictor of severe oliguria is the pre-indomethacin urine output (Barrington 1994). Most often oliguria is self limited and of little significance. However major complications do occasionally occur (Barrington 1994), and hyponatremia, hyperkalemia, and fluid retention requiring adjustments of fluid therapy are fairly common. Rarely, renal failure may occur. Fluid retention could possibly lead to worse pulmonary outcomes. Studies of agents to prevent oliguria are thus warranted. Although dopamine in this review did cause a slight increase in urine output, this result was largely due to one study with very small sample size (Seri 1984).
As noted above there is little evidence that dopamine improves either renal perfusion or renal function in the newborn. Indeed the role of dopamine for this indication has recently been called into question for adult patients (Thompson 1994; McCrory 1997), and recent systematic reviews of the effects of low dose dopamine on renal function in the critically ill adult (Kellum 2001) and the critically ill infant and child (Prins 2001) also show no evidence of effect .
Changes in intestinal blood flow parallel those in renal blood flow (Mosca 1997); they may mediate an increased risk for gastrointestinal bleeding, perforation (Kuhl 1985), and necrotizing enterocolitis which has been demonstrated in some studies. Indomethacin may reduce both cerebral blood flow and cerebral oxygenation in preterm infants with PDA (Mosca 1997). Indomethacin also increase bleeding time (Corazza 1984). All of these side effects should be taken into account when considering indomethacin therapy in the preterm infant with a PDA.
Dopamine has uncertain effects on the cerebral circulation. Thus, the effects of combined dopamine and indomethacin therapy on cerebral perfusion in newborn infants warrants study. Dopamine is an important neurotransmitter. Although systemic infusion of dopamine largely does not cross the blood brain barrier and does not affect the majority of CNS dopamine receptors, such therapy has been shown to have other effects. Dopamine receptors in the anterior pituitary and the hypothalamus are functionally outside of the blood brain barrier (Van den Berghe 1996). It appears that systemic dopamine infusion suppresses pituitary function and administration of dopamine therefore might worsen the apparent hypothyroid state that is common in preterm infants and is statistically associated with poorer developmental outcome (Van Wassenaer 1997; Van Wassenaer 1999). Dopamine may also decrease growth hormone and prolactin secretion. Dopamine receptors in the carotid body are also affected by systemic dopamine infusion, and respiratory depression may result. Thus, adequate evaluation of the efficacy and of the potential toxicities of dopamine in clinical usage is necessary.
The currently available data do not support the use of dopamine at any dose to protect renal function during indomethacin therapy. The use of dopamine for this indication in preterm infants is not supported by the published studies.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Baenziger 1999 | Single centre randomized trial. Masking of allocation: not stated. Masking of intervention: no. Masking of outcome assessment: no. Completeness of outcome assessment: one control patient died and not analyzed. | 33 newborn infants with symptomatic PDA. 18 dopamine infants and 15 controls. | Dopamine commenced at 4 microg/kg/min 2 hours before first dose of indomethacin, which was administered at 0.2 mg/kg iv every 12 hours for 3 doses. | Failure to close the ductus arteriosus, indices of renal function, blood pressure | B | |
| Fajardo 1992 | Single centre randomized trial. Masking of allocation: not stated. Masking of intervention: yes, the low dose dopamine and no dopamine groups were masked. Masking of outcome assessment: not clear. Completeness of outcome assement: yes. | 26 preterm (<36 weeks gestation) infants with symptomatic PDA, hemodynamically significant by echocardiogram, were randomly allocated, 14 to the dopamine group and 12 to the control group. An additional group of 10 non randomized dopamine infants received a higher dosage of 5 microg/kg/min after the initial dose did not show an effect. (these non-randomized infants were not included in this review). | Dopamine was commenced at 2 microg/kg/min, (n=14), 6 hours before the
first dose of indomethacin.
The latter was administered every 12 hours for 3 doses ranging from 0.1 to 0.25 mg/kg depending on postnatal age. |
Failure to close the ductus arteriosus, indices of renal function. | B | |
| Seri 1984 | Single centre randomized trial. Masking of allocation: probably yes (envelopes with random assignment to group 1 or 2). Masking of intervention: no. Masking of outcome assessment: no. Completeness of outcome assessment: no: One patient in the control group developed intraventricular bleeding and irreversible hypotensive shock and was not analyzed. | 16 preterm infants (28 to 34 weeks), 8 dopamine treated and 8 controls. | Dopamine was used at either 2 microg/kg/min or 4 microg/kg/min, commenced 2 minutes before indomethacin which was administered at 0.3 mg/kg every 12 hours for 2 doses. | Failure to close the ductus arteriosus, various indices of renal function | A |
| Study | Reason for exclusion |
| Seri 1988 | Infants received dopamine on the basis of clinical condition. Controls did not require dopamine, whereas patients in the treatment group received dopamine for edema, moderate oliguria, poor peripheral perfusion and/or mild systemic hypotension. Thus, this study is not a randomized or quasi-randomized study. |
| Tulassay 1983 | The authors used historical controls. |
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Fajardo 1992 {published data only}
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Seri 1984 {published data only}
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Tulassay 1983 {published data only}
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