Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs
Hypotension (Lou 1977; Walther 1985; Martin-Ancel 1995), reduced left ventricular function (Barberi 1999; Bennhagen 1998; Tsivyan 1991; Walther 1985) and reduced cardiac output (Van Bel 1990; Walther 1985) have been documented in infants with perinatal asphyxia. However, there is no evidence for a relationship between low cardiac output or hypotension and subsequent neurodevelopment in term infants born with evidence of perinatal asphyxia. Infants with a poor neurodevelopmental outcome have been found to have high cerebral blood flow (Meek 1999), low cerebral blood flow (Lou 1977) and impaired cerebral autoregulation (Pryds 1990) on the first day of life. Despite the difficulties in interpreting cardiovascular parameters, one would assume that minimisation of ongoing end-organ damage may be important to ensure the best possible neurodevelopmental outcome. This raises two questions. The first is, do cardiovascular interventions improve outcomes for these infants? Secondly, if they do, which interventions are best at improving cardiovascular function in newborns with acidosis and low Apgar scores? Interventions with the potential to improve cardiac function include the administration of volume and inotropes.
Dopamine is an endogenous catecholamine that has been used extensively in the management of shock in both infants and children. Improvements in cardiovascular variables like blood pressure (Padbury 1987), cardiac output and stroke volume (Fiddler 1980, Walther 1985) have been documented with doses of dopamine up to 10 mcg/kg/min. Concerns have been expressed regarding higher doses of dopamine in view of the increases in ventricular afterload which may reduce cardiac output (Seri 1995). Repetto 1999 reported increasing pressor response at doses greater than 20 mcg/kg/min without suppression of urine output. Reported adverse effects of dopamine use in the neonate include severe vasoconstriction after extravasation, gangrene, cardiac arrhythmias (Seri 1995) and hepatic injury after inappropriately placed umbilical venous catheters (Venkataraman 1984). Dopamine has been administered at doses that correspond to differing renal and cardiovascular responses (Goldberg 1988, Seri 1995). Low infusion rates (0.5 to 5mcg/kg/min) are used to improve renal perfusion and treat oliguria. The medium dose range (6 to 10mcg/kg/min) is used for treatment of heart failure and the high dose range (15 to 20mcg/kg/min) is used for the treatment of shock.
Primary outcomes of this review include mortality and long term disability. Important secondary outcomes include evidence of organ dysfunction in the neonatal period. As clinical predictors of adverse neurodevelopmental outcomes include grade of encephalopathy (Thornberg 1995) and abnormal neurobehaviour at discharge (Aggarwal 1998), these will be included as secondary outcomes. Intervening effects of inotrope treatment such as successful treatment of low cardiac output and low organ blood flow will also be reported. In view of the association between high cerebral blood flow and adverse outcomes (Meek 1999), improvements in cerebral blood flow will only be assessed in infants with low cerebral blood flow. Subgroup analyses will be performed to assess the effects of dopamine according to a) severity of HIE (Sarnat staging, Sarnat 1976) in order to determine which infants benefit most from therapy, b) indicator of poor cardiovascular function (HIE, low blood pressure, low cardiac output) and c) maximal dose of dopamine used (in view of differing dose-response pharmacodynamics).
Randomised cross-over studies will be included for the short-term secondary outcomes of cardiac output and hypotension only.
Trials should have adequate randomisation and >75% follow up of participants for outcomes measures as described below.
Secondary outcome measures include any of the following:
1. Length of stay in
·neonatal intensive care
·hospital.
2. Evidence of organ dysfunction
·Severity and duration of HIE (eg Sarnat staging, Sarnat
1976)
·Neurological abnormality at discharge (eg abnormal neurological
examination, abnormal feeding)
·Persistent low cardiac output (defined echocardiographically)
·Persistent hypotension (eg mean blood pressure [mmHg] less
than gestational age [wk])
·Failed treatment (need for volume or other inotrope)
·Renal failure (oliguria, ie urine output < 0.5 ml/kg/hr
for > 24 hours or creatinine > 120 umol/l)
·Gastrointestinal complications (perforation, necrotising enterocolitis,
haemorrhage)
·Respiratory failure defined by the need for rescue measures
like ECMO and HFOV (when not routine).
3. Failure to increase low organ blood flow (cardiac output, renal
and cerebral blood flow in ml/kg/min)
4. Evidence of adverse event from inotrope infusion
·extravasation
·hepatic injury
·arrhythmias
The search of MEDLINE 1966 to March 2002 included MeSH searches using the following terms ("[asphyxia neonatorum or perinatal asphyxia or birth asphyxia) and [dopamine or inotrope]", and text searches using the terms "infant-newborn and [dopamine or inotrop$]". Searches were limited to "clinical trials". No language restrictions were applied.
Methods used to collect data from the included trials: Each author extracted data separately, then compared and resolved differences.
In planned subgroup analyses, the effects of dopamine vs placebo or no treatment, dopamine vs other inotropic agents, and dopamine vs volume were to be examined. Planned subgroup analyses also included analysis according to a) severity of HIE according to Sarnat staging, b) indicator of poor cardiovascular function (HIE, low BP, low cardiac output), and c) maximal dose of dopamine used, classified as </=5, 6-14, and =/> 15 mcg/kg/min.
Methods used to analyse the data: Standard method of the Cochrane Neonatal Review Group using relative risk (RR), risk difference (RD), number needed to treat (NNT), weighted mean difference (WMD) and 95% confidence intervals where appropriate. Meta-analysis, if appropriate, was to be undertaken assuming a fixed effect model.
It was the intention of the reviewers to perform sensitivity analysis including only trials with adequate allocation concealment and no losses to follow up.
DiSessa 1981 - In this trial fourteen infants with birthweight over 2000 gms and gestation > 35 weeks were selected on the basis of Apgar score at 5 minutes less than 6. All infants had received ventilatory support and fluid expansion of 5mls/kg/hour (the total period of which was not reported). Only infants with a systolic blood pressure >= 50mmHg were enrolled. Infants were randomised to receive an infusion of dopamine at 2.5mcg/kg/min or placebo (dextrose water), seven in each group. Blood pressure was monitored invasively and recorded hourly both pre and post infusion. An echocardiogram was performed between six and 12 hours after commencement of infusion. There are no data to suggest that these echocardiograms were standardised in timing or method. From this, a shortening fraction and mean velocity of circumferential fibre shortening were calculated and reported. Mortality and neurodevelopmental follow-up were reported. Neurodevelopmental assessment was not standardised. The only data regarding secondary outcomes as stated above are for duration of hospitalisation in days.
No studies comparing dopamine to other pressors were noted. No potentially relevant on-going trials were identified.
Secondary Outcomes: DiSessa 1981 reported length of hospitalisation as a mean of 10.8 days for placebo, compared to 12.4 days for dopamine treated infants. No standard deviations are provided and it is unclear whether or not these figures pertain to survivors alone. No information is provided regarding any other of the pre-specified secondary outcomes. DiSessa 1981 reported a significantly higher systolic blood pressure post dopamine infusion (mean increase of 7 mmHg, p=0.001), compared to the placebo group who experienced no significant change in blood pressure post-infusion. Two echocardiographic parameters were also reported. Infants receiving dopamine had a significantly greater shortening fraction and mean velocity circumferential fractional shortening compared to pre-infusion. There was no significant difference in the placebo group. However, post-infusion the dopamine and placebo groups were not significantly different.
No sub-group analysis was possible. With only one eligible study, issues of heterogeneity do not apply and sensitivity analysis could not be undertaken.
No study was found that examined the effect of dopamine in infants with evidence of cardiovascular compromise. Studies are warranted in term infants with evidence of cardiovascular compromise (either low blood pressure, low cardiac output or low organ perfusion) to determine the best approach to the cardiovascular support of term infants with suspected perinatal asphyxia. Until there are more data available from larger and better designed studies, the questions posed by this review will remain unanswered.
Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
DiSessa 1981 | Random study: yes, method not stated.
Allocation concealment: uncertain. Blinding of intervention: yes (placebo used). Blinding of measurement: uncertain. Losses to follow-up: yes, two infants excluded from each group for BP data as one received tolazoline and one received pancuronium in each group. Echocardiographic data only available for 6/7 infants in each group. Neurodevelopmental follow-up data available for 3/5 survivors in placebo group, and 6/7 survivors in treatment group. |
Infants > 2000gms, >35 weeks gestation, with 5'Apgar < 6.
Inclusion criteria: systolic BP > 50 mmHg. Mean gestation: Treatment group - 41.1 weeks (sd 1.5); Control group - 39.8 weeks (sd 0.89). Mean birthweight: Treatment group: 2960gms (sd 490); Control group: 3460gms (sd 340). |
Treatment group (n=7): Dopamine 2.5ug/kg/min - further dose increases
and titration endpoint unstated. No explanation of measure of effect of
treatment, or mechanism for dealing with failed treatment.
Placebo (n=7): dextrose and water. Co-intervention: Both groups received volume expansion with either colloid or blood (5ml/kg/hr - for unstated total period). |
Stated primary outcome: "cardiovascular effects of low dose dopamine
in the severely asphyxiated newborn".
Other outcomes: None stated. Mortality and neurodevelopmental disability reported. Echocardiographic data reported not standardised; examination took place 6-12 hours post infusion. Method of neurodevelopmental assessment neither stated or standardised. No adverse events reported. |
B |
Study | Reason for exclusion |
Cason 1999 | Subjects infants < or = 34 weeks with RDS. |
Padbury 1990 | Descriptive study exploring pharmacokinetics of dopamine in sick neonates. |
Phillipos 1996 | RCT of dopamine vs epinephrine, however subjects not asphyxiated infants. |
Phillipos 2000 | Subjects infants < 1750 grams with hypotension. |
* DiSessa TG, Leitner M, Ti CC, Gluck L, Coen R, Friedman WF. The cardiovascular effects of dopamine in the severely asphyxiated neonate. J Pediatr 1981;99:772-776.
Leitner MJ, DiSessa TG, Coen RW, Ti C. Cardiovascular effects of low dose dopamine in the severely asphyxiated infant. Pediatr Res 1980;14:447A.
Cason DL, Amaker D, Carter D, Sutherland D, Bhatia J. Randomized double-blind trial of dopamine versus epinephrine for treatment of hypotension in premature infants with respiratory distress syndrome. J Invest Med 1999;47:119A.
Padbury 1990 {published data only}
Padbury JF, Agata Y, Baylen BG, Ludlow JK, Polk D, Habib DM, Martinez AM. Pharmacokinetics of dopamine in critically ill newborn infants. J Pediatr 1990;117:472-6.
Phillipos 1996 {published data only}
Phillipos EZ, Barrington KJ, Robertson MA. Dopamine versus epinephrine for inotropic support in the neonate: A randomized double blinded controlled trial. Pediatr Res 1996;39:238A.
Phillipos 2000 {published data only}
* Phillipos EZ, Robertson MA. A randomized double blinded controlled trial of dopamine versus epinephrine for inotropic support in premature infants <1750 grams. Pediatr Res 2000;47:425A.
* indicates the primary reference for the study
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Barberi I, Calabro MP, Cordaro S, Gitto E, Sottile A, Prudente D et al. Myocardial ischaemia in neonates with perinatal asphyxia. Electrocardiographic, echocardiographic and enzymatic correlations. Eur J Pediatr 1999;158:742-7.
Baumgart S, Graziani LJ. Predicting the future for term infants experiencing an acute neonatal encephalopathy: electroencephalogram, magnetic resonance imaging, or crystal ball? Pediatrics 2001;107:588-90.
Bennhagen RG, Weintraub RG, Lundstrom NR, Svenningsen NW. Hypoxic-ischaemic encephalopathy is associated with regional changes in cerebral blood flow velocity and alterations in cardiovascular function. Biol Neonate 1998;73:275-86.
Burnard ED, James LS. Failure of the heart after undue asphyxia at birth. Pediatrics 1961;28:545-64.
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Goldberg LI. Dopamine and new dopamine analogs: receptors and clinical applications. J Clin Anesth 1988;1:66-74.
Hall RT, Hall FK and Daily DK. High-dose phenobarbital therapy in term newborn infants with severe perinatal asphyxia: A randomized, prospective study with three-year follow-up. J Pediatr 1998;132:345-348.
Lou HC, Lassen NA, Friis-Hansen B. Low cerebral blood flow in hypotensive perinatal distress. Acta Neuro Scand 1977;56:343-52.
MacLennan A. A template for defining a causal relation between acute intrapartum events and cerebral palsy: international consensus statement. BMJ 1999;319:1054-9.
Maggi JC, Angelats J, Scott JP. Gangrene in a neonate following dopamine therapy. J Pediatr 1982;100:323-5.
Martin-Ancel A, Garcia-Alix A, Gaya F, Cabanas F, Burgueros M, Quero J. Multiple organ involvement in perinatal asphyxia. J Pediatr 1995;127:786-93.
Meek JH, Elwell CE, McCormick DC, Edwards AD, Townsend JP, Stewart AL et al. Abnormal cerebral haemodynamics in perinatally asphyxiated neonates related to outcome. Arch Dis Child 1999;81:F110-5.
Mizoguchi MB, Chu TG, Murphy FM, Willits N, Morse LS. Dopamine use is an indicator for the development of threshold retinopathy of prematurity. Br J Ophthalmol 1999;83:425-8.
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Padbury JF, Agata Y, Baylen BG, Ludlow JK, Polk DH, Goldblatt E, Pescetti J. Dopamine pharmacokinetics in critically ill newborn infants. J Pediatr 1987;110:293-8.
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Seri I, Abbasi S, Wood DC, Gerdes JS. Regional hemodynamic effects of dopamine in the sick preterm neonate. J Pediatr 1998;133:728-34.
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01.01 Mortality before hospital discharge
(among all randomised)
01.02 Neurodevelopmental disability (among
all randomised)
01.03 Death or neurodevelopmental disability
(among all randomised)
01.04 Neurodevelopmental disability (among
survivors examined)