Should dopamine be the first line inotrope in the treatment of neonatal hypotension? Review of the evidence

Table 1 Levels of evidence, according to the oxford centre for evidence based medicine

Level of evidence	Type of study
1a	Systematic review (with homogeneity) of RCTs
1b	Individual RCT (with narrow confidence interval)
1c	All or none (when patients died before the treatment became available, and now some survive)
2a	Systematic review (with homogeneity) of cohort studies
2b	Individual cohort study (including low quality RCT)
2c	“Outcomes” research, ecological studies
3a	SR (with homogeneity) of case-control studies
3b	Individual case-control study
4	Case-series (and poor quality cohort and case-control studies)
5	Expert opinion without explicit critical appraisal, or based on physiology, bench research or “first principles”

RCT: Randomized clinical trial.

Table 2 Review of evidence

Ref.	Title of study	Study group	Study type (evidence)	Outcome	Key result	Comment
All inotropes
Dempsey et al[29]	Treating hypotension in the preterm infant: When and with what: a critical and systematic review	Preterm infant	Critical systematic review	Which preterm may benefit from treatment and with what intervention	17 studies reviewed. No threshold BP that was predictive of a poor outcome. None of the interventions (volume expansion, catecholamines or steroids) for hypotensive infants improved the outcome	Not able to comment which inotropes were beneficial
Dopamine
Sassano-Higgins et al[13]	A meta-analysis of dopamine use in hypotensive preterm infants: Blood pressure and cerebral hemodynamics	Preterm infants	Meta analysis	Dopamine effect on Hypotension CNS injury	Dopamine increases mean arterial blood pressure (12 studies; n = 163; r = 0.88, 95%CI: 0.76 to 0.94) and systolic blood pressure (8 studies; n = 142; r = 0.81, 95%CI: 0.42 to 0.94). Dopamine administration was associated with a significantly greater overall efficacy for increase in BP than dobutamine (7 studies; n = 251; r = 0.26; 95%CI: 0.20 to 0.32), colloid (2 studies; n = 67; r = 0.60; 95%CI: 0.41 to 0.74) and hydrocortisone (1 study; n = 28; r = 0.40; 95%CI: 0.034 to 0.67); There were no statistically significant differences in adverse neurological outcomes between dopamine and dobutamine	Dopamine is more effective than dobutamine, colloid or hydrocortisone alone. No increased incidence of adverse effects compared to other therapies
Dopamine and dobutamine
Subhedar et al[16]	Dopamine vs dobutamine for hypotensive preterm infants	Preterm infant	Cochrane review	Effectiveness and safety of dopamine and dobutamine in the treatment of systemic hypotension	5 trials = 209 infants. Fewer infants having treatment failure of hypotension with dopamine than dobutamine (RD -0.23, 95%CI: -0.34 to -0.13; NNT = 4.4, 95%CI: 2.9 to 7.7). No evidence of a significant difference in neonatal mortality between dopamine and dobutamine (RD 0.02, 95%CI: -0.12 to 0.16), incidence of periventricular leukomalacia (RD -0.08, 95%CI: -0.19 to 0.04), or severe periventricular haemorrhage (RD -0.02, 95%CI: -0.13 to 0.09), or incidence of tachycardia (RD -0.06, 95%CI: -0.25 to 0.14)	Dopamine is more effective than dobutamine in the short term treatment, none of the studies reported the incidence of adverse long term neurodevelopmental outcomes
Filippi et al[19]	Dopamine vs dobutamine in very low birthweight infants: Endocrine effects	VLBW	Prospective RCT (non-blinded)	Endocrine effects of dopamine and dobutamine in hypotensive VLBW	Suppression of TSH, T(4) and PRL was observed in dopamine-treated newborns from 12 h of treatment onwards, whereas levels of growth hormone reduced significantly only at 12 h and 36 h of treatment (P < 0.01). TSH, T(4) and PRL rebound was observed from the first day onwards after stopping dopamine. Dobutamine administration did not alter the profile of any of the hormones and no rebound was observed after stopping treatment	Dopamine induced a transient pituitary suppression, comparing to dobutamine. But this is totally reversible
Dopamine and adrenaline
Pellicer et al[25]	Cardiovascular support for low birth weight infants and cerebral hemodynamics: A randomized, blinded, clinical trial	LBW	RCT double blinded	Quantitative changes in cerebral concentrations of oxyhemoglobin and deoxyhemoglobin, cerebral intravascular oxygenation (HbD), and cerebral blood volume	Among hypotensive LBW infants, cardiovascular support with low/moderate-DP or low-dose EP increased cerebral perfusion. Low-dose EP was as effective as low/moderate-dose DP in increasing MBP among LBW infants. Heart rate was higher in the EP group than in the DP group (respectively 167 vs 159 when optimal BP was obtained)	Low-dose EP was as effective as low/moderate-dose DP in increasing MBP among LBW infants. EP led to a higher heart rate than DP
Valverde et al[23]	Dopamine vs epinephrine for cardiovascular support in low birth weight infants: Analysis of systemic effects and neonatal clinical outcomes	LBW	RCT	Short-term changes in heart rate, mean BP, acid-base status, lactate, glycemia, urine output, and fluid-carbohydrate Debit. Medium-term morbidity, enteral nutrition tolerance, gastrointestinal complications, severity of lung disease, patent ductus arteriosus, cerebral ultrasound diagnoses, retinopathy of prematurity, and mortality	Mean blood pressure showed a significant increase from baseline throughout the first 96 h with no differences between groups (dopamine: 36%; epinephrine: 37%). However, epinephrine produced a greater increase in heart rate than dopamine. After treatment began, epinephrine patients showed higher plasma lactate (first 36 h) and lower bicarbonate and base excess (first 6 h) and received more bicarbonate, and had higher blood glucose levels (P < 0.05). For medium-term morbidity, there were no differences in neonatal clinical outcomes in responders	Transitory adverse effects of epinephrine on carbohydrate and lactate metabolism could undermine the use of epinephrine as a first-line inotrope in preterm infants who are prone to such metabolic disturbances
Paradisis et al[24] (2004, reviewed in 2009)	Adrenaline for prevention of morbidity and mortality in preterm infants with cardiovascular compromise	Preterm infant	Cochrane review	Effectiveness and safety of adrenaline compared to no treatment or other inotropes in reducing mortality and morbidity in preterm infants with cardiovascular compromise	One trial comparing adrenaline with dopamine infusion was included. It enrolled hypotensive, predominantly preterm infants in the first 24 h. Only infants > 1750 g are included in this review. Both adrenaline and dopamine significantly increased heart rate and mean BP, with no statistically significant effect on left or right ventricular outputs. No significant difference was reported between the 2 inotropes	The study was reported as being randomised and double blinded, but methods were not reported. Published abstract, side effects and safety were not reported
Dopamine and steroids
Ibrahim et al[27]	Corticosteroids for treating hypotension in preterm infants	Preterm infant	Cochrane review	Effectiveness and safety of corticosteroids used either as primary treatment of hypotension or for the treatment of refractory hypotension	4 studies were included in this review enrolling a total of 123 babies. In one study, persistent hypotension was more common in hydrocortisone treated infants as compared to those who received dopamine as primary treatment for hypotension (RR 8.2, 95%CI: 0.47 to 142.6; RD 0.19, 95%CI: 0.01 to 0.37). There were no statistically significant effects on any other short or long-term outcome	Long term benefit or safety data is lacking with steroids

DP: Dose dopamine; EP: Epinephrine; RCT: Randomized clinical trial; LBW: Low birth weight; VLBW: Very low birth weight; TSH: Thyroid stimulating hormone.