Abstract
Objectives
To compare the endocrine effects of dopamine and dobutamine in hypotensive very low birthweight (VLBW) infants.
Design
Non‐blinded randomised prospective trial.
Setting
Level III neonatal intensive care unit.
Patients
35 hypotensive VLBW infants who did not respond to volume loading, assigned to receive dopamine or dobutamine.
Measurements
Haemodynamic variables and serum levels of thyroid stimulating hormone (TSH), total thyroxine (T4), prolactin (PRL) and growth hormone were assessed during the first 72 h of treatment and the first 72 h after stopping treatment.
Results
Demographic and clinical data did not significantly differ between the two groups. Necessary cumulative and mean drug doses and maximum infusion required to normalise blood pressure were significantly higher in the dobutamine than in the dopamine group (p<0.01). Suppression of TSH, T4 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, T4 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.
Conclusion
Dopamine and dobutamine both increase the systemic blood pressure, though dopamine is more effective. Dopamine reduces serum levels of TSH, T4 and PRL in VLBW infants but such suppression is quickly reversed after treatment is stopped. Further research is required to assess if short‐term iatrogenic pituitary suppression has longer‐term consequences.
Keywords: dopamine, dobutamine, preterm newborn, hypotension
About 20% of very low birthweight (VLBW) infants in neonatal intensive care units become hypotensive within 24 h of admission.1 Hypotension is a major risk factor for periventricular‐intraventricular haemorrhage and poor long‐term neurodevelopmental outcome,2,3,4 probably because of the low cerebral perfusion pressure and blood flow.5,6,7 Therefore hypotension is usually treated with volume expansion8 and inotropic agents,9,10,11,12,13 mostly dopamine and dobutamine.
Treatment with dopamine is more successful than with dobutamine.14 However, dopamine suppresses anterior pituitary function in VLBW infants15,16,17,18,19,20 and treatment is associated with hypothyroxinaemia of prematurity15 and low levels of prolactin (PRL).16
It has been shown that dobutamine treatment induces a small but important decrease in levels of thyroid stimulating hormone (TSH) in adults through unknown mechanisms.21,22 It is currently not known whether dobutamine has similar effects in VLBW infants. Such hormonal suppression would be of great relevance because decreased thyroid function and hypoprolactinaemia are associated with worse neurodevelopmental23 and clinical outcomes, respectively.24
The aim of the present study was to compare efficacy and endocrine effects of dopamine and dobutamine in hypotensive VLBW infants.
Patients and methods
We conducted a prospective, randomised study in hypotensive VLBW infants weighing <1500 g born between July 2003 and June 2005 at the level III maternity hospital at Careggi, Florence, Italy. The exclusion criteria were: inherited metabolic endocrine diseases; major congenital abnormalities; shock requiring immediate treatment in delivery room; treatment with glucocorticoids or dopamine antagonists; and ascertained or presumed pituitary or thyroidal disorders in either the newborn or the mother. The institutional review board approved the study, and written informed consent was obtained from one parent.
Hypotension was defined as mean arterial pressure (MAP) <25 mm Hg, 30 mm Hg and 32 mm Hg for birth weight of <750 g, 750–1250 g and 1250–1500 g, respectively; the blood pressure was measured twice with an interval of 30 minutes between the two recordings.2 Hypotensive newborns were given isotonic saline, 10 ml/kg, by slow intravenous infusion. Those newborns who remained hypotensive after two doses of crystalloid were allocated to receive dopamine or dobutamine. The newborns received dopamine (group A) if they were enrolled in the study on odd days and dobutamine (group B) if they were enrolled on even days. Drug infusion was started at 4 μg/kg/min and the dose increased by 2 μg/kg/min in a step‐wise fashion until either the MAP normalised or a maximal dose of 20 μg/kg/min was reached. If the hypotension persisted after giving the maximum dose of 20 μg/kg/min, the other inotrope was added.
Heart rate, MAP and oxygen requirement were evaluated at 0, 2, 4, 8, 12, 18, 24, 48 and 72 h. Serum sodium, potassium and chloride were measured at 12, 18, 24, 48 and 72 h. Creatinine, fluid intake and mean urine output were measured daily for the first three days. All these measurements were repeated once a day in the first three days after cessation of inotropic treatment. The newborns were nursed in a thermoneutral environment, and fluid intake was started on average at 50 ml/kg/day on the first day of life and then increased depending on the postnatal age and serum level of sodium. Minimal enteral feeding was usually started on the first day of life. Arterial blood pressure was monitored with a non‐invasive oscillometric blood pressure monitor (Symphony N‐3100, Nellcor Puritan Bennett, Pleasanton, California, USA) every 15 min from birth. The accuracy of measurement of this monitor is ±3 mm Hg.
To study endocrine profiles, we obtained dried blood on filter paper by heel puncture every 12 h for the first 72 h, 60 min after feeding. The 0 sample was taken before starting inotropic treatment. These measurements were repeated once a day for three days after stopping treatment. None of our newborns was treated with iodine‐containing contrast media or disinfectants. Hormone assays were done at the Laboratory of Inborn Errors of Metabolism, University of Florence. TSH, T4, PRL and growth hormone were measured with commercial enzyme‐linked immunosorbent assay kits (AutoDelfia Neonatal hTSH Ultra, T4, Prolactin and hGH, Wallac OY, Turku, Finland) using the AutoDelfia spectrophotometer (Wallac 1235, Turku, Finland). Measurements by time‐resolved fluoroimmunoassay kit are correlated with radioimmunoassay.25
Statistical analysis
We first analysed the group variables using analysis of variance (threshold p = 0.05). Where necessary, the analysis of variance for repeated measurements was carried out. Where significant differences in a variable were found, the groups were compared using Student's t test (threshold p = 0.01).
Results
A total of 486 (283 VLBW) newborns were admitted to our eight‐bed NICU during the study period. Of these, 84 (28 VLBW) were transferred to other hospitals because of lack of beds or surgical problems. Eight newborns with extremely low birthweight and gestational age died during the first hours of life. Thus from 247 VLBW newborns, 53 hypotensive newborns were enrolled in the study. One hypotensive newborn, whose mother was being given L‐T4 was excluded. In two cases, consent was not obtained or the investigators could not collect blood properly. Thirty‐five (66%) newborns remained hypotensive after two doses of isotonic saline solution.
We did not find significant differences between the groups with regard to demographic data, mortality and main neonatal morbidities before discharge (table 1) or the haemodynamic and metabolic profile at study entry (table 2). The necessary cumulative and mean administered dose, and the maximum infusion rate required to normalise MAP were significantly higher for the dobutamine group than the dopamine group (table 2; p<0.01 for all). In the two newborns who remained hypotensive despite being given the maximal dobutamine dose, dopamine was added at 8 μg/kg/min and 10 μg/kg/min. We did not find any significant differences between the two groups with regard to heart rate, oxygen requirement, fluid intake and mean urine output during the treatment, and serum levels of sodium, potassium, chloride and creatinine.
Table 1 Demographic and clinical data of the two study groups.
| Group A (dopamine) | Group B (dobutamine) | p Value | |
|---|---|---|---|
| Newborns, n | 18 | 17 | |
| Male, n (%) | 9 (50.0) | 10 (58.8) | 0.613 |
| Gestational age (days), mean (SD) | 196.2 (14.6) | 193.1 (15.4) | 0.649 |
| Birthweight (g), mean (SD) | 1014 (166) | 995 (257) | 0.843 |
| Caesarean section, n (%) | 13 (72.2) | 14 (82.4) | 0.490 |
| Prenatal steroids, n (%) | 14 (77.8) | 14 (82.4) | 0.744 |
| Apgar score (5 min), mean (SD) | 7.0 (1.4) | 7.5 (0.7) | 0.886 |
| Crib score, mean (SD) | 5.0 (2.1) | 5.2 (2.9) | 0.864 |
| Survivors, n (%) | 18 (100) | 17 (100) | 1.000 |
| Infant respiratory distress syndrome, n (%) | 18 (100) | 16 (94.1) | 0.311 |
| Surfactant therapy, n (%) | 15 (83.3) | 14 (82.4) | 0.941 |
| Sepsis, n (%) | 5 (27.8) | 4 (23.6) | 0.782 |
| Patent ductus arteriosus, n (%) | 9 (50.0) | 8 (47.1) | 0.867 |
| Bronchopulmonary dysplasia*, n (%) | 4 (22.2) | 4 (23.6) | 0.929 |
| Retinopathy of prematurity†, n (%) | 4 (22.2) | 3 (17.6) | 0.744 |
| Intraventricular haemorrhage‡, n (%) | 3 (16.7) | 4 (23.6) | 0.624 |
| Necrotising enterocolitis§, n (%) | 0 | 0 | 1.000 |
*Oxygen requirement at 36 weeks' postmenstrual age.
†IIA, IIB, IIIA and IIIB of modified Bell's stages26; ‡Grades III–IV; §Grades III–IV.
Table 2 Haemodynamic and metabolic status at study entry and inotropic infusions during the study.
| Group A (dopamine) | Group B (dobutamine) | p Value | |
|---|---|---|---|
| Newborns, n | 18 | 17 | |
| Study entry | |||
| Age (hours of life) | 4.6 (2.0) | 4.1 (1.6) | 0.318 |
| Systolic arterial pressure (mmHg) | 43.8 (2.1) | 42.9 (2.3) | 0.376 |
| Diastolic arterial pressure (mmHg), | 23.2 (1.4) | 22.1 (1.8) | 0.143 |
| Mean arterial pressure (mmHg) | 28.7 (1.6) | 28.7 (0.9) | 1.000 |
| Heart rate (bpm) | 153.4 (7.8) | 149.5 (11.2) | 0.427 |
| Maximum fractional inspired O2 (%) | 28.8 (8.8) | 29.3 (8.4) | 0.449 |
| pH (−log[H+]) | 7.311 (0.09) | 7.314 (0.08) | 0.469 |
| pCO2 (mmHg) | 43.0 (11.4) | 45.3 (8.8) | 0.309 |
| pO2 (mmHg) | 74.8 (9.4) | 72.3 (11.5) | 0.297 |
| HCO3− (mmol/l) | 19.1 (2.5) | 18.8 (2.8) | 0.411 |
| Anion gap (mmol/l) | 4.3 (3.5) | 4.5 (3.5) | 0.452 |
| During the study | |||
| Duration of infusion (h) | 71.4 (18.9) | 73.6 (14.3) | 0.386 |
| Cumulative dose of infusion (μg/kg) | 21440 (6256) | 27704 (6709) | <0.01 |
| Mean dose of infusion (μg/kg/day) | 5.0 (0.5) | 6.2 (0.8) | <0.01 |
| Maximum infusion rate (μg/kg/min) | 7.4 (2.1) | 11.6 (4.9) | <0.01 |
Values are mean (SD).
At study entry, serum levels of TSH, total thyroxine (T4), PRL and growth hormone were similar in the two groups. From 12 h onwards, serum levels of TSH, T4 and PRL were significantly lower in group A (p<0.01), whereas growth hormone was significantly lower only at 12 and 36 h (fig 1; p<0.01).
Figure 1 Three‐day serum levels of (A) thyroid stimulating hormone (TSH), (B) total thyroxine (T4), (C) prolaction (PRL) and (D) growth hormone (GH) in the two study groups (dopamine group, n = 18; dobutamine group, n = 17). *p<0.01.
The levels of TSH, T4 and PRL increased briskly after stopping dopamine treatment. TSH increased from a mean (SD) 0.3 (0.2) mU/l when the treatment was stopped to 1.3 (0.8) mU/l (p<0.01), 1.5 (1.1) mU/l (p<0.01) and 1.8 (1.1) mU/l (p<0.01) after 24, 48 and 72 h, respectively. T4 increased from 20.8 (7.9) nmol/l to 45.6 (7.5) nmol/l (p<0.01), 50.1 (8.4) nmol/l (p<0.01) and 56.3 (10.4) nmol/l (p<0.01), respectively. PRL increased from 42.9 (10.4) μg/l to 74.8 (13.5) μg/l (p<0.01), 86.6 (15.1) μg/l (p<0.01) and 114.6 (21.2) μg/l (p<0.01), respectively. We also found a mild, but not significant, increase in levels of growth hormone from 34.1 (14.8) μg/l to 42.7 (17.0) μg/l (p = 0.351), 50.6 (11.2) μg/l (p = 0.015) and 52.8 (14.8) μg/l (p = 0.015), respectively (fig 2A). Stopping dobutamine did not significantly affect the hormonal levels (fig 2B).
Figure 2 Serum levels of thyroid stimulating hormone (TSH), total thyroxine (T4), prolactin (PRL) and growth hormone (GH) after stopping (A) dopamine or (B) dobutamine treatment, expressed as percentage of values on the day before the drug was stopped. Numbers of neonates studies at each time point are given in parenthesis. *p<0.01.
What is already known on this topic
Hypotension in preterm infants is a major risk factor for periventricular‐intraventricular haemorrhage and poor long‐term neurodevelopmental outcome.
Dopamine treatment is more successful than dobutamine but is associated with hypothyroxinaemia of prematurity and low levels of prolactin.
It is not known whether dobutamine has similar effects in very low birthweight infants.
What this study adds
Dopamine and dobutamine are both effective in the treatment of hypotensive very low birthweight infants who do not respond to volume loading, with dopamine being more effective.
Dopamine causes a marked reduction in thyroid stimulating hormone, T4 and prolactin levels, and there is significant hormonal rebound 24 h after stopping treatment.
Discussion
Although in the present study we did not measure systemic and organ blood flow, aggressive treatment of hypotension is widely advised to preserve adequate organ perfusion.14 The firstline treatment is volume expansion and we gave our newborns isotonic saline rather than colloids because albumin infusion had been reported to increase mortality in critically ill patients.27 Only a third of hypotensive newborns in the present study responded to volume replacement, confirming that left ventricular dysfunction and reduced vascular tone may have a central role in shocked VLBW infants.28
With regard to the first aim of the study, both inotropes resulted in increase in blood pressure, but we also confirmed dopamine to be more effective.1,29,30,31,32,33,34 The second aim of our study was to compare the influence of dopamine and dobutamine on the thyroid axis and on PRL and growth hormone secretion as this has not previously investigated in VLBW newborns. Previous studies have suggested that dopamine infusion suppresses PRL, TSH and T4 secretion by acting on specific D2 receptors.35 In our study also, dopamine soon induced pituitary suppression, on the first day of treatment, with TSH decreasing in group A to 14.3%, 6.3% and 5.9% of the 0 sample at 24, 48 and 72 h of life, respectively. In contrast, TSH levels fell quickly in group B as expected physiologically,36,37 and remained approximately three to four times higher than in group A (fig 1A). However, TSH levels in group B infants were lower than in newborns not receiving inotropes,16 suggesting a possible mild dobutamine‐induced TSH suppression. Similarly, T4 and PRL profiles differed significantly between the two groups. In group A, T4 levels decreased to 39.1% of the initial values at 24 h, and to 34.1% at 48 and 72 h, three times lower than in group B (fig 1B). PRL levels in group A decreased to 54.0%, 46.8% and 51.6% at 24, 48 and 72 h, respectively, about two times lower than in group B (fig 1C). Levels of growth hormone were also lower in group A but the difference was significant only at 12 and 36 h (fig 1D). On the contrary, dobutamine administration did not alter T4, PRL and growth hormone production, suggesting that the therapeutic concentrations affect different receptors.38 Compared with previous studies,15,16,36,37 our dopamine‐treated infants had lower levels of TSH, T4, PRL and growth hormone, probably because the dopamine cumulative dose was considerably higher.
The high pulsatility of growth hormone secretion means that for a proper profile assessment sampling should be done every 15–20 min, but we did not do this because it would have meant shortening the time intervals in our study. As the levels of growth hormone rise after feeding,39 blood was collected 1 h after feeding. However, the timing of blood sampling was probably not relevant in our study population because only small meals were given in the first days of life. Even though we did not measure the levels of active thyroid hormones, T4 was considerably low in our dopamine‐treated newborns. Crucially, thyroid homoeostasis controls important functions such as surfactant production, gastrointestinal motility and cardiac activity,40,41 and decreased thyroid function in preterm infants is associated with increased risk of unfavourable neurodevelopmental outcome.23,42 However, thyroid hormone treatment in very preterm infants has not been found to have any clinical or long‐term benefit.43 Also, hypoprolactinaemia is associated with worse clinical outcome24 probably because PRL takes part in immune regulation in critical patients.44 At present, however, there are no data on such interactions in newborns.
Hormonal rebound was significant 24 h after stopping dopamine, when TSH was at least three to four times higher than the mean value on the last day of dopamine treatment, and T4 and PRL levels were two to three times higher. In a previous study, dopamine‐induced decrease in PRL levels seemed to be markedly influenced by gestational age and birth weight, suggesting a developmental regulation of dopamine control of PRL secretion.20 Despite the very low gestational age and birth weight of our study population, PRL suppression and rebound were more evident than in previous studies.16,20 This is probably because we gave higher doses and the treatment was of longer duration. The mean increase in growth hormone levels was non‐significant, confirming that dopamine does not exert major effects on secretion of growth hormone.
In conclusion, our data confirm that dopamine and dobutamine are both effective for treating volume loading refractory hypotension in VLBW preterm infants. In contrast with dobutamine, dopamine significantly reduces the levels of TSH, T4 and PRL. On the basis of the rapid reversal that occurred after dopamine was stopped, we can speculate that the iatrogenic pituitary suppression that is induced for a short time with dopamine infusion will probably not cause long‐term injury. Caution is required mainly if dopamine is administered for a long time. We recommend adequately powered long‐term follow‐up studies to rule out long‐term effects.
Acknowledgements
We thank the nursing staff of the Neonatal intensive Care Unit, Careggi Hospital, for their assistance in conducting this study.
Abbreviations
MAP - mean arterial pressure
PRL - prolactin
T4 - total thyroxine
TSH - thyroid stimulating hormone
VLBW - very low birth weight
Footnotes
Competing interests: None.
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