Nigerian Journal of Paediatrics

A randomized controlled trial of the impact of dopamine on outcome of asphyxiated neonates

Niger J Paediatr 2018; 45 (2):86 – 90

ORIGINAL

Abiodun MT

CC – BY A randomized controlled trial of

Oluwafemi RO

Badejoko O

the impact of dopamine on out-

come of asphyxiated neonates

DOI:http://dx.doi.org/10.4314/njp.v45i2.3

Accepted: 23rd March 2018

Abstract : Background: Vasoac-

subgroups.

tive drugs such as low dosage

Results: A total of fifty five as-

Abiodun MT

(

)

dopamine are often used in the

phyxiated infants took part in the

Department of Child Health, Uni-

intensive care of asphyxiated term

study: 27 in the intervention group

versity of Benin Teaching Hospital

neonates but there is insufficient

while 28 were in the control group.

Benin City, Nigeria

evidence to support the practice.

The subgroups were similar in

Email:

Aims: To evaluate the impact of

mean gestational age, Apgar

moses.abiodun@uniben.edu.ng.

low dose dopamine on the clinical

scores, age at admission and

course and outcome of newborns

modes of delivery (p>0.05). HIE

Oluwajemi RO, Badejoko BO

with severe perinatal asphyxia and

occurred in over a half of the sub-

Department of Paediatrics,

to determine factors that predict

jects. The frequency of apnoea,

Mother and Child Hospital

survival.

oxygen requirement, duration of

Akure-Ondo State, Nigeria

Methods: This was a randomized

anticonvulsant treatment and urine

controlled trial. Term asphyxiated

outputs were similar between the

newborns were alternately re-

subgroups(p > 0.05).The mean

cruited into ‘dopamine’ and ‘no -

durations of admission (days) were

dopamine’ sub groups. Asphyxia

5.13±3.0 and 5.3±3.0 for the inter-

was defined as Apgar score ≤3 at

vention and non-intervention sub-

one minute or ≤5 at five minutes,

groupsrespectively

(t=0.183,

and/or clinical evidence of hy-

p=0.856). Likewise,survival rates

were similar (x = 1.261, p =

poxic ischemic encephalopathy

(HIE). The intervention com-

0.948). Selected perinatal events-

prised

dopamine

infusion

did

not

influence

outcome

3.0mcg/kg/minute. Primary out-

(p>0.05).

come was death or survival till

Conclusion: Low-dosedopamine

discharge while secondary meas-

has no impact on the short term

ures were apnoea, oliguria, sei-

outcome of asphyxiated infants.

zures and other clinical morbid-

ities. The Student t-test was used

Key words: hypoxic ischemic

to compare outcomes between the

encephalopathy, clinical course,

outcome, dopamine

Introduction

mine in asphyxiated infants is widespread among clini-

cians but the only available clinical trial on the impact of

Perinatal asphyxia manifests with adverse systemic ef-

dopamine on mortality and neurocognitive development

fects in newborn infants. The nervous, cardiovascular

of asphyxiated term infants found no benefit compared

and renal systems are often affected. Several interven-

to placebo. The study is however, limited by the small

tions have been attempted to minimize organ damage in

number of subjects- only seven neonates were recruited

into each cohort. Treatment of asphyxiated infants with

asphyxiated neonates. These include cardiovascular sup-

port using ionotropes, reduction of reperfusion injuries

dopamine is often done based on the theoretical reason-

and neuroprotection. Available evidence suggest that

2,3

ing that it can prevent hypotension and hence enhance

tissue perfusion. Dopaminehas been shown to signifi-

prophylactic barbiturate has no significant impact on the

outcome of perinatal asphyxia but the neuro protective

cantly improve splanchnic blood flow but it does not

improve splanchnic oxygen consumption. When infused

effects of cooling therapies have been clearly proven in

recent years. In a meta-analysis of 11 randomized con-

at a low dose (<5 µg/kg per minute), dopamine dilates

trolled trials, Jacobs et al found that therapeutic hypo-

the afferent and efferent renalarterioles. The net effect is

thermia is beneficial in term and late preterm asphyxi-

a relatively large increase in renal blood flow without

significant increase in creatinine clearance. Hence,

ated newborns, reducing their mortality without increas-

ing neuro developmental deficits.

theutility of low dose dopaminein clinical practice re-

mains doubtful. Hunt et al in a recent systematic review

In contrast, the use of inotropic agents such as dopa-

concluded that there was insufficient data to make com-

patible drugs such as sodium bicarbonate were not

mentson the benefits of dopamine infusion in perinatal

mixed with dopamine to avoid deactivation. Participants

asphyxia.

in the control group received maintenance intravenous

Considering the forgoing and diverse opinions on the

fluids and other relevant medications except dopamine.

usefulness of low – dose dopamine, we evaluated the im-

This did not preclude the use of adrenaline during resus-

pact of this intervention on the clinical course and out-

citation of any of the participants, when necessary, as

per standard guidelines.

come of infants with severe perinatal asphyxia. Also, we

determined factors that predict survival in the cohort.

Data Collection

Data on each asphyxiated infant was extracted using a

Methods

structured questionnaire comprising biodata, clinical

Study Setting and Participants

features at presentation, clinical course and outcome.

Primary outcome was death or survival till discharge

The study was carried out at the level II Neonatal Inten-

while secondary measures were apnea, oliguria, seizures

sive Care Units (NICUs) of two Mother and Child Hos-

and other clinical morbidities. Hypotension was diag-

pitals (MCHs) in Ondo State, which are public facilities

nosed based on absent peripheral pulses and prolonged

providing specialized free healthcare services to people

capillary refill time>3secs and was managed according

in the State and communities in neighboring states. The

to unit protocols. Clinical evaluation of the participants

two hospitals were the busiest in the State with over

was done at admission into NICU and repeated12 hourly

10,000 deliveries per year at MCH Akure.

thereafter by the researchers/ attending paediatricians.

The study population was all asphyxiated term normal

The clinical notes of the infants were reviewed to ascer-

birth weight inborn infants admitted into the NICUs

tain the frequency of evolving morbidities as well as

from October 2014 to March 2015. Asphyxia was de-

their outcome. Participants that were discharged/ re-

fined as Apgar score ≤3 at one minute or ≤ 5 at five min-

ferred were considered to have a good outcome while

utes, and/ or clinical evidence of hypoxic ischemic en-

death or leaving against medical outcome (LAMA) was

cephalopathy (HIE) in the neonate.

11,12

described as a poor outcome.

Ethical considerations

Data Analysis

Ethical clearance was obtained from the Research and

The data were analyzed using SPSS version 20.0 statisti-

Ethics Committee of the MCH, Akure. Informed con-

cal software for Windows (IBM, Armonk, N.Y., United

sent was obtained from parents of the participants, hav-

States). Fisher’s Exact test or Chi -square was used to

ing explained to them the purpose of the study, the

compare categorized data ( gender, modes of delivery,

safety profile of low dosage dopamine and that partici-

outcome and presence of maternal systemic illness ) be-

pation was entirely voluntary. No participant was de-

tween the intervention and control groups. The Student t

prived of any necessary medication throughout the

-test determined any significant difference between the

study; bedside labeling of infant’s study group was not

mean gestational ages, Apgar scores and durations of

done to avoid observer bias and inadvertent influence of

therapies/ admission of the cohorts. Binary analysis was

NICU staff.

done to identify factors associated with good outcome

The minimum sample size was determined using the

among the asphyxiated infants. The level of significance

formula for detection of a difference between two pro-

of each test was set at p<0.05.

portions proposed by Bonita et al . A total of 55neo-

nates were recruited consecutively from the MCHs dur-

ing the study period: 27of them into the intervention

(dopamine) group and28 into the control (no-dopamine)

Results

group.

Baseline characteristics of the participants

Study design

A total of fifty five asphyxiated inborn infants took part

in the study: 27 in the intervention group while 28 in the

This was an interventional study using a randomized

control group. The overall male: female ratio was 1.8:1;

controlled trial design. Participants were coded and re-

the gender distribution was similar in both groups

cruited into alternate study groups (dopamine vs. no-

(p>0.05). Mean gestational age (weeks) at delivery, Ap-

dopamine) consecutively; there was no bedside labeling

gar scores and age at admission (hours) were similar in

of participants’ study groups.

both groups (p > 0.05). Likewise, mode of delivery was

similar between the groups (x =1.344, p=0.81), with

Intervention

caesarian section (40%) being the commonest route. In

addition, the pattern of maternal systemic illnesses was

Dopamine infusion at 3.0mcg/kg/minute was adminis-

comparable in both groups (p > 0.05; Table 1).

tered to the asphyxiated infants in the interventional

group for 48 hours, alongside routine maintenance intra-

venous fluids and other relevant medications. Incom-

Clinical features and diagnoses

HIE= hypoxic ischaemic encephalopathy;DIC= disseminated

intravascular coagulopathy; others include neonatal jaundice

and skull fracture. Fishers Exact for expected frequency <5.

There were several multi-systemic manifestations of

asphyxia among the participants at admission. The com-

monest symptoms were cyanosis (40.0%), respiratory

Clinical course and outcome

distress (34.0%), convulsion (18.0%) and hypotonia

(18.0%). The frequency of cardiovascular, nervous and

Table 3 shows the clinical course and outcome of the

respiratory system involvement was similar in both sub-

dopamine and no-dopaminesubgroups. The frequency of

groups at admission (p > 0.05;Table 2). Hypoxic is

apnoea, oxygen requirement, duration of anticonvulsant

chaemic encephalopathy (HIE) occurred in over a half

treatment and urine outputs were similar between the

of the participants: mild (8.0%), moderate (18.0%) and

cohorts (p > 0.05). Also, oral feeding was tolerated after

severe (26.0%) . Co-morbid disorders such as sepsis

a similar length of stay (days) on admission (2.9±1.0 vs.

(54.0%) and meconium aspiration syndrome (6.0%) had

3.0±0.8; t= 0.336, p = 0.739).

Mean hematocrits

similar incidence in both groups (p>0.05; Table 2).

( 39.5±6.9 vs. 43.5±7.3 ) and mean random blood glucose

levels( 5.4±2.6 vs.6.8±3.8mMol/L )were similar on admis-

Table 1: Baseline characteristics of the asphyxiated infants

sion ( p>0.05 ).Mean durations of admission (days)

were5.1±3.0 and 5.3±3.0 in the treatment and non-

Study groups

Characteristics

Dopamine

No-

Tests

treatment subgroups respectively (t=0.183, p=0.86).The

(x ,t)

Dopamine

value

survival outcomes of both subgroups were also similar

( x = 1.261, p = 0.948 ).

Gender

0.439

Male

16(59.3)

19(67.9)

0.508

Female

11(40.7)

9(32.1)

Gestational age (wks.)

Table 3: Clinical course and outcome of the asphyxiated

0.520

Mean ±SD

38.67±3.21

37.2±4.15

0.622

infants

Age at admission (hrs.)

Study groups

0.649

Mean ±SD

0.83±0.55

0.74±0.38

0.519

Clinical course/

No-

Test

(t,x )

2 *

Apgar Score

outcome

Dopamine

value

0.700

1 minute

2.46±0.95

2.29±0.90

0.486

Clinical course

0.100

5 minutes

5.05±1.53

5.00±1.51

0.920

0.547

Episodes of apnea

2.50±1.29

3.00±1.41

0.601

1.162

10 minutes

6.14±2.67

4.88±1.46

0.266

Duration of oxy-

1.60±0.99

Mode of Delivery

0.946

gen therapy ( days )

2.00±1.34

0.352

1.029

Breech

4(15.4)

4(14.8)

0.862

Duration of anti-

Emergency CS

11(42.3)

20(37.0)

convulsant use

3.50±2.20

2.75±1.96

Forceps

1(3.8)

3(11.1)

0.798

( days )

0.435

SVD

10(38.5)

10(37.0)

Day of life oral

2.90±1.04

3.00±0.78

Maternal Illness

feeding tolerated

0.336

0.739

Eclampsia

4(28.6)

3(27.3)

0.273

0.697

Oliguria (urine<

3 (11.1)

0 (0.0)

APH

2(14.3)

3(27.3)

0.142

1.000

1ml/kg/hour )

3.291

0.111

Malaria

5(35.7)

0(0.0)

6.019

1.000

Duration on ad-

5.13±2.98

5.28±2.95

Others

6(42.9)

6(54.5)

0.025

0.874

mission ( days )

0.183

0.856

Outcome

aChi -square-test; bStudent t-test; CS = caesarian section, SVD

1.261

Discharge

17(73.1)

16(66.7)

0.948

= spontaneous vertex delivery, APH= antepartum haemorrhage

Died

4(15.4)

4(16.7)

LAMA

3(11.1)

3(12.5)

Table 2: Clinical features and diagnoses of the asphyxiated

Referred

0(0.0)

1(4.2)

infants

Student t-test, Chi -square-test; LAMA = leaving against

Study groups

Clinical Features/

Test

medical advice; Fishers Exact test for expected frequency <5

(x )

2 *

Diagnosis

Dopamine

No-

p-value

dopamine

Clinical Features

Factors influencing survival

Convulsion

2(15.4)

7(38.9)

2.922

0.142

Hypertonia

2(15.4)

2(11.1)

0.007

1.000

Bivariate analysis for possible factors associated with

Hypotonia

2(15.4)

7(38.9)

2.922

0.142

Coma

3(23.1)

1(5.6)

1.270

0.340

outcome of the asphyxiated infants is shown on Table 4.

Participants’ gender did not influence survival (x =

Respiratory distress

7(53.8)

10(55.6)

0.480

0.559

Cyanosis

7(53.8)

13(72.2)

2.257

0.159

2.00, p = 0.156). Also, perinatal events (mode of deliv-

Apnea

0(0.0)

3(16.7)

2.946

0.236

ery, Apgar score), clinical course and therapies were not

Bleeding

3(23.1)

1(5.6)

1.270

0.340

Cephalohaematoma

5(38.5)

3(16.7)

0.802

0.456

significantly associated with outcome in this study (p >

Pallor

3(23.1)

3(16.7)

0.011

1.000

0.05).

Shock

0(0.0)

2(11.1)

1.923

0.491

Diagnosis

Severe Perinatal As-

phyxia/HIE

27(100.0)

28(100.0)

-----

------

Sepsis/ DIC

11(45.8)

16(61.5)

1.239

0.266

Meconium Aspiration

Syndrome

3(12.5)

0(0.0)

3.457

0.103

Others

4(16.7)

0(0.0)

4.473

0.051

Table 4: Bivariate analysis of possible factors influencing

was rare among our participants.

outcome of the infants

Low dose dopamine infusion has a predominant reno-

vascular effect, shown by an improved renal blood flow

Good

Test (c )

2 *

Factors

Outcome

Bad

value

without associated improved creatinine clearance. The

Gender

few cases of oliguric acute kidney injury (AKI) requir-

Male

25(69.4)

7(50.0)

1.654

0.198

ing a fluid challenge/furosemide in this trial occurred in

Female

11(30.6)

7(50.0)

the intervention group. This study did not find any im-

Mode of Delivery

provement in urine output attributable to low dose dopa-

EMCS

12(34.3)

6(42.9)

0.316

0.574

mine. Nonetheless, neonatal AKI is often non-oliguric

Others

23(65.7)

8(57.1)

and serial creatinine measurement is required for its di-

Apgar score (5min)

agnosis. Serum creatinine level is highly variable in

1-3

4(14.3)

3(25.0)

0.668

0.410

newborns and it is a late marker of neonatal AKI. De-

24(85.7)

9(75.0)

Episode of Apnea

termination of participants’ serum creatinine level was

1-2

0(0.0)

3(62.5)

1.406

0.444

not included in the current trial.

1(100.0)

5(37.5)

Convulsion

The overall outcome was similar in both subgroups con-

sistent with the earlier findings by DiSessa et al that

Yes

5(13.9)

3(21.4)

0.426

0.514

31(86.1)

11(78.6)

dopamine infusion did not significantly improve the

Dopamine infusion

long term outcome of asphyxiated infants, despite its

Yes

19(52.8)

7(50.0)

0.031

1.000

transient cardiovascular effects. This corresponds with

17(47.2)

7(50.0)

the essentially similar clinical course of participants in

Days on Oxygen

both the intervention and control groups throughout the

1-2 days

11(64.7)

10(90.9)

2.446

0.191

current study. Early neonatal deaths of asphyxiated in-

>2days

6(35.3)

1(9.1)

fants occur less in developed settings due to the use of

Oral feeding

advanced respiratory supports, as well as therapeutic

≤3days

23(71.9)

3(50.0)

1.119

0.357

hypothermia. Only short term outcome was assessed in

>3days

9(28.1)

3(50.0)

the current study. Long term neurodevelopmental out-

Fishers Exact test for expected frequency <5

come are often similar among asphyxia survivors, as

reported by Hunt etal and Osborn et al .

Hence, the

usefulness of low dose dopamine in the management of

severely asphyxiated infants remains unproven.

Discussion

Electroencephalograph (EEG) is the “gold standard” for

The current study found no difference between the clini-

predicting outcome of perinatal asphyxia.

It is non-

cal course of asphyxiated infants in the experimental

invasive, detecting subclinical seizure and has early pre-

group and the controls, consistent with a prior report by

dictive value if normal. Other prognostic tools include

DiSessa et al in 1981 that dopamine infusion did not

acid-base balance, Apgar score and temporal neurologic

influence the clinical course of asphyxiated infants.

manifestations but these may not strongly predict long-

There is paucity of data on the utility of dopamine infu-

term outcome. In a retrospective study in Osogbo

sion compared to ‘no inotrope’ in asphyxiated term and

southwestern Nigeria, Adebami et al found that more

preterm neonates. Osborn et al found in a systematic

babies with respiratory distress, apnoea, feed intoler-

review that there was no significant difference in the

ance, oliguria, bleeding, seizures and coma died than

incidence of renal impairment, pulmonary haemorrhage

those without multi-systemic complications. Also, Kuti

and neurologic complications among hypotensive pre-

et al associated seizures with neonatal mortality. None

term infants treated with dopamine when compared to

of these clinical variables significantly predict adverse

controls that received other inotropes. This shows that

outcome in this trial, perhaps due to its relatively smaller

low dose dopamine may not prevent organ injuries in

sample size.

critically ill infants.

2,17

The strength of the current study includes its experimen-

tal design and the baseline clinical-demographic similar-

Dose – dependent response to dopamine infusion has

ity of the participants.

been described. Its neurotransmission effect is dopa-

minergic at the low dosage used in the current study;

beta-adrenergic at an intermediate dosage (5-15µg/kg/

minute) and alpha-adrenergic at a high dosage.

Conclusion

Hence,high dose dopamine should be administered with

caution to avoid adverse systemic effects such as tachy-

The current study confirms that a low dose dopamine

cardia and increased myocardial oxygen consumption.

infusion does not influence the short term outcome of

The cardiovascular effect of dopamine is not superior to

asphyxiated infants. A longitudinal study of the impact

other ionotropes and does not significantly influence

of moderate dosage dopamine on the long-term outcome

neonatal survival.

6,16

Although cardiovascular complica-

of asphyxiated infants is desirable.

tions including hypotension can occur in nearly one half

of asphyxiated infants especially in those with HIE stage

III, clinical evidence of cardiovascular compromise

Authors’ Contribution

Acknowledgement

This work was carried out in collaboration among the

authors. Author MTA and BD designed the study; MTA

MTA is thankful to Dr. Akinwumi at the Department of

wrote the protocol, and wrote the first draft of the manu-

Paediatrics, Mother and Child Hospital, University of

script. Author ROO participated in the literature

Medical Sciences, Ondo State .

searches, data collection and critical review of the manu-

script. All authors approved the final manuscript.

Conflict of interest: None

Funding: None

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